exons definition biology

The completed human sequence can now identify their locations. But only about 1.5% of the genome codes for proteins, while the rest consists of non-coding RNA genes, regulatory sequences, introns, and noncoding DNA (once known as ""junk DNA""

"WHAT IS THE HUMAN GENOME AND HOW BIG IS IT? You can view a 3-D rotatable image of DNA here... The hereditary material of all multi-cellular organisms is the famous double helix of deoxyribonucleic acid (DNA).

This contains all of our genes. DNA, itself is made up of four chemical bases, pairs of which form the ""rungs"" of the twisted, ladder-shaped DNA molecules. These four molecules are adenine (A), thymine (T), cytosine (C), and guanine (G). All genes are made up of stretches of these four bases (arranged in different ways and in different lengths).

Photo: National Institute of Health A critical feature of DNA is the ability of the nucleotides to make specific pairs: . Adenine pairs with Thymine and Cytosine pairs with Guanine. We say A is complementary to T (and U) and C is complementary to GThe double helical structure of DNA, is due largely to hydrogen bonding between the base pairs (shown as green dotted lines in image to left), which link one complementary strand to the other Hydrogen bonds between guanine and cytosine The human genome of Homo sapiens is stored on 23 chromosome pairs.

22 of these are autosomal chromosome pairs, while the remaining pair is sex-determining. The haploid human genome occupies a total of just over 3 billion DNA base pairs that means 6 billion base pairs per diploid cell.

""The Human Genome Project (HGP) was one of the great feats of exploration in history - an inward voyage of discovery rather than an outward exploration of the planet or the cosmos; an international research effort to sequence and map all of the genes - together known as the genome - of members of our species, --Homo Sapiens""--genome.gov Human Chromosomes How many genes does the Human Genome contain? The Human Genome Project has revealed that there are probably about 20,000-25,000 'haploid' protein coding genes.

). Surprisingly, the number of human genes seems to be less than a factor of two greater than that of many much simpler organisms, such as the roundworm and the fruit fly -- see table showing number of genes for different organisms.

How many genes do other organisms have?chromosomes --diploid base pairs genome size (#genes) Referencefruit fly 8 1.65x10 8 13,600 ref Budding yeast 16 12,462,637 6,275 refhuman 46 3.3 x 10 9 ~21,000 refhuman mitochondria 16,569 13 refrice 24 4.66 x 10 8 46,022 -55,615 refdog 78 2.4 x 10 9 ~25,000 refmouse 40 3.4 x 10 9 ~23,000 ref Humans though have on average three times as many kinds of proteins as the fly or worm because of m RNA transcript ""alternative splicing"" and chemical modifications to the proteins.

This process can yield different protein products from the same gene. -------- Fruit flies share nearly 60% of human genes and are studied by What do genes actually do? Although genes get a lot of attention, it’s the proteins that perform most life functions and even make up the majority of cellular structures.

Proteins are large, complex molecules made up of smaller subunits called amino acids. Chemical properties that distinguish the 20 different amino acids cause the protein chains to fold up into specific three-dimensional structures that define their particular functions in the cell. A ribosome is the component of a biological cell that creates proteins from all amino acids and RNA representing the protein.

Image: Wikipedia Mitochondrial genome The human mitochondrial genome, while usually not included when referring to the ""human genome"", is of tremendous interest to geneticists, since it undoubtedly plays a role in mitochondrial disease. It also sheds light on human evolution; for example, analysis of variation in the human mitochondrial genome has led to the postulation of a recent common ancestor for all humans on the maternal line of descent.

How different is the human genome from one person to the next? Scientists have identified about 1.4 million locations where single-base DNA differences (SNPs) occur in humans. This information promises to revolutionize the processes of finding chromosomal locations for disease-associated sequences and tracing human history. ref Further Readings Dog Genome Resources The Science Behind the Human Genome Project Basic Genetics, Genome Draft Sequence, and Post-Genome Science What Genes in the Human Genome cause Celiac Disease? - Genetics of Celiac Disease and Gluten Sensitivity "

ff? The RNA strand is processed so that its introns are removed and the exons are pushed together to make a continuous, shorter strand. This process is called RNA splicing. It produces a 'final draft' of the m RNA before translation gets under way.

RNA Processing in a Eukaryotic Cell: Splicing of Introns & Exons

Instructor: April Koch April teaches high school science and holds a master's degree in education. In this lesson, we'll explore the unique considerations for gene regulation in the eukaryotic cell.

We'll walk through RNA splicing of introns and exons and the addition of the 5' cap and poly (A) tail. Gene Regulation in Eukaryotes All living things have methods for regulating their genes by controlling when and how their genes are expressed. When scientists first learned about gene regulation, they studied the bacterium E. coli and one of its gene clusters: the lac operon. Scientists used the lac operon to study gene regulation. Their research revealed plenty of information about the regulation of operons, but it didn't tell them much about the regulation of human genes.

After all, we humans don't have operons. Humans, remember, are eukaryotes. Unlike the prokaryotic bacteria, eukaryotes don't have clusters of related genes.

Our genes are scattered throughout the genome over multiple chromosomes. Also, our cells contain a nucleus, meaning that we have to perform transcription and translation separately. Transcription has to happen in the nucleus, but translation must occur in the cytoplasm. So, unlike prokaryotes, eukaryotes undergo an RNA processing step right after transcription and before translation.

RNA processing is a challenge that's unique to eukaryotes because only eukaryotic cells have a nucleus. In this lesson, we'll walk through the most important aspects of RNA processing. Introns and Exons

Eukaryotic genes are split up into parts that are expressed as RNA products and parts that are not. The parts that are expressed are called exons. They appear in short sequences scattered throughout the gene. Exons are the parts of a eukaryotic gene that are expressed through transcription and translation.

You can think of them like the 'meat' of the gene; they're typically considered the actual coding regions that specify our proteins.

In between all the exons lie the other segments, called introns. Introns are the intervening sequences that are removed from a gene before the RNA product is made. Introns and exons alternate with each other along the length of a gene. Introns are usually considered non-coding regions because they don't seem to code for any enzymes or structural proteins.

However, scientists are still learning about the importance of introns. One thing we do know is that introns are removed from an RNA sequence right after transcription. They exist in DNA, they're transcribed into RNA, but then they're taken out before the RNA has a chance to make any products. Introns are removed from the RNA sequence after transcription RNA Splicing and Spliceosomes So, exons hold the important coding regions of our genes, and introns aren't much more than extra fluff.

How do we get hold of only the good stuff? How do we separate the wheat from the cha

nts: The base sequences that appear in eukaryotic DNA and are used to make m RNA for a specific protein are the exons of a gene.

Exon

Exonnavigation search Definitionnoun, plural: exons (molecular biology)1. The protein -coding region in the DNA .2. The nucleic acid sequence in the DNA, or RNA transcript following genetic splicing . Supplem

ent Genes contain exons which are regions coding for proteins and which are interrupted by the unused sequences called introns. Exons have been found to include both sequences coding for amino acids and untranslated sequences. The introns are removed and the exons are joined together to form the final functional m RNA.

Related forms: exonic ( adjective ). Compare: intron . See also: DNA, RNA, translation, m RNA, protein synthesis . User Contributions / Comme

In many species, only a small fraction of the total sequence of the genome encodes protein. For example, only about 1.5% of the human genome consists of protein-coding exons, with over 50% of human DNA consisting of non-coding repetitive sequences.

DNA

"From Wikipedia, the free encyclopedianavigation search For a non-technical introduction to the topic, see Introduction to genetics. For other uses, see DNA (disambiguation). The structure of the DNA double helix. The atoms in the structure are colour-coded by element and the detailed structures of two base pairs are shown in the bottom right.

The structure of part of a DNA double helix Deoxyribonucleic acid ( / d i ˈ ɒ k s i ˌ r aɪ b oʊ nj ʊ ˌ k l iː ɪ k, - ˌ k l eɪ ɪ k / ( listen); [1] DNA) is a thread-like chain of nucleotides carrying the genetic instructions used in the growth, development, functioning and reproduction of all known living organisms and many viruses.

DNA and ribonucleic acid (RNA) are nucleic acids; alongside proteins, lipids and complex carbohydrates ( polysaccharides ), they are one of the four major types of macromolecules that are essential for all known forms of life. Most DNA molecules consist of two biopolymer strands coiled around each other to form a double helix.

The two DNA strands are called polynucleotides since they are composed of simpler monomer units called nucleotides. [2] [3] Each nucleotide is composed of one of four nitrogen-containingnucleobases ( cytosine [C], guanine [G], adenine [A] or thymine [T]), a sugar called deoxyribose, and a phosphate group.

The nucleotides are joined to one another in a chain by covalent bonds between the sugar of one nucleotide and the phosphate of the next, resulting in an alternating sugar-phosphate backbone. The nitrogenous bases of the two separate polynucleotide strands are bound together, according to base pairing rules (A with T and C with G), with hydrogen bonds to make double-stranded DNA.

The complementary nitrogenous bases are divided into two groups, pyrimidines and purines. In a DNA molecule, the pyrimidines are thymine and cytosine, the purines are adenine and guanine.

DNA stores biological information. The DNA backbone is resistant to cleavage, and both strands of the double-stranded structure store the same biological information. This information is replicated as and when the two strands separate. A large part of DNA (more than 98% for humans) is non-coding, meaning that these sections do not serve as patterns for protein sequences.

The two strands of DNA run in opposite directions to each other and are thus antiparallel. Attached to each sugar is one of four types of nucleobases (informally, bases ). It is the sequence of these four nucleobases along the backbone that encodes biological information.

RNA strands are created using DNA strands as a template in a process called transcription. Under the genetic code, these RNA strands are translated to specify the sequence of amino acids within proteins in a process called translation. Within eukaryotic cells DNA is organized into long structures called chromosomes. During cell division these chromosomes are duplicated in the process of DNA replication, providing each cell its own complete set of chromosomes. Eukaryotic organisms ( animals, plants, fungi and protists) store most of their DNA inside the cell nucleus and some of their DNA in organelles, such as mitochondria or chloroplasts.

[4] In contrast prokaryotes ( bacteria and archaea) store their DNA only in the cytoplasm. Within the eukaryotic chromosomes, chromatin proteins such as histones compact and organize DNA.

These compact structures guide the interactions between DNA and other proteins, helping control which parts of the DNA are transcribed.

DNA was first isolated by Friedrich Miescher in 1869. Its molecular structure was first identified by James Watson and Francis Crick at the Cavendish Laboratory within the University of Cambridge in 1953, whose model-building efforts were guided by X-ray diffraction data acquired by Raymond Gosling, who was a post-graduate student of Rosalind Franklin. DNA is used by researchers as a molecular tool to explore physical laws and theories, such as the ergodic theorem and the theory of elasticity.

The unique material properties of DNA have made it an attractive molecule for material scientists and engineers interested in micro- and nano-fabrication.

Among notable advances in this field are DNA origami and DNA-based hybrid materials. [5]Contents1 Properties1.1 Nucleobase classification1.2 Non canonical bases1.3 Listing of non canonical bases found in DNA1.4 Grooves1.5 Base pairing1.6 Sense and antisense1.7 Supercoiling1.8 Alternative DNA structures1.9 Alternative DNA chemistry1.10 Quadruplex structures1.11 Branched DNA2 Chemical modifications and altered DNA packaging2.1 Base modifications and DNA packaging2.2 Damage3 Biological functions3.1 Genes and genomes3.2 Transcription and translation3.3 Replication3.4 Extracellular nucleic acids4 Interactions with proteins4.1 DNA-binding proteins4.2 DNA-modifying enzymes4.2.1 Nucleases and ligases4.2.2 Topoisomerases and helicases4.2.3 Polymerases5 Genetic recombination6 Evolution7 Uses in technology7.1 Genetic engineering7.2 DNA profiling7.3 DNA enzymes or catalytic DNA7.4 Bioinformatics7.5 DNA nanotechnology7.6 History and anthropology7.7 Information storage8 History of DNA research9 See also10 References11 Further reading12 External links Properties Chemical structure of DNA; hydrogen bonds shown as dotted lines DNA is a long polymer made from repeating units called nucleotides.

[6] [7] The structure of DNA is dynamic along its length, being capable of coiling into tight loops, and other shapes. [8] In all species it is composed of two helical chains, bound to each other by hydrogen bonds. Both chains are coiled round the same axis, and have the same pitch of 34 ångströms (3.4 nanometres ). The pair of chains has a radius of 10 ångströms (1.0 nanometre). [9] According to another study, when measured in a different solution, the DNA chain measured 22 to 26 ångströms wide (2.2 to 2.6 nanometres), and one nucleotide unit measured 3.3 Å (0.33 nm) long.

[10] Although each individual nucleotide repeating unit is very small, DNA polymers can be very large molecules containing millions to hundreds of millions of nucleotides.

For instance, the DNA in the largest human chromosome, chromosome number 1, consists of approximately 220 million base pairs [11] and would be 85 mm long if straightened. In living organisms, DNA does not usually exist as a single molecule, but instead as a pair of molecules that are held tightly together.

[12] [13] These two long strands entwine like vines, in the shape of a double helix. The nucleotide contains both a segment of the backbone of the molecule (which holds the chain together) and a nucleobase (which interacts with the other DNA strand in the helix).

A nucleobase linked to a sugar is called a nucleoside and a base linked to a sugar and one or more phosphate groups is called a nucleotide. A polymer comprising multiple linked nucleotides (as in DNA) is called a polynucleotide. [14]The backbone of the DNA strand is made from alternating phosphate and sugar residues.

[15] The sugar in DNA is 2- deoxyribose, which is a pentose (five- carbon) sugar. The sugars are joined together by phosphate groups that form phosphodiester bonds between the third and fifth carbon atoms of adjacent sugar rings.

These asymmetric bonds mean a strand of DNA has a direction. In a double helix, the direction of the nucleotides in one strand is opposite to their direction in the other strand: the strands are antiparallel. The asymmetric ends of DNA strands are said to have a directionality of five prime (5′) and three prime (3′), with the 5′ end having a terminal phosphate group and the 3′ end a terminal hydroxyl group.

One major difference between DNA and RNA is the sugar, with the 2-deoxyribose in DNA being replaced by the alternative pentose sugar ribose in RNA. [13]A section of DNA. The bases lie horizontally between the two spiraling strands. [16] ( animated version ). The DNA double helix is stabilized primarily by two forces: hydrogen bonds between nucleotides and base-stacking interactions among aromatic nucleobases.

[17] In the aqueous environment of the cell, the conjugated π bonds of nucleotide bases align perpendicular to the axis of the DNA molecule, minimizing their interaction with the solvation shell. The four bases found in DNA are adenine (A), cytosine (C), guanine (G) and thymine (T). These four bases are attached to the sugar-phosphate to form the complete nucleotide, as shown for adenosine monophosphate.

Adenine pairs with thymine and guanine pairs with cytosine. It was represented by A-T base pairs and G-C base pairs. [18] [19]Nucleobase classification The nucleobases are classified into two types: the purines, A and G, being fused five- and six-membered heterocyclic compounds, and the pyrimidines, the six-membered rings C and T. [13] A fifth pyrimidine nucleobase, uracil (U), usually takes the place of thymine in RNA and differs from thymine by lacking a methyl group on its ring.

In addition to RNA and DNA, many artificial nucleic acid analogues have been created to study the properties of nucleic acids, or for use in biotechnology. [20]Non canonical bases Uracil is not usually found in DNA, occurring only as a breakdown product of cytosine.

However, in several bacteriophages, Bacillus subtilis bacteriophages PBS1 and PBS2 and Yersinia bacteriophage pi R1-37, thymine has been replaced by uracil. [21] Another phage - Staphylococcal phage S6 - has been identified with a genome where thymine has been replaced by uracil.

[22]5-hydroxymethyldeoxyuracil ( hm5 d U) is also known to replace thymidine in several genomes including the Bacillus phages SPO1, ϕe, SP8, H1, 2C and SP82. Another modified uracil - 5-dihydroxypentauracil – has also been described. [23]Base J (beta-d-glucopyranosyloxymethyluracil), a modified form of uracil, is also found in several organisms: the flagellates Diplonema and Euglena, and all the kinetoplastid genera.

[24] Biosynthesis of J occurs in two steps: in the first step, a specific thymidine in DNA is converted into hydroxymethyldeoxyuridine; in the second, HOMed U is glycosylated to form J. [25] Proteins that bind specifically to this base have been identified. [26] [27] [28] These proteins appear to be distant relatives of the Tet1 oncogene that is involved in the pathogenesis of acute myeloid leukemia.

[29] J appears to act as a termination signal for RNA polymerase II. [30] [31]In 1976 a bacteriophage - S-2L - which infects species of the genus Synechocystis was found to have all the adenosine bases within its genome replaced by 2,6-diaminopurine.

[32] In 2016 deoxyarchaeosine was found to be present in the genomes of several bacteria and the Escherichia phage 9g. [33]Modified bases also occur in DNA. The first of these recognised was 5-methylcytosine which was found in the genome of Mycobacterium tuberculosis in 1925.

[34] The complete replacement of cytosine by 5-glycosylhydroxymethylcytosine in T even phages (T2, T4 and T6) was observed in 1953 [35] In the genomes of Xanthomonas oryzae bacteriophage Xp12 and halovirus FH the full complement of cystosine has been replaced by 5-methylcytosine. [36] [37] 6N-methyadenine was discovered to be present in DNA in 1955. [38] N6-carbamoyl-methyladenine was described in 1975.

[39] 7- methylguanine was described in 1976. [40] N4-methylcytosine in DNA was described in 1983. [41] In 1985 5-hydroxycytosine was found in the genomes of the Rhizobium phages RL38JI and N17. [42] α-putrescinylthymine occurs in both the genomes of the Delftia phage ΦW-14 and the Bacillus phage SP10.

[43] α-glutamythymidine is found in the Bacillus phage SP01 and 5-dihydroxypentyluracil is found in the Bacillus phage SP15.

The reason for the presence of these non canonical bases in DNA is not known. It seems likely that at least part of the reason for their presence in bacterial viruses (phages) is to avoid the restriction enzymes present in bacteria. This enzyme system acts at least in part as a molecular immune system protecting bacteria from infection by viruses. This does not appear to be the entire story. Four modifications to the cytosine residues in human DNA have been reported.

[44] These modifications are the addition of methyl (CH 3 )-, hydroxymethyl (CH 2 OH)-, formyl (CHO)- and carboxyl (COOH)- groups. These modifications are thought to have regulatory functions. Listing of non canonical bases found in DNASeventeen non canonical bases are known to occur in DNA. Most of these are modifications of the canonical bases plus uracil. Modified Adenosine N6-carbamoyl-methyladenine N6-methyadenine Modified Guanine7-Methylguanine Modified Cytosine N4-Methylcytosine5-Carboxylcytosine5-Formylcytosine5-Glycosylhydroxymethylcytosine5-Hydroxycytosine5-Methylcytosine Modified Thymidineα-Glutamythymidineα-Putrescinylthymine Uracil and modifications Base JUracil5-Dihydroxypentauracil5-Hydroxymethyldeoxyuracil Others Deoxyarchaeosine2,6-Diaminopurine DNA major and minor grooves.

The latter is a binding site for the Hoechst stain dye 33258. Grooves Twin helical strands form the DNA backbone. Another double helix may be found tracing the spaces, or grooves, between the strands. These voids are adjacent to the base pairs and may provide a binding site.

As the strands are not symmetrically located with respect to each other, the grooves are unequally sized. One groove, the major groove, is 22 Å wide and the other, the minor groove, is 12 Å wide. [45] The width of the major groove means that the edges of the bases are more accessible in the major groove than in the minor groove.

As a result, proteins such as transcription factors that can bind to specific sequences in double-stranded DNA usually make contact with the sides of the bases exposed in the major groove.

[46] This situation varies in unusual conformations of DNA within the cell (see below), but the major and minor grooves are always named to reflect the differences in size that would be seen if the DNA is twisted back into the ordinary B form.

Base pairing Further information: Base pair In a DNA double helix, each type of nucleobase on one strand bonds with just one type of nucleobase on the other strand.

This is called complementary base pairing. Here, purines form hydrogen bonds to pyrimidines, with adenine bonding only to thymine in two hydrogen bonds, and cytosine bonding only to guanine in three hydrogen bonds. This arrangement of two nucleotides binding together across the double helix is called a Watson-Crick base pair.

Another type of base pairing is Hoogsteen base pairing where two hydrogen bonds form between guanine and cytosine. [47] As hydrogen bonds are not covalent, they can be broken and rejoined relatively easily. The two strands of DNA in a double helix can thus be pulled apart like a zipper, either by a mechanical force or high temperature.

[48] As a result of this base pair complementarity, all the information in the double-stranded sequence of a DNA helix is duplicated on each strand, which is vital in DNA replication. This reversible and specific interaction between complementary base pairs is critical for all the functions of DNA in living organisms.

[7]Top, a GC base pair with three hydrogen bonds. Bottom, an AT base pair with two hydrogen bonds. Non-covalent hydrogen bonds between the pairs are shown as dashed lines. The two types of base pairs form different numbers of hydrogen bonds, AT forming two hydrogen bonds, and GC forming three hydrogen bonds (see figures, right).

DNA with high GC-content is more stable than DNA with low GC-content. As noted above, most DNA molecules are actually two polymer strands, bound together in a helical fashion by noncovalent bonds; this double-stranded ( ds DNA) structure is maintained largely by the intrastrand base stacking interactions, which are strongest for G,C stacks.

The two strands can come apart – a process known as melting – to form two single-stranded DNA ( ss DNA) molecules. Melting occurs at high temperature, low salt and high p H (low p H also melts DNA, but since DNA is unstable due to acid depurination, low p H is rarely used).

The stability of the ds DNA form depends not only on the GC-content (% G,C basepairs) but also on sequence (since stacking is sequence specific) and also length (longer molecules are more stable).

The stability can be measured in various ways; a common way is the ""melting temperature"", which is the temperature at which 50% of the ds molecules are converted to ss molecules; melting temperature is dependent on ionic strength and the concentration of DNA.

As a result, it is both the percentage of GC base pairs and the overall length of a DNA double helix that determines the strength of the association between the two strands of DNA. Long DNA helices with a high GC-content have stronger-interacting strands, while short helices with high AT content have weaker-interacting strands.

[49] In biology, parts of the DNA double helix that need to separate easily, such as the TATAAT Pribnow box in some promoters, tend to have a high AT content, making the strands easier to pull apart.

[50]In the laboratory, the strength of this interaction can be measured by finding the temperature necessary to break the hydrogen bonds, their melting temperature (also called T m value). When all the base pairs in a DNA double helix melt, the strands separate and exist in solution as two entirely independent molecules. These single-stranded DNA molecules have no single common shape, but some conformations are more stable than others. [51]Sense and antisense Further information: Sense (molecular biology)A DNA sequence is called ""sense"" if its sequence is the same as that of a messenger RNA copy that is translated into protein.

[52] The sequence on the opposite strand is called the ""antisense"" sequence. Both sense and antisense sequences can exist on different parts of the same strand of DNA (i.e. both strands can contain both sense and antisense sequences). In both prokaryotes and eukaryotes, antisense RNA sequences are produced, but the functions of these RNAs are not entirely clear. [53] One proposal is that antisense RNAs are involved in regulating gene expression through RNA-RNA base pairing.

[54]A few DNA sequences in prokaryotes and eukaryotes, and more in plasmids and viruses, blur the distinction between sense and antisense strands by having overlapping genes. [55] In these cases, some DNA sequences do double duty, encoding one protein when read along one strand, and a second protein when read in the opposite direction along the other strand.

In bacteria, this overlap may be involved in the regulation of gene transcription, [56] while in viruses, overlapping genes increase the amount of information that can be encoded within the small viral genome. [57]Supercoiling Further information: DNA supercoil DNA can be twisted like a rope in a process called DNA supercoiling.

With DNA in its ""relaxed"" state, a strand usually circles the axis of the double helix once every 10.4 base pairs, but if the DNA is twisted the strands become more tightly or more loosely wound.

[58] If the DNA is twisted in the direction of the helix, this is positive supercoiling, and the bases are held more tightly together. If they are twisted in the opposite direction, this is negative supercoiling, and the bases come apart more easily.

In nature, most DNA has slight negative supercoiling that is introduced by enzymes called topoisomerases. [59] These enzymes are also needed to relieve the twisting stresses introduced into DNA strands during processes such as transcription and DNA replication.

[60]From left to right, the structures of A, B and Z DNAAlternative DNA structures Further information: Molecular Structure of Nucleic Acids: A Structure for Deoxyribose Nucleic Acid, Molecular models of DNA, and DNA structure DNA exists in many possible conformations that include A-DNA, B-DNA, and Z-DNA forms, although, only B-DNA and Z-DNA have been directly observed in functional organisms.

[15] The conformation that DNA adopts depends on the hydration level, DNA sequence, the amount and direction of supercoiling, chemical modifications of the bases, the type and concentration of metal ions, and the presence of polyamines in solution. [61]The first published reports of A-DNA X-ray diffraction patterns —and also B-DNA—used analyses based on Patterson transforms that provided only a limited amount of structural information for oriented fibers of DNA.

[62] [63] An alternative analysis was then proposed by Wilkins et al., in 1953, for the in vivo B-DNA X-ray diffraction-scattering patterns of highly hydrated DNA fibers in terms of squares of Bessel functions.

[64] In the same journal, James Watson and Francis Crick presented their molecular modeling analysis of the DNA X-ray diffraction patterns to suggest that the structure was a double-helix. [9]Although the B-DNA form is most common under the conditions found in cells, [65] it is not a well-defined conformation but a family of related DNA conformations [66] that occur at the high hydration levels present in living cells.

Their corresponding X-ray diffraction and scattering patterns are characteristic of molecular paracrystals with a significant degree of disorder. [67] [68]Compared to B-DNA, the A-DNA form is a wider right-handed spiral, with a shallow, wide minor groove and a narrower, deeper major groove.

The A form occurs under non-physiological conditions in partly dehydrated samples of DNA, while in the cell it may be produced in hybrid pairings of DNA and RNA strands, and in enzyme-DNA complexes.

[69] [70] Segments of DNA where the bases have been chemically modified by methylation may undergo a larger change in conformation and adopt the Z form. Here, the strands turn about the helical axis in a left-handed spiral, the opposite of the more common B form.

[71] These unusual structures can be recognized by specific Z-DNA binding proteins and may be involved in the regulation of transcription. [72]Alternative DNA chemistry For many years exobiologists have proposed the existence of a shadow biosphere, a postulated microbial biosphere of Earth that uses radically different biochemical and molecular processes than currently known life.

One of the proposals was the existence of lifeforms that use arsenic instead of phosphorus in DNA. A report in 2010 of the possibility in the bacterium GFAJ-1, was announced, [73] [73] [74] though the research was disputed, [74] [75] and evidence suggests the bacterium actively prevents the incorporation of arsenic into the DNA backbone and other biomolecules. [76]Quadruplex structures Further information: G-quadruplex At the ends of the linear chromosomes are specialized regions of DNA called telomeres.

The main function of these regions is to allow the cell to replicate chromosome ends using the enzyme telomerase, as the enzymes that normally replicate DNA cannot copy the extreme 3′ ends of chromosomes.

[77] These specialized chromosome caps also help protect the DNA ends, and stop the DNA repair systems in the cell from treating them as damage to be corrected. [78] In human cells, telomeres are usually lengths of single-stranded DNA containing several thousand repeats of a simple TTAGGG sequence. [79]DNA quadruplex formed by telomere repeats. The looped conformation of the DNA backbone is very different from the typical DNA helix.

The green spheres in the center represent potassium ions. [80]These guanine-rich sequences may stabilize chromosome ends by forming structures of stacked sets of four-base units, rather than the usual base pairs found in other DNA molecules. Here, four guanine bases form a flat plate and these flat four-base units then stack on top of each other, to form a stable G-quadruplex structure.

[81] These structures are stabilized by hydrogen bonding between the edges of the bases and chelation of a metal ion in the centre of each four-base unit. [82] Other structures can also be formed, with the central set of four bases coming from either a single strand folded around the bases, or several different parallel strands, each contributing one base to the central structure. In addition to these stacked structures, telomeres also form large loop structures called telomere loops, or T-loops.

Here, the single-stranded DNA curls around in a long circle stabilized by telomere-binding proteins. [83] At the very end of the T-loop, the single-stranded telomere DNA is held onto a region of double-stranded DNA by the telomere strand disrupting the double-helical DNA and base pairing to one of the two strands. This triple-stranded structure is called a displacement loop or D-loop. [81]Single branch Multiple branches Branched DNA can form networks containing multiple branches.

Branched DNAFurther information: Branched DNA and DNA nanotechnology In DNA, fraying occurs when non-complementary regions exist at the end of an otherwise complementary double-strand of DNA.

However, branched DNA can occur if a third strand of DNA is introduced and contains adjoining regions able to hybridize with the frayed regions of the pre-existing double-strand. Although the simplest example of branched DNA involves only three strands of DNA, complexes involving additional strands and multiple branches are also possible. [84] Branched DNA can be used in nanotechnology to construct geometric shapes, see the section on uses in technology below. Chemical modifications and altered DNA packagingcytosine 5-methylcytosine thymine Structure of cytosine with and without the 5-methyl group. Deamination converts 5-methylcytosine into thymine. Base modifications and DNA packaging Further information: DNA methylation and Chromatin remodeling The expression of genes is influenced by how the DNA is packaged in chromosomes, in a structure called chromatin.

Base modifications can be involved in packaging, with regions that have low or no gene expression usually containing high levels of methylation of cytosine bases.

DNA packaging and its influence on gene expression can also occur by covalent modifications of the histone protein core around which DNA is wrapped in the chromatin structure or else by remodeling carried out by chromatin remodeling complexes (see Chromatin remodeling ).

There is, further, crosstalk between DNA methylation and histone modification, so they can coordinately affect chromatin and gene expression. [85]For one example, cytosine methylation produces 5-methylcytosine, which is important for X-inactivation of chromosomes. [86] The average level of methylation varies between organisms – the worm Caenorhabditis elegans lacks cytosine methylation, while vertebrates have higher levels, with up to 1% of their DNA containing 5-methylcytosine. [87] Despite the importance of 5-methylcytosine, it can deaminate to leave a thymine base, so methylated cytosines are particularly prone to mutations. [88] Other base modifications include adenine methylation in bacteria, the presence of 5-hydroxymethylcytosine in the brain, [89] and the glycosylation of uracil to produce the ""J-base"" in kinetoplastids.

[90] [91]Damage Further information: DNA damage (naturally occurring), Mutation, and DNA damage theory of aging A covalent adduct between a metabolically activated form of benzo [ a ]pyrene, the major mutagen in tobacco smoke, and DNA [92]DNA can be damaged by many sorts of mutagens, which change the DNA sequence.

Mutagens include oxidizing agents, alkylating agents and also high-energy electromagnetic radiation such as ultraviolet light and X-rays. The type of DNA damage produced depends on the type of mutagen. For example, UV light can damage DNA by producing thymine dimers, which are cross-links between pyrimidine bases.

[93] On the other hand, oxidants such as free radicals or hydrogen peroxide produce multiple forms of damage, including base modifications, particularly of guanosine, and double-strand breaks.

[94] A typical human cell contains about 150,000 bases that have suffered oxidative damage. [95] Of these oxidative lesions, the most dangerous are double-strand breaks, as these are difficult to repair and can produce point mutations, insertions, deletions from the DNA sequence, and chromosomal translocations. [96] These mutations can cause cancer. Because of inherent limits in the DNA repair mechanisms, if humans lived long enough, they would all eventually develop cancer.

[97] [98] DNA damages that are naturally occurring, due to normal cellular processes that produce reactive oxygen species, the hydrolytic activities of cellular water, etc., also occur frequently. Although most of these damages are repaired, in any cell some DNA damage may remain despite the action of repair processes.

These remaining DNA damages accumulate with age in mammalian postmitotic tissues. This accumulation appears to be an important underlying cause of aging. [99] [100] [101]Many mutagens fit into the space between two adjacent base pairs, this is called intercalation. Most intercalators are aromatic and planar molecules; examples include ethidium bromide, acridines, daunomycin, and doxorubicin.

For an intercalator to fit between base pairs, the bases must separate, distorting the DNA strands by unwinding of the double helix. This inhibits both transcription and DNA replication, causing toxicity and mutations. [102] As a result, DNA intercalators may be carcinogens, and in the case of thalidomide, a teratogen. [103] Others such as benzo [ a ]pyrene diol epoxide and aflatoxin form DNA adducts that induce errors in replication.

[104] Nevertheless, due to their ability to inhibit DNA transcription and replication, other similar toxins are also used in chemotherapy to inhibit rapidly growing cancer cells. [105]Biological functions Location of eukaryote nuclear DNA within the chromosomes. DNA usually occurs as linear chromosomes in eukaryotes, and circular chromosomes in prokaryotes.

The set of chromosomes in a cell makes up its genome; the human genome has approximately 3 billion base pairs of DNA arranged into 46 chromosomes. [106] The information carried by DNA is held in the sequence of pieces of DNA called genes. Transmission of genetic information in genes is achieved via complementary base pairing.

For example, in transcription, when a cell uses the information in a gene, the DNA sequence is copied into a complementary RNA sequence through the attraction between the DNA and the correct RNA nucleotides. Usually, this RNA copy is then used to make a matching protein sequence in a process called translation, which depends on the same interaction between RNA nucleotides.

In alternative fashion, a cell may simply copy its genetic information in a process called DNA replication.

The details of these functions are covered in other articles; here the focus is on the interactions between DNA and other molecules that mediate the function of the genome. Genes and genomes Further information: Cell nucleus, Chromatin, Chromosome, Gene, and Noncoding DNAGenomic DNA is tightly and orderly packed in the process called DNA condensation, to fit the small available volumes of the cell. In eukaryotes, DNA is located in the cell nucleus, with small amounts in mitochondria and chloroplasts. In prokaryotes, the DNA is held within an irregularly shaped body in the cytoplasm called the nucleoid. [107] The genetic information in a genome is held within genes, and the complete set of this information in an organism is called its genotype. A gene is a unit of heredity and is a region of DNA that influences a particular characteristic in an organism. Genes contain an open reading frame that can be transcribed, and regulatory sequences such as promoters and enhancers, which control transcription of the open reading frame.

In many species, only a small fraction of the total sequence of the genome encodes protein. For example, only about 1.5% of the human genome consists of protein-coding exons, with over 50% of human DNA consisting of non-coding repetitive sequences.

[108] The reasons for the presence of so much noncoding DNA in eukaryotic genomes and the extraordinary differences in genome size, or C-value, among species, represent a long-standing puzzle known as the "" C-value enigma "". [109] However, some DNA sequences that do not code protein may still encode functional non-coding RNA molecules, which are involved in the regulation of gene expression.

[110]T7 RNA polymerase (blue) producing an m RNA (green) from a DNA template (orange). [111]Some noncoding DNA sequences play structural roles in chromosomes. Telomeres and centromeres typically contain few genes but are important for the function and stability of chromosomes. [78] [112] An abundant form of noncoding DNA in humans are pseudogenes, which are copies of genes that have been disabled by mutation.

[113] These sequences are usually just molecular fossils, although they can occasionally serve as raw genetic material for the creation of new genes through the process of gene duplication and divergence. [114]Transcription and translation Further information: Genetic code, Transcription (genetics), and Protein biosynthesis A gene is a sequence of DNA that contains genetic information and can influence the phenotype of an organism.

Within a gene, the sequence of bases along a DNA strand defines a messenger RNA sequence, which then defines one or more protein sequences. The relationship between the nucleotide sequences of genes and the amino-acid sequences of proteins is determined by the rules of translation, known collectively as the genetic code.

The genetic code consists of three-letter 'words' called codons formed from a sequence of three nucleotides (e.g. ACT, CAG, TTT). In transcription, the codons of a gene are copied into messenger RNA by RNA polymerase. This RNA copy is then decoded by a ribosome that reads the RNA sequence by base-pairing the messenger RNA to transfer RNA, which carries amino acids.

Since there are 4 bases in 3-letter combinations, there are 64 possible codons (4 3 combinations). These encode the twenty standard amino acids, giving most amino acids more than one possible codon.

There are also three 'stop' or 'nonsense' codons signifying the end of the coding region; these are the TAA, TGA, and TAG codons. DNA replication. The double helix is unwound by a helicase and topoisomerase. Next, one DNA polymerase produces the leading strand copy. Another DNA polymerase binds to the lagging strand. This enzyme makes discontinuous segments (called Okazaki fragments) before DNA ligase joins them together.

Replication Further information: DNA replication Cell division is essential for an organism to grow, but, when a cell divides, it must replicate the DNA in its genome so that the two daughter cells have the same genetic information as their parent. The double-stranded structure of DNA provides a simple mechanism for DNA replication. Here, the two strands are separated and then each strand's complementary DNA sequence is recreated by an enzyme called DNA polymerase. This enzyme makes the complementary strand by finding the correct base through complementary base pairing and bonding it onto the original strand.

As DNA polymerases can only extend a DNA strand in a 5′ to 3′ direction, different mechanisms are used to copy the antiparallel strands of the double helix. [115] In this way, the base on the old strand dictates which base appears on the new strand, and the cell ends up with a perfect copy of its DNA. Extracellular nucleic acids Naked extracellular DNA (e DNA), most of it released by cell death, is nearly ubiquitous in the environment.

Its concentration in soil may be as high as 2 μg/L, and its concentration in natural aquatic environments may be as high at 88 μg/L.

[116] Various possible functions have been proposed for e DNA: it may be involved in horizontal gene transfer; [117] it may provide nutrients; [118] and it may act as a buffer to recruit or titrate ions or antibiotics.

[119] Extracellular DNA acts as a functional extracellular matrix component in the biofilms of several bacterial species. It may act as a recognition factor to regulate the attachment and dispersal of specific cell types in the biofilm; [120] it may contribute to biofilm formation; [121] and it may contribute to the biofilm's physical strength and resistance to biological stress.

[122]Cell-free fetal DNA is found in the blood of the mother, and can be sequenced to determine a great deal of information about the developing fetus.

[123]Interactions with proteins All the functions of DNA depend on interactions with proteins. These protein interactions can be non-specific, or the protein can bind specifically to a single DNA sequence. Enzymes can also bind to DNA and of these, the polymerases that copy the DNA base sequence in transcription and DNA replication are particularly important. DNA-binding proteins Further information: DNA-binding protein Interaction of DNA (in orange) with histones (in blue). These proteins' basic amino acids bind to the acidic phosphate groups on DNA. Structural proteins that bind DNA are well-understood examples of non-specific DNA-protein interactions. Within chromosomes, DNA is held in complexes with structural proteins. These proteins organize the DNA into a compact structure called chromatin.

In eukaryotes, this structure involves DNA binding to a complex of small basic proteins called histones, while in prokaryotes multiple types of proteins are involved.

[124] [125] The histones form a disk-shaped complex called a nucleosome, which contains two complete turns of double-stranded DNA wrapped around its surface. These non-specific interactions are formed through basic residues in the histones, making ionic bonds to the acidic sugar-phosphate backbone of the DNA, and are thus largely independent of the base sequence.

[126] Chemical modifications of these basic amino acid residues include methylation, phosphorylation, and acetylation. [127] These chemical changes alter the strength of the interaction between the DNA and the histones, making the DNA more or less accessible to transcription factors and changing the rate of transcription.

[128] Other non-specific DNA-binding proteins in chromatin include the high-mobility group proteins, which bind to bent or distorted DNA. [129] These proteins are important in bending arrays of nucleosomes and arranging them into the larger structures that make up chromosomes.

[130]A distinct group of DNA-binding proteins is the DNA-binding proteins that specifically bind single-stranded DNA. In humans, replication protein A is the best-understood member of this family and is used in processes where the double helix is separated, including DNA replication, recombination, and DNA repair. [131] These binding proteins seem to stabilize single-stranded DNA and protect it from forming stem-loops or being degraded by nucleases.

The lambda repressor helix-turn-helix transcription factor bound to its DNA target [132]In contrast, other proteins have evolved to bind to particular DNA sequences. The most intensively studied of these are the various transcription factors, which are proteins that regulate transcription. Each transcription factor binds to one particular set of DNA sequences and activates or inhibits the transcription of genes that have these sequences close to their promoters.

The transcription factors do this in two ways. Firstly, they can bind the RNA polymerase responsible for transcription, either directly or through other mediator proteins; this locates the polymerase at the promoter and allows it to begin transcription. [133] Alternatively, transcription factors can bind enzymes that modify the histones at the promoter.

This changes the accessibility of the DNA template to the polymerase. [134]As these DNA targets can occur throughout an organism's genome, changes in the activity of one type of transcription factor can affect thousands of genes.

[135] Consequently, these proteins are often the targets of the signal transduction processes that control responses to environmental changes or cellular differentiation and development. The specificity of these transcription factors' interactions with DNA come from the proteins making multiple contacts to the edges of the DNA bases, allowing them to ""read"" the DNA sequence.

Most of these base-interactions are made in the major groove, where the bases are most accessible. [46]The restriction enzyme Eco RV (green) in a complex with its substrate DNA [136]DNA-modifying enzymes Nucleases and ligases Nucleases are enzymes that cut DNA strands by catalyzing the hydrolysis of the phosphodiester bonds. Nucleases that hydrolyse nucleotides from the ends of DNA strands are called exonucleases, while endonucleases cut within strands.

The most frequently used nucleases in molecular biology are the restriction endonucleases, which cut DNA at specific sequences. For instance, the Eco RV enzyme shown to the left recognizes the 6-base sequence 5′-GATATC-3′ and makes a cut at the horizontal line.

In nature, these enzymes protect bacteria against phage infection by digesting the phage DNA when it enters the bacterial cell, acting as part of the restriction modification system. [137] In technology, these sequence-specific nucleases are used in molecular cloning and DNA fingerprinting.

Enzymes called DNA ligases can rejoin cut or broken DNA strands. [138] Ligases are particularly important in lagging strand DNA replication, as they join together the short segments of DNA produced at the replication fork into a complete copy of the DNA template. They are also used in DNA repair and genetic recombination. [138]Topoisomerases and helicases Topoisomerases are enzymes with both nuclease and ligase activity.

These proteins change the amount of supercoiling in DNA. Some of these enzymes work by cutting the DNA helix and allowing one section to rotate, thereby reducing its level of supercoiling; the enzyme then seals the DNA break. [59] Other types of these enzymes are capable of cutting one DNA helix and then passing a second strand of DNA through this break, before rejoining the helix. [139] Topoisomerases are required for many processes involving DNA, such as DNA replication and transcription.

[60]Helicases are proteins that are a type of molecular motor. They use the chemical energy in nucleoside triphosphates, predominantly adenosine triphosphate (ATP), to break hydrogen bonds between bases and unwind the DNA double helix into single strands. [140] These enzymes are essential for most processes where enzymes need to access the DNA bases. Polymerases Polymerases are enzymes that synthesize polynucleotide chains from nucleoside triphosphates. The sequence of their products is created based on existing polynucleotide chains—which are called templates. These enzymes function by repeatedly adding a nucleotide to the 3′ hydroxyl group at the end of the growing polynucleotide chain.

As a consequence, all polymerases work in a 5′ to 3′ direction. [141] In the active site of these enzymes, the incoming nucleoside triphosphate base-pairs to the template: this allows polymerases to accurately synthesize the complementary strand of their template.

Polymerases are classified according to the type of template that they use. In DNA replication, DNA-dependent DNA polymerases make copies of DNA polynucleotide chains. To preserve biological information, it is essential that the sequence of bases in each copy are precisely complementary to the sequence of bases in the template strand.

Many DNA polymerases have a proofreading activity. Here, the polymerase recognizes the occasional mistakes in the synthesis reaction by the lack of base pairing between the mismatched nucleotides. If a mismatch is detected, a 3′ to 5′ exonuclease activity is activated and the incorrect base removed.

[142] In most organisms, DNA polymerases function in a large complex called the replisome that contains multiple accessory subunits, such as the DNA clamp or helicases.

[143]RNA-dependent DNA polymerases are a specialized class of polymerases that copy the sequence of an RNA strand into DNA. They include reverse transcriptase, which is a viral enzyme involved in the infection of cells by retroviruses, and telomerase, which is required for the replication of telomeres. [77] [144] For example, HIV reverse transcriptase is an enzyme for AIDS virus replication. [144] Telomerase is an unusual polymerase because it contains its own RNA template as part of its structure. It synthesizes telomeres at the ends of chromosomes. Telomeres prevent fusion of the ends of neighboring chromosomes and protect chromosome ends from damage. [78]

Transcription is carried out by a DNA-dependent RNA polymerase that copies the sequence of a DNA strand into RNA. To begin transcribing a gene, the RNA polymerase binds to a sequence of DNA called a promoter and separates the DNA strands.

In this paper we describe data exploration techniques designed to classify DNA sequences. Several visualization and data mining techniques were used to validate and attempt to discover new methods for distinguishing coding DNA sequences, or exons, from non-coding DNA sequences, or introns.

1 Introduction

"DNA Visual And Analytic Data Mining Patrick Hoffman 1, Georges Grinstein 1Kenneth Marx 2, Ivo Grosse 3, Eugene Stanley 31 Institute for Visualization and Perception Research Department of Computer Science University of Massachusetts Lowell Lowell, MA 018542 Center for Intelligent Biomaterials Department of Chemistry University of Massachusetts Lowell Lowell, MA 018543 Center for Polymer Studies and Department of Physics Boston University Boston, MA 02215Abstract

The goal of the data mining was to see whether some other possibly non-linear combination of the fundamental position dependent DNA nucleotide frequency values could be a better predictor than the AMI [6]. We tried many different classification techniques including rule-based classifiers and neural networks. We also used visualization of both the original data and the results of the data mining to help verify patterns and to understand the distinction between the different types of data and classifications. In particular, the visualization helped us develop refinements to neural network classifiers, which have accuracy's as high as any known method.

In the conclusion, we discuss the interactions between visualization and data mining and suggest an integrated approach.1 Introduction The international effort called the Human Genome Project is rapidly sequencing the complete DNA sequences of all 24 human chromosomes.

As well, the chromosomes from a number of other organisms are being entirely sequenced. The DNA component of chromosomes are long linear molecules comprised of strings of the four nucleotides (A, C, T, G), the information bearing chemical units. Coding sequences (exons) are interspersed by non-coding sequences (introns) along the chromosomes whose information encodes protein structures.

Transcription of the coding DNA sequence into m RNA, which is then translated into proteins in the cell comprise the general flow of information.

This process is responsible for all normal cellular functions as diverse as development into multicellular organisms, organ development, the immune system, to name a few, as well as abnormal function such as cancer, birth defects, etc. The current approach for finding genes (protein coding sequences) is both experimental and computational.

Any small increase in the accuracy of computer classification can therefore result in substantial time and cost savings. In this paper we describe our experiences to harness data exploration techniques to classify DNA sequences. In order to use visualization and data mining techniques to develop new methods for distinguishing coding DNA sequences (exons) from non-coding DNA sequences (introns), it is necessary to represent symbolic DNA sequences by numbers or vectors.

It has been demonstrated by Fickett et al. [4] that the proper choice of this representation is as important as the later processing of the numbers by neural nets or other classification schemes. The representation of DNA sequences we chose was guided by the recent discovery that a non-linear correlation statistic for DNA sequences, called the average mutual information (AMI), [6], is capable of distinguishing coding from non-coding DNA sequences in all taxonomic classes ranging from the most simple to the most complex organisms.

mathematically, the AMI is a non-linear function based on the vector of 12 frequencies p_i^k by which the nucleotide i = a, c, g, t appears in position k = 1, 2, 3 relative to a given reading frame in a small segment of a DNA.

The goal of our study was to see whether some possibly non-linear combination of these position dependent DNA frequency values could be a better predictor than the AMI. After a brief introduction to the various data mining techniques, we discuss our analytic approach, the visualizations we used and developed, and the results of these analyses. We also briefly suggest how visualization and data mining could be integrated in the future.2 Data Mining2.1 Tools A number of data mining tools are available.

Some of the ones we used include Tooldiag [12], and Stuttgart Neural Network Simulator SNNS [15,17] . We concentrated our efforts on applying Clementine [2]. Clementine is a data mining suite based on the data flow visual programming paradigm similar to AVS or IBM's Data Explorer. It provides four machine learning modules: two rule-based algorithms, a standard neural net (multi-layer Perceptron), and a Kohonen neural net for clustering, each with default settings.

Elaborate tuning is possible but not necessary to get some early results. One rule-based classifier in Clementine is the C4.5 algorithm by Quinlan [11].2.2 Data Mining DNA Sequences Fickett [4] developed databases consisting of sequences of known exons and introns and described the accuracy of several classification methods.

Some methods depend on knowing the particular starting and ending sequences and most require elaborate training on exon and intron data sets from the organism under consideration. In [6] the Mutual Information function was developed and studied. It provides a non-linear measure of the correlation between a particular nucleotide and another n nucleotides away. For biochemical reasons coding sequences possess a triplet codon information structure. Thus nucleotides at positions 3, 6, 9, and generally 3n , positions away from each other have higher correlations.

Thus we only need to look at the frequencies of A, C, T, G extracted from a small segment of DNA, at positions 1, 2, and 3. [7] defines the AMI as a particular combination of these 12 values and uses it as a predictor for distinguishing exons from introns.

It classifies DNA sequences with a high degree of accuracy (76 for 108 bp and 81% for 162 bp). Is it possible that there are other functions of these values that can even better distinguish exons from introns?

We decided to use data mining to help find these functions. In our initial study we examined several thousands of Fickettís sequences of various length exons and introns.

Our first task was to divide the data into training and test sets. The training sets were used to build a classifier, similar to the rule-based ID3 [10], and a neural net. The test sets were used to evaluate the accuracy of the classifier. To date the various classification programs have reached accuracy's between 73 and 81 percent [4].

This provided a baseline that we were comparing against. Since there are only two classes of data any classifier should reach at least a minimum accuracy of 50%. Initially, only 200 points (100 exons and 100 introns) were used to train Clementineís 2 rule-based classifiers and neural net.

We used DNA sequences of 162 base pairs for all of our classifiers. The default NN used 12 input nodes , 4 hidden layers and 1 output node. After training the rule-based classifiers were correct 93 and 94 percent of the time while the NN was only about 80% accurate on the small training data.

However, with 800 non-training samples (400 exons and 400 introns) we obtained the following accuracy: Correct Wrong Neural Net 638 ( 79.55%) 164 (20.45%)C4.5 RULE 551 ( 68.70%) 251 (31.30%)Clementine Rule573 ( 71.45%) 229 (28.55%)Here, rule based classifiers were inferior to the NN classifiers.

These initial results were very promising for the neural network, since we knew we could potentially tune the network for better performance, and we still were using a small training set.

At this point we were ready to explore other packages, but more pressing was trying to understand in greater detail the structure of the data we had generated. Unfortunately, neural networks and classification rules do not easily reveal their insights into the data.

We wanted to ""see"" these differences! Visualization was needed.3 Visualization We used several visualization approaches to look both at the original Fickett data as well as processed data.3.1 Radial Visualizations Spring constants can be used to represent relational values between points [1,9].

We developed a radial visualization (Radviz), similar in spirit to parallel coordinates (lossless visualization), in which n -dimensional data points are laid out as points equally spaced around the perimeter of a circle. One end of n springs are attached to these n perimeter points. The other ends of the springs are attached to a data point.

The spring constant K i equals the values of the i-th coordinate of the fixed point. Each data point is then displayed where the sum of the spring forces equals 0.

All the data point values are usually normalized to have values between 0 and 1. For example if all n coordinates have the same value the data point will lie exactly in the center of the circle.

If the point is a unit vector then that point will lie exactly at the fixed point on the edge of the circle (where the spring for that dimension is fixed). Many points can map to the same position as in the Exvis displays [3]. This represents a non-linear transformation of the data which preserves certain symmetries and which produces an intuitive display.

Some features of this visualization include:points with approximately equal coordinate values will lie close to the centerpoints with similar values whose dimensions are opposite each other on the circle will lie near the centerpoints which have one or two coordinate values greater than the others lie closer to those dimensions An n-dimensional line will map to a line A sphere will map to an ellipse An n-dimensional plane maps to a bounded polygon Figure 1 Radviz 1000 exons (red) 1000 introns (green)Figure 1 displays 2000 points using Radviz: red points are exons and green points are introns.

Most points lie close to the center implying equal forces. However, introns lie closer to the center than exons. Figure 2 500 Introns - expanded X 10In Figure 2, 500 Introns are displayed, zoomed by a factor of 10 with the point size increased.

In this picture we discovered a ""symmetry"" of the data around a line drawn between dimensions c2 & g2 and a1 & t3. This mirror image is a consequence of the complementary pair nature of Fickett DNA sequences: consecutive lines of the sequences were the reverse of the previous lines. This symmetry needed to be corrected for some aspects of the data mining. Figure 3 2000 pts expanded 5 times Figure 3 displays 2000 points zoomed up by a factor of 5 .

In this picture we can see that the exons (red +) are more spread out, and the introns (green ) are closer to the center of the circle. Figure 4 Expanded X 8Figure 4 represents the same data with a zoom factor of 8 and larger points. Notice that zooming produces points well outside the circle which is not possible with real springs. The explanation for the spreading of exons is that they are not as random as introns. The random frequency distribution tends to make the forces balance, hence points closer to the center.

Radviz can effectively display many dimensions. Figures 5 and 6 show exons/introns using 16 dinucleotide dimensions and 48 dimensions of dinucleotides in 3 frames. Figure 5 16 dimensions (dinucleotides) Figure 6 48 dimensions (3 X 16 dinucleotides)3.2 Parallel Coordinates As a comparison with Radviz, we used the Parallel Coordinate implementation in Xmdv [16].

In Figure 7 Exons are highlighted in red and Introns are in green. Notice some spreading of Exons is still apparent.

Also notice the symmetry line can still be seen between c2 and g2 (ignoring the last dimension, used for brushing between exons and introns). Figure 7 Parallel Coordinates (100 pts)3.3 Sammon Plots Another interesting visualization is a Sammon plot [14]. We used Tooldiag to produce Figure 8. Figure 8 Sammon Plot (600 pts)The Sammon plot reduces dimensions by trying to preserve the distances between data points.

Notice there is some spreading of exons but that the exact symmetry is lost. Both Radviz and Parallel Coordinates let one see how individual dimensions affect the data. When using Sammon plots or other Multidimensional Scaling techniques like Kohonen nets, it is difficult to preserve any of the original dimensional information.4 Further Analysis The previous visualizations helped us cleanse the Fickett datasets by eliminating the redundancies. Additionally the outside/inside pattern of exons and introns from the visualizations also suggested a highly non-linear discriminating function was needed.

This would imply that more hidden nodes were needed in the Neural Net. The table below shows NN accuracy results from using 3000 exons and 3000 introns for training. The test data shown below (a and b are similar test sets) included over 7000 exons and 34000 introns from two of the Fickett test sets.5 hidden nodes 20 hidden nodes Exons - a 80.27% (3076) 80.27% (3076)Exons - b 76.95% (4178) 76.59% (4178)Introns -a 86.80% (17000) 87.64% (17000)Introns -b 86.58% (17000) 87.78% (17000)avg.

82.65 % 83.07%From the data, it is clear that increasing the hidden node numbers from 5 to 20, as the visualization suggested, resulted in more accurate prediction. These are promising results, showing that input coding, (the 12 extracted values), number of NN nodes, and Visualization are very important for successful Data Mining.5 Conclusion & Future directions This case study demonstrates the need for integrating multi-dimensional visualization tools with data mining tools.

Many packages provide standard scatter plots, and some have 3-d plots. However, reducing data to 2 or 3 dimensions from many is a difficult task (which dimensions to select) and one which always produces the feeling that something is missing (is the other dimension more important ?

). Analytic tools do help. Neural nets, classifying and clustering algorithms, are clearly powerful but they still need to be guided by human insight. However, when the only output of analytic results presented is a few numbers such as ""82% accuracy"", or some 500 line rule of nested if statements, the user is left stranded.

Does the user understand the rules? Can the user believe the accuracy? Thus, there is a need to integrate the analytic with the visual [5]. Such integration with intelligent visualizations which automatically map data dimensions to the ""best"" display parameters such as color, texture, or the coordinate systems will prove attractive [e.g., 13].

Acknowledgments This work is funded in part by a grant from Pfizer to the Center for Intelligent Biomaterials and the Institute for Visualization and Perception Research at the University of Massachusetts Lowell and Boston University's Center for Polymer Studies and the Department of Physics; and in part by a grant from the National Institute for Standards and Technology.

References [1] M. Ankerst, D. A. Keim, H. P. Kriegel Circle Segments: A Technique for Visually Exploring Large Multidimensional Data Sets, IEEE Visualizationí96 Proceedings, Hot Topic, San Francisco, CA, 1996.

[2] Clementine. http://www.isl.co.uk/clem.html [3] R Erbacher and G. Grinstein, Issues in the development of 3D Icons, Proceedings of the Fifth Eurographics Workshop on Visualization in Scientific Computing, Springer-Verlag Publishers, pp109-131, 1994. [4] J. W. Fickett and Chang-Shung Tung, Nucl. Acids Res. 20 (1992) 6441 [5] G. Grinstein (1996) Harnessing the Human in Knowledge Discovery , Proceedings of the second International Conference on Knowledge Discovery and Data Mining, August 1996, Portland, Simoudis, Han, and Fayyad (eds), pp384-385. [6] I. Grosse, K. Marx, S. Buldyrev, G. Grinstein, H. Herzel, P. Hoffman, A. Li, C. Meneses, and H. E. Stanley.

Data Mining of Large Gene Datasets Using the Mutual Information Function. to appear in Journal of Biomolecular Structure and Dynamics. [7] I. Grosse, H. Herzel, S. Buldyrev, and H. E Stanley, Mutual information of coding and noncoding DNA. To appear in Nature. [8] P. Hoffman. Radviz. http://www.cs.uml.edu/~phoffman/viz [9] K. A. Olsen, R. R. Korfhage, K. M. Sochats, M. B. Spring and J. G. Williams,Visualisation of a Document Collection: The VIBE System, Information Processing and Management, Vol. 29, No. 1, pp. 69-81, Pergamon Press Ltd, 1993. [10] J R. Quinlan. Induction of deciscion trees. In Machine learning, volume 1, pages 81-106. Kluwer Academic Publishers, 1986. [11] J. R. Quinlan, C4.5: Programs for Machine Learning, Morgan Kaufmann, 1993. [12] T. W. Rauber. Tooldiag. Universidade de Lisboa, Dept. of Electrical Engineering. http://www.uninova.pt/~tr/home/tooldiag.html [13] S. F. Roth. The SAGE Project. http://www.cs.cmu.edu/Web/Groups/sage/sage.html [14] J. W. Sammon, Jr. A nonlinear mapping for data structure analysis. IEEE Transactions on Computers, C-18 (5):401-409, May 1969. [15] (SNNS)http://www.informatik.uni-stuttgart.de/ipvr/bv/projekte/snns/snns.html [16] M. Ward, A. Martin, High Dimensional Brushing for Interactive Exploration of Multivariate Data. Visualization'95 , Atlanta, GA , 1995 [17] A. Zell, G. Mamier, M. Vogt, N. Mache A. Der Stuttgarter Neuronale Netze Simulator, in G. Dorffner, K. Möller, G. Paaß, S. Vogel (Hrsg. ): Konnektionismus und Neuronale Netze, GMD-Studien Nr. 272, Okt. 1995, pp. 335-350. "

YB-1 protein is involved in regulation of alternative splicing, a process by which one gene can provide the code for many different proteins. Genes are organized into portions that code for proteins (called exons) and intervening sequences (called introns).

Rett Gene Regulates Alternative Splicing

"Science News from research organizations Rett Gene Regulates Alternative Splicing Date: October 19, 2005Source: Baylor College of Medicine Summary: The gene responsible for Rett syndrome, a devastating neurological disease found mostly in girls, not only silences some genes but in combination with another also regulates alternative splicing, crucial to the formation of proteins said Baylor College of Medicine researchers in a report appearing online today in the Proceedings of the National Academy of Sciences.

Share: FULL STORYThe gene responsible for Rett syndrome, a devastating neurological disease found mostly in girls, not only silences some genes but in combination with another also regulates alternative splicing, crucial to the formation of proteins -- a finding that may explain the symptoms associated with this puzzling disorder and others related to it, said Baylor College of Medicine researchers in a report appearing online today in the Proceedings of the National Academy of Sciences.

The finding brings a new understanding to the ongoing process of unraveling the mystery behind why neurons work and do not work.

""There are multiple steps that a neuron goes through as it makes a decision to communicate with another neuron,"" said senior author Dr. Huda Y. Zoghbi, professor of pediatrics and human and molecular genetics at BCM as well as a Howard Hughes Medical Institute investigator. ""The neuron will express certain genes producing RNA, make certain proteins from these RNAs, and then carry some of these proteins to synapse. Alternative RNA splicing is one way for the cell to create many different forms of RNA and proteins from the same gene.

We are just beginning to learn the importance of alternative splicing in neuronal activity."" Zoghbi discovered the role of the gene methyl-Cp G binding protein 2 (Me CP2) in Rett. ""In fact, the effect of this protein (Me CP2) on RNA splicing is more noticeable than its effect on gene expression,"" she said.

Rett syndrome occurs in approximately 1 in 10,000 girls. As infants, those who have the disorder seem normal at birth and at least six months after. Between the ages of 6 and 18 months, however, their development stops and they begin to regress, losing the ability to talk. Then they begin to have problems walking and keeping their balance and develop typical hand-wringing behavior. Often they develop a curvature of the spine, difficulty in interacting with other people and mood disorders, among other problems.

At some point, the regression stops but they do not acquire new abilities. Scientists know that mutations in MECP2 are associated with these symptoms in Rett as well as other disorders such as autism and a variety of X-linked mental retardation syndromes as well.

Understanding how one gene could result in all these problems led Zoghbi and her team to take a new look at Me CP2, which was known to repress the expression of some genes. In studies involving cells and mice, they found that a protein called Y box-binding protein 1 or YB-1 binds to Me CP2 consistently.

Normally a cell pastes together the exons to generate the RNA that will be translated to a protein. In alternative splicing, the cell uses various combinations of exons to generate diverse sets of RNA and proteins.

That is the reason that fewer than 30,000 human genes are predicted to make more than 100,000 proteins. Loss of Me Cp2 function can cause dramatic changes in alternative splicing, said Zoghbi. In fact, these changes are more evident in a mouse model of Rett syndrome than than the expected gene expression changes given the known role of Me CP2 in regulating gene expression.

""When a gene level is increased or decreased by 20 to 40 percent, as has been found for some of the gene targets of this protein, you expect consequences,"" she said. ""When the gene makes a different protein, however, you can expect more severe consequences in the neuron.

""###Others who participated in this research include: Juan I. Young, Eugene P. Hong, John Castle, Aaron B.

Bowman, Matthew F. Rose, Dongcheul Kang, Ron Richman and Susan Berget, all of BCM, and Juan Crespo-Barreto and Jason Johnson of Rosetta Inpharmatics, LLC, Merck & Co. Funding for this work came form the Howard Hughes Medical Institute, Rett Syndrome Research Foundation, the National Institutes of Health, the Hereditary Disease Foundation and Cure Autism Now.

Story Source: Materials provided by Baylor College of Medicine. Note: Content may be edited for style and length. Cite This Page: MLA APA Chicago Baylor College of Medicine. ""Rett Gene Regulates Alternative Splicing."" Science Daily. Science Daily, 19 October 2005. <www.sciencedaily.com/releases/2005/10/051019002531.htm>. RELATED TOPICSHealth & Medicine Genes Human Biology Gene Therapy Birth Defects Medical Topics Diseases and Conditions Personalized Medicine Children's Healthadvertisement RELATED TERMSRett syndrome BRCA2Gene Alternative medicine BRCA1Huntington's disease Gene therapy Yoga (alternative medicine)RELATED STORIESSymptoms in Neurologic Disease Reversed in Model Jan. 29, 2018 — Rett syndrome is a devastating genetic, neurologic disorder that typically affects girls, resulting in severe disability and often accompanied by autistic behavior.

Most Rett patients will live into ... read more Scientists Uncover Possible Therapeutic Targets for Rare Autism Spectrum Disorder Jan. 31, 2017 — Researchers have uncovered 30 genes that could, one day, serve as therapeutic targets to reverse Rett syndrome, a rare neurological disorder that affects only girls and is a severe form of an autism ... read more New Studies Contradict Earlier Findings on Rett Syndrome May 20, 2015 — Bone marrow transplant does not rescue mouse models of Rett syndrome, a severe neurological disease that affects very young girls, a new study shows.

The findings contradict seemingly promising ... read more Rett Syndrome Protein Surrenders Some of Its Secrets June 17, 2013 — Discovery of a mutant gene responsible for a disease is a milestone, but for most conditions, it may be only a first step towards a treatment or cure. Understanding Rett Syndrome, an autism spectrum ... read more FROM AROUND THE WEBBelow are relevant articles that may interest you. Science Daily shares links and proceeds with scholarly publications in the Trend MD network. "

e. Premessenger RNA has a base sequence identical to the DNA coding strand. Genes consist of sequences encoding m RNA (exons) that are interrupted by non-coding sequences of variable length, called introns. Introns are removed and exons joined together before translation begins in a process called m RNA splicing.

DNA and RNA

DNA and RNA1. DNA1.1 DNA basics / structure DNA (deoxyribonucleic acid) is the genomic material in cells that contains the genetic information used in the development and functioning of all known living organisms. DNA, along with RNA and proteins, is one of the three major macromolecules that are essential for life. Most of the DNA is located in the nucleus, although a small amount can be found in mitochondria (mitochondrial DNA).

Within the nucleus of eukaryotic cells, DNA is organized into structures called chromosomes. The complete set of chromosomes in a cell makes up its genome; the human genome has approximately 3 billion base pairs of DNA arranged into 46 chromosomes. The information carried by DNA is held in the sequence of pieces of DNA called genes. DNA consists of two long polymers of simple units called nucleotides, with backbones made of sugars and phosphate groups joined by ester bonds.

These two strands run in opposite directions to each other and are therefore anti-parallel. Attached to each sugar is one of four types of molecules called nucleobases (bases). It is the sequence of these four bases along the backbone that encodes information. The sequence of these bases comprises the genetic code, which subsequently specifies the sequence of the amino acids within proteins.

The ends of DNA strands are called the 5′ (five prime) and 3′ (three prime) ends. The 5′ end has a terminal phosphate group and the 3′ end a terminal hydroxyl group. One of the major structural differences between DNA and RNA is the sugar, with the 2-deoxyribose in DNA being replaced by ribose in RNA.

The structure of DNABases are classified into two types: the purines, A and G, and the pyrimidines, the six-membered rings C, T and U. Uracil (U), takes the place of thymine in RNA and differs from thymine by lacking a methyl group on its ring.

Uracil is not usually found in DNA, occurring only as a breakdown product of cytosine. In the DNA double helix, each type of base on one strand normally interacts with just one type of base on the other strand.

This is complementary base pairing. Therefore, purines form hydrogen bonds to pyrimidines, with A bonding only to T, and C bonding only to G.1.2 The central dogma The central dogma of molecular biology is “DNA makes RNA makes protein.” This general rule emphasizes the order of events from transcription through translation and provides the basis for much of the genetic code research in the post double helix 1950s.

The central dogma is often expressed as the following: “DNA makes RNA, RNA makes proteins, proteins make us”.

Protein is never back translated to RNA or DNA. Furthermore, DNA is never translated directly to protein. The structure of DNASee also: The central dogma (external link).1.3 DNA replication Cell division is essential for cells to multiply and organisms to grow.

As the final step in the Central Dogma, DNA replication must occur in order to faithfully transmit genetic material to the progeny of any cell or organism. When a cell divides, it must correctly replicate the DNA in its genome so that the two daughter cells have the same genetic information as their parent.

The double-stranded structure of DNA provides a simple mechanism for DNA replication. The two strands are separated and then an enzyme called DNA polymerase recreates each strand’s complementary DNA sequence. This enzyme makes the complementary strand by finding the correct base through complementary base pairing.

As DNA polymerases can only extend a DNA strand in a 5′ to 3′ direction, different mechanisms are used to copy the antiparallel strands of the double helix. In this way, the base on the old strand dictates which base appears on the new strand, and the cell ends up with a perfect copy of its DNA.

This process typically takes place during S phase of the cell cycle.1.4 DNA transcription to RNAThe process by which DNA achieves its control of cell life and function through protein synthesis is called gene expression.

A gene is a DNA sequence that contains genetic information for one functional protein. Proteins are essential for the modulation and maintenance of cellular activities. The formation of new protein molecules is made from amino acid building blocks based on information encoded in DNA/RNA.

The amino acid sequence of each protein determines its conformation and properties (e.g. ability to interact with other molecules, enzymatic activity etc). Directed protein synthesis follows two major steps: gene transcription and transcript translation. Transcription is the process by which the genetic information stored in DNA is used to produce a complementary RNA strand. In more detail, the DNA base sequence is first copied into an RNA molecule, called premessenger RNA, by messenger RNA (m RNA) polymeras

Messenger RNA splicing has proved to be an important mechanism for greatly increasing the versatility and diversity of expression of a single gene. It takes place in the nucleus in eukaryotes and in the cytoplasm in bacteria and archaea and leads to the formation of mature m RNA.

Several different m RNA and protein products can arise from a single gene by selective inclusion or exclusion of individual exons from the mature m RNA products. This phenomenon is called alternative m RNA splicing. It permits a single gene to code for multiple m RNA and protein products with related but distinct structures and functions 1.

Once introns are excised from the final mature m RNA molecule, this is then exported to the cytoplasm through the nuclear pores where it binds to protein-RNA complexes called ribosomes 2. Ribosomes contain two subunits: the 60S subunit contains a single, large (28S) ribosomal RNA molecule complexed with multiple proteins, whereas the RNA component of the 40S subunit is a smaller (18S) ribosomal RNA molecule.

The structure of DNA1.5 Epigenetics Although every somatic cell in the human body contains the same genome, activation and silencing of specific genes in a cell-type-specific manner is necessary. Moreover, a cell must silence expression of genes specific to other cell types to ensure genomic stability. This type of repression must be maintained throughout the life of each cell in normal development.

Epigenetic modifications that are defined as heritable, yet reversible changes that influence the expression of certain genes but with no alteration in the primary DNA sequence are ideal for regulating these events.

The best studied epigenetic modification in human is DNA methylation, however it becomes increasingly acknowledged that DNA methylation does not work alone, but rather occurs in the context of other epigenetic modifications such as the histone modifications.

DNA methylation: DNA methylation consists of the addition of a methyl group to carbon 5 of the cytosine within the dinucleotide Cp G. Regions of DNA in the human genome, ranging from 0.5 to 5 kb, that are CG rich are called Cp G islands and are usually found in the promoters of genes.

Approximately half of all gene promoters have Cp G islands that when methylated lead to transcriptional silencing. De nove DNA methylation is brought about by DNA methyltransferases (DNMT) 3A and 3b whereas DNA methylation maintenance by DNMT1.

Aberrant DNA methylation patterns have been described in various human malignancies. In particular, global hupomethylation has been implicated in the earlier stages of carcinogenesis, whereas hypermethylation of tumour suppressor genes has been implicated in cancer progression 3. DNA hypomethylating agents are used for the treatment of certain haematological malignancies. Histone modifications: Histones are proteins around which DNA winds to form nucleosomes.

Nucleosome is the basic unit of DNA packaging within the nucleus and consists of 147 base pairs of genomic DNA wrapped twice around a highly conserved histone octamer, consisting of 2 copies each of the core histones H2A, H2B, H3 and H4. The histone tails may undergo many posttranslational chemical modifications, such as acetylation, methylation, phosphorylation, ubiquitylation, and sumoylation.

Combinations of these modifications are thought to constitute a code, named the “histone code”. Histone modifications act except for chromatin condention and transcriptional repression in various other biological processes including gene activation and DNA repair 4. Epigenetic Modifications2. RNARNA, is another macromolecule essential for all known forms of life.

Like DNA, RNA is made up of nucleotides. Once thought to play ancillary roles, RNAs are now understood to be among a cell’s key regulatory players where they catalyze biological reactions, control and modulate gene expression, sensing and communicating responses to cellular signals, etc. The chemical structure of RNA is very similar to that of DNA: each nucleotide consists of a nucleobase a ribose sugar, and a phosphate group.

There are two differences that distinguish DNA from RNA: (a) RNA contains the sugar ribose, while DNA contains the slightly different sugar deoxyribose (a type of ribose that lacks one oxygen atom), and (b) RNA has the nucleobase uracil while DNA contains thymine.

s Functional cysts Exon Skipping in development for DMDThe dystrophin gene is the largest gene in the body, consisting of 79 exons. Exons are small sequences of genetic code which, via an intermediate step involving RNA, lead to the assembly of sections...

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? Whole genome sequencing is different than gene sequencing. It is also different from whole exome sequencing which only looks at a person’s exons, the parts of DNA that code for proteins in the body. Researchers like this method because it is faster and cheaper.

What is whole genome sequencing?

What is whole genome sequencing?

Whole genome sequencing is the mapping out of a person’s unique DNA. Your genome is the unique blueprint for your body. Sometimes, because of new or inherited genetic mutations, your genes can cause a disease or increase your risk for disease.

By sequencing your genome, health professionals can look at the unique variations found in your genes.

Some of it matters. Some doesn’t matter. Some is still unknown or uncertain. It is most often used in medical research and is beginning to be used more in clinical practice. For example, a doctor or genetic counselor could use whole genome sequencing to see if a patient has a genetic disorder or is at risk for a disease. Did You Know

Instead of a deletion of DNA sequence that characterized the earlier disease discovery, the new condition is caused by a substitution of DNA in an exon of the gene. Exons are sub-parts of DNA sequence within a gene that carry the code for proteins. The alternate DNA sequence modifies the function of the enzyme.

NIH researchers discover gene alteration in rare autoinflammatory disease

"Home / Research at NHGRI / DIR News Features / NIH researchers discover gene alteration in rare autoinflammatory disease News Features from DIRNIH researchers discover gene alteration in rare autoinflammatory disease NIH researchers discover gene alteration in rare autoinflammatory disease By Raymond Mac Dougall Associate Director of Communications, Division of Intramural Research Researchers use a molecular structure model of PLCG2 to depict the substitution of DNA in the rare disorder APLAID.

The small blue element at the top-left of the structure on the left is substituted for the small red element shown in the PLCG2 structure model on the right.

Just 10 months after publishing a new disease discovery, researchers from the National Institutes of Health have repeated the achievement, bringing their attention back to the same gene. Both diseases cause ultra-rare autoinflammatory conditions, but because the gene is altered in different ways in each disorder, they present distinct symptoms.

The team includes researchers studying inflammatory diseases at the National Human Genome Research Institute (NHGRI) and collaborators at the Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases.

The newly identified rare condition is caused by an alteration in the gene that encodes phospholipase C-gamma2 ( PLCG2 ), an enzyme involved in the regulation of immune cells as well as inflammation and immune responses.

Researchers found the gene through whole-exome sequencing, a technique that focuses on the 1 to 2 percent of the human genome that code for proteins. Their report appeared in the Oct. 5, 2012, issue of the American Journal of Human Genetics. The earlier report appeared in the Jan. 11, 2012, issue of the New England Journal of Medicine.

""Advanced techniques in genetic analysis have enabled us to identify the causes of a number of autoinflammatory diseases and to recognize that they are not one large group,"" said Ivona Aksentijevich, senior author and staff scientist in NHGRI's Medical Genetics Branch. ""We expect that a better understanding of such conditions will ultimately help with development of more targeted therapies.

""The researchers discovered the distinct condition with remarkably few cases. A father and daughter are the only affected patients in this study. Each participated for more than 10 years, along with four unaffected family members, in an NIH clinical study directed by Daniel Kastner, M. D., Ph. D., co-author and NHGRI scientific director. Their symptoms include recurring blisters, joint pain, bronchial infection, eye and colon inflammation and mild immunodeficiency.

Until now, Dr. Kastner's clinical research team at NIH was unable to diagnose what caused the father and daughter's symptoms. Each of the patients exhibited a range of the symptoms that failed to respond to most conventional therapies.

The NHGRI team has studied genetics of inflammatory disorders for 20 years, even establishing the concept of autoinflammatory diseases. This class of diseases is caused by variants in one or more genes regulating innate immune responses, a type of immunity distinct from that acquired by prior exposure to pathogens.

People with autoinflammatory diseases suffer from lifelong recurrent episodes of systemic inflammation. Although disease-causing variants &mdash: versions of the genes with function-changing alterations — are identified in 12 genes responsible for various single-gene autoinflammatory diseases, more than 50 percent of patients with autoinflammatory symptoms are still undiagnosed.

The researchers call the new disorder APLAID, which is an abbreviation of the descriptive name, autoinflammation, PLCG2 -associated antibody deficiency and immune dysregulation.

They used part of the name in their earlier disease discovery, calling that condition PLAID. The DNA sequence substitution in APLAID leads to more pronounced symptoms of autoinflammation than experience by patients with PLAID. The most remarkable, among many physical distinctions, is that symptoms of PLAID are triggered by the cold unlike the symptoms of APLAID.

""Different alterations in the same gene may exhibit very different effects,"" said Qing Zhou, Ph. D., a co-author and postdoctoral fellow in NHGRI's Inflammatory Diseases Section. She noted that research on people with different alterations in PLCG2 shows the wide variability that can occur with mutations within a gene, especially differences in cell signaling that likely are tied to a broad range of diseases of the innate immune system.

The group continues research into the role in inflammation of PLCG2 as well as to discover genetic causes in patients with other autoinflammatory diseases. Posted: October 31, 2012 "

In some genes, not all of the DNA sequence is used to make protein. Introns are noncoding sections of an RNA transcript, or the DNA encoding it, that are spliced out before the RNA molecule is translated into a protein. The sections of DNA (or RNA) that code for proteins are called exons.

intron / introns

intron / introns

Following transcription, new, immature strands of messenger RNA, called pre-m RNA, may contain both introns and exons. The pre-m RNA molecule thus goes through a modification process in the nucleus called splicing during which the noncoding introns are cut out and only the coding exons remain.

Splicing produces a mature messenger RNA molecule that is then translated into a protein. Introns are also referred to as intervening sequences. Further Exploration Concept Links for further explorationgene | RNA | DNA | transcription | splicing | translation | exon

In humans, the gene CYP19, located on chromosome 15q 21.1, encodes the aromatase enzyme. [7] The gene has nine coding exons and a number of alternative non-coding first exons that regulate tissue specific expression.

Aromatase

"From Wikipedia, the free encyclopedianavigation search CYP19A1Available structures PDB Ortholog search: PDBe RCSB [ show] List of PDB id codes Identifiers Aliases CYP19A1, ARO, ARO1, CPV1, CYAR, CYP19, CYPXIX, P-450AROM, cytochrome P450 family 19 subfamily A member 1External IDs OMIM: 107910 MGI: 88587 Homolo Gene: 30955Gene Cards: CYP19A1 [ hide] Gene location (Human)Chr.

Chromosome 15 (human) [1]Band 15q21.2 Start 51,208,057 bp [1]End 51,338,610 bp [1] [ show] Gene location (Mouse) [ hide]RNA expression pattern More reference expression data [ show]Gene ontology Orthologs Species Human Mouse Entrez158813075Ensembl ENSG00000137869ENSMUSG00000032274Uni Prot P11511P28649Ref Seq (m RNA) [ show]NM_000103NM_001347248NM_001347249NM_001347250NM_001347251NM_007810NM_001348171NM_001348172NM_001348173Ref Seq (protein) [ show]NP_000094NP_001334177NP_001334178NP_001334179NP_001334180NP_001335100NP_001335101NP_001335102NP_031836Location (UCSC) Chr 15: 51.21 – 51.34 Mb Chr 9: 54.17 – 54.27 Mb Pub Med search [3] [4]Wikidata View/Edit Human View/Edit Mou

se Aromatase, also called estrogen synthetase or estrogen synthase, is an enzyme responsible for a key step in the biosynthesis of estrogens. It is CYP19A1, a member of the cytochrome P450 superfamily ( EC 1.14.14.1 ), which are monooxygenases that catalyze many reactions involved in steroidogenesis.

In particular, aromatase is responsible for the aromatization of androgens into estrogens. The aromatase enzyme can be found in many tissues including gonads ( granulosa cells ), brain, adipose tissue, placenta, blood vessels, skin, and bone, as well as in tissue of endometriosis, uterine fibroids, breast cancer, and endometrial cancer.

[ citation needed] It is an important factor in sexual development. Contents [ hide ]1 Function2 Genomics3 Activity4 Role in sex-determination5 Role in neuroprotection6 Disorders6.1 Aromatase excess syndrome6.2 Aromatase deficiency syndrome7 Inhibition of aromatase7.1 Pharmaceutical aromatase inhibitors8 See also9 References10 Further reading11 External links Function [ edit]Aromatase is localized in the endoplasmic reticulum where it is regulated by tissue-specific promoters that are in turn controlled by hormones, cytokines, and other factors.

It catalyzes the last steps of estrogen biosynthesis from androgens (specifically, it transforms androstenedione to estrone and testosterone to estradiol ). These steps include three successive hydroxylations of the 19-methyl group of androgens, followed by simultaneous elimination of the methyl group as formate and aromatization of the A-ring.

General reaction for the conversion of testosterone to estradiol catalyzed by aromatase. Steroids are composed of four fused rings (labeled A-D). Aromatase converts the ring labeled ""A"" into an aromatic state. Catalytic mechanism of aromatase. The methyl group is oxidized and subsequently eliminated. [5]Genomics [ edit]The gene expresses two transcript variants. [6]

. Each exon codes for a particular part of the protein that is about to be created. Ribosomes The workhouse of the cell - this is where the proteins are created. Genes are written in the language of DNA, but for proteins the language is amino acids. So the messenger RNA (which is initially formed as a complimentary strand to a sequence of DNA) has to be translated.

Ribonucleic Acid: Where is it Found in the Human Body?

Ribonucleic Acid: Where is it Found in the Human Body?written by: Paul Arnold •edited by: Paul Arnold •updated: 3/30/2009RNA is primarily a linear nucleic acid polymer.

Unlike DNA, it is not a double helix. The most common locations are in the cell nucleus, mitochondria and ribosomes. Function RNA, which stands for ribonucleic acid stores and transmits genetic information that is vital for the manufacture of protein

s. It carries this information from DNA, which is housed inside the cell nucleus, to the ribosomes. These can be found in the cytoplasm and are the 'factories' which make the proteins. Inside the nucleus RNA transcribes the genetic information by producing a complimentary nucleic acid strand - a copy of a DNA sequence. When it reaches the ribosomes the information is translated to produce a protein.

Where RNA is Found Cell Nucleus Here RNA comes into existence as the newly created messenger RNA (m RNA) molecules known as primary transcripts or pre-m RNA.

It undergoes some modification before being transported out into the cytoplasm. Modifications include 5' capping, 3' polyadenylation, and RNA splicing. Messenger RNA sequences that are not modified are assigned to the rubbish bin; they are degraded. RNA splicing is where non-coding sequences of DNA known as introns are removed.

For many years introns have been referred to as 'junk DNA' - this view is now changing, and they may have some use after all. Only the exons now remain after the spliceosome has gone to work

Citeintronnoun A segment of a gene situated between exons that is removed before translation of messenger RNA and does not function in coding for protein synthesis.

intron

intronin·tronan intervening sequence in the eukaryote genetic code, interrupting protein formation Origin of introncoined (1978) by W. Gilbert, United States molecular biologist from intra- (because within the gene) + -on, as in operon Webster's New World College Dictionary, Fifth Edition Copyright © 2014 by Houghton Mifflin Harcourt Publishing Company. All rights reserved. Link/

Origin of intronintr (agenic) occurring within a gene ( intra- ) ( genic ) -on 1THE AMERICAN HERITAGE® DICTIONARY OF THE ENGLISH LANGUAGE, FIFTH EDITION by the Editors of the American Heritage Dictionaries. Copyright © 2016, 2011 by Houghton Mifflin Harcourt Publishing Company. Published by Houghton Mifflin Harcourt Publishing Company.

All rights reserved. Link/Citeintron Noun ( plural introns) (genetics) A portion of a split gene that is included in pre- RNA transcripts but is removed during RNA processing and rapidly degraded. Origin From intr (agenic) + -on. English Wiktionary. Available under CC-BY-SA license. Link/Cite

ron A DNA segment of largely unknown function within a gene that specifically interupts the coding (exon) sequences of that gene; transcribed to precursor m RNA and and subsequently removed by a process called splicing during the processing to mature RNA

Transcription/Translation Bio Quiz

"46 terms 5thgrade1Transcription/Translation Bio Quiz Learn Flashcards Write Spell Test Match Gravity Advertisement Upgrade to remove ads Like this study set?

Create a free account to save it. Create a free account Maybe later Sorttranscription The synthesis of RNA using a DNA template (general term)initiation (transcription) the binding of RNA polymerase to the promoter in DNA; before this, DNA is unwoundpromoter A region of DNA to which RNA polymerase binds in order to initiate transcriptiontranscription factor a protein that binds to specific DNA sequences, thereby controlling the movement (or transcription) of genetic information from DNA to m RNA; contain one or more DNA-binding domains (DBDs), which attach to specific sequences of DNA adjacent to the genes that they regulateelongation (transcription) RNA polymerase traverses the template strand and uses base pairing complementarity with the DNA template to create an RNA copy5' to 3' during elongation in transcription, this is the direction which the RNA copy is made from the DNA template RNA polymerase The enzyme that polymerizes RNA by using DNA as a templatetranscription unit segment of DNA where transcription occurs, begins with start point and ends with termination pointtermination in transcription, required to release the newly made RNA from the transcription complexterminator section of genetic sequence that marks the end of gene on DNA for transcriptiontermination point the exact point on a transcription unit where transcription endssense strand strand that does not code for RNAantisense strand codes for the RNA that is translated into proteinpre-m RNA immature single strand of RNA; synthesized from a DNA template in the cell nucleus by transcription; comprises the bulk of heterogeneous nuclear RNAleader The sequence at the 5' end of an m RNA that is not translated into protein.

sequence at the 5′ end, preceding the initiation codon (untranslated)trailer sequence following the termination codon, at the 3′ end (RNA untranslated)int

exon A region of a gene that is present in the final functional transcript (m RNA) from that genesn RPs RNA-protein complexes that combine with unmodified pre-m RNA and various other proteins to form a spliceosome, a large RNA-protein molecular complex upon which splicing of pre-m RNA occurs; essential to the removal of introns from pre-m RNAspliceosome complex of specialized RNA and protein subunits that removes introns from a transcribed pre-m RNA (hn RNA) segment5' cap specially altered nucleotide on the 5' end of precursor messenger RNA; vital to creating mature messenger RNA, which is then able to undergo translation; ensures stabilitypoly A tail a stretch of RNA which only has Adenine basesm RNA molecule of RNA encoding a chemical ""blueprint"" for a protein product.

(general)start codon A group of three adjacent nucleotides that initiates polypeptide formation, specifically RNAredundancy describing that most amino acids have multiple codons Genetic Code The linear correspondence between nucleotide triplets in DNA and amino acids in proteintranslation The process of protein synthesis whereby the primary structure of the protein is determined by the nucleotide sequence in m RNAtranslocation part of the translation process in which the m RNA is shifted one codon in relation to the ribosomecodon A sequence of three RNA or DNA nucleotides that specifies (codes for) either an amino acid or the termination of translation (general)t RNA Small RNA molecules that carry amino acids to the ribosome for polymerization into a polypeptide; During translation the amino acid is inserted into the growing polypeptide chain when the anticodon of the ( ) pairs with a codon on the m RNA being translated.amino acid Containing a basic amino and side chain, building block of protein CCA tail cytosine-cytosine-adenine sequence at the 3' end of the t RNA molecule.

This sequence is important for the recognition of t RNA by enzymes critical in translationamino acid binding site located at the 3' end of a t RNA moleculet RNA-activating enzyme enzyme which binds specific amino acid to t RNA; they are aminoacyl-activating enzymesaminoacyl-t RNA synthesase enzyme that attaches an amino acid to its cognate t RNAanticodon A nucleotide triplet in a t RNA molecule that aligns with a particular codon in m RNA under the influence of the ribosome, so that the amino acid carried by the t RNA is added to a growing protein chainribosome A complex organelle (composed of proteins plus r RNA) that catalyzes translation of messenger RNA into an amino acid sequence; made up of two subunitsr RNA The RNA molecules which are essential structural and functional components of ribosomes, the organelles responsible for protein synthesisribosomal protein any of the proteins that, in conjunction with r RNA, make up the ribosomal subunits involved in the cellular process of translationnucleolus r RNA is transcribed and assembled heresmall ribosomal subunit this ribosomal subunit binds to the m RNAm RNA binding site The region of an m RNA molecule that binds the ribosome to initiate translationelongation (translation) begins by the appropriate aminoacyl-t RNA binding to the codon in the A site of the ribosome.large ribosomal subunit this ribosomal subunit is summoned by the other subunit APE sites three RNA binding sitespolysome The configuration of several ribosomes simultaneously translating the same m RNAAdvertisement Upgrade to remove ads Features Quizlet Live Quizlet Learn Diagrams Flashcards Mobile Help Sign up Help Center Honor Code Community Guidelines Students Teachers About Company Press Jobs Privacy Terms Follow us Language© 2018 Quizlet Inc. "

ly. Alternative splicing (AS) therefore is a process by which exons or portions of exons or noncoding regions within a pre-m RNA transcript are differentially joined or skipped, resulting in multiple protein isoforms being encoded by a single gene.

What is Alternative Splicing, and Why is it Important?

What is Alternative Splicing, and Why is it Important? By Yevgeniy Grigoryev Genetic information of an organism is stored in the genes, the functional subunits of the genome, arranged in the strands of the DNA double helix in the nucleus.

This information is transcribed from DNA into a messenger RNA (m RNA) template by a process called transcription. However, in eukaryotes, before the m RNA can be translated into proteins, non-coding portions of the sequence, called introns, must be removed and protein-coding parts, called exons, joined by RNA splicing to produce a mature m RNA.

The discovery of alternative splicing RNA splicing was first discovered in 1970s in viruses and subsequently in eukaryotes. Not long after, scientists discovered alternative patterns of pre-m RNA splicing that produced different mature m RNAs containing various combinations of exons from a single precursor m RNA.

The first example of alternative splicing of a cellular gene in eukaryotes was identified in the Ig M gene, a member of the immunoglobulin superfami

This mechanism increases the informational diversity and functional capacity of a gene during post-transcriptional processing and provides an opportunity for gene regulation ( Figure 1 ). Figure 1. Alternative Splicing generates transcriptome diversity and provides an opportunity for gene regulation. Alternative splicing can generate m RNAs encoding proteins with different, even opposite functions.

Figure used by permission. *Alternative splicing generates a tremendous amount of proteomic diversity in humans and significantly affects various functions in cellular processes, tissue specificity, developmental states, and disease conditions. The mechanism of alternative splicing During alternative splicing, cis-acting regulatory elements in the m RNA sequence determine which exons are retained and which exons are spliced out.

These cis-acting regulatory elements alter splicing by binding different trans-acting protein factors, such as SR (Serine-Arginine rich) proteins that function as splicing facilitators, and heterogeneous nuclear ribonucleoproteins (hn RNPs) that suppress splicing. Inhibition of silencing could be achieved sterically, when binding of splicing inhibitors to splicing silencers located in close proximity to splicing enhancers blocks the binding of sn RNPs and other activator proteins or prevents the spliceosome assembly.

The final decision to include or splice an alternative exon is thus determined by combinatorial effects, cellular abundance, and competitive binding between SR activators and hn RNP inhibitors.

The outcome of alternative splicing depends on the stoichiometry and interactions of splicing activators and inhibitors as well as the steric conformation and accessibility of the splicing sites. The importance of alternative splicing It is thought that at least 75% of roughly 30,000 human genes undergo alternative splicing to encode two or more splice isoforms, with striking variation across tissue types and developmental stages.

Recent advances in high-throughput technologies have facilitated studies of genome-wide alternative splicing. These studies estimate that greater than 95% of human multi-exon genes express multiple splice isoforms. Furthermore, there is evidence for alternatively splicing events that are often differentially regulated across tissues and during development, as well as among individuals and populations, suggesting that individual isoforms may serve specific spatial or temporal roles.

Alternative splicing is known to be involved in the regulation of normal physiological functions as well as pathologies.

For example, a number of alternatively spliced genes in immunity are known. Studies indicate that alternative splicing of CD44, a protein involved in T cell homing with 10 variable cassette exons and six distinct protein isoforms, is crucial for T cell function. The variable exons of CD44 all encode portions of the membrane-proximal extracellular domain of the protein, and the presence of some of the variable exons has been shown to increase the association of CD44 with various proteins.

Isoform expression has been shown to be activation dependent, such that the naive T cells mainly express the smallest CD44 isoform that lacks all variable exons, whereas activated T cells express multiple CD44 isoforms, indicating that CD44 alternative splicing is important for activation.

While these examples demonstrate the utility of alternative splicing in humans, the scope and exact role of this regulatory mechanism still remains to be investigated on a genome-wide scale. Current technological advances suggest that alternative splicing is more widespread than initially thought and is likely to be involved in a number of human pathologies. Stay tuned for the next article in this series, when we’ll talk about what alternative splicing means for your experiments. * “Post-transcriptional mechanisms of gene regulation and information control in immunity”, by Grigoryev, Yevgeniy A., Ph. D., THE SCRIPPS RESEARCH INSTITUTE, 2011, 282 pages; 3488985, http://gradworks.umi. com/34/88/3488985.html Share 8 Tweet Share 19 +1

sm. These arguments lead to the conclusion that the vast majority of cellular DNA isn't functional. Genes that are expressed usually have introns that interrupt the coding sequences. A typical eukaryotic gene, therefore, consists of a set of sequences that appear in mature m RNA (called exons) interrupted by introns. The regions between genes are likewise not expressed, but may help with chromatin assembly, contain promoters, and so forth. See Figure 1.

Eukaryotic Gene Structure

Eukaryotic Gene Structure Although humans contain a thousand times more DNA than do bacteria, the best estimates are that humans have only about 20 times more genes than do the bacteria.

This means that the vast majority of eukaryotic DNA is apparently nonfunctional. This seems like a contradiction. Why wouldn't more complicated organisms have more DNA? However, the DNA content of an organism doesn't correlate well with the complexity of an organism—the most DNA per cell occurs in a fly species.

Other arguments suggest that a maximal number of genes in an organism may exist because too many genes means too many opportunities for mutations. Current estimates say that humans have about 100,000 separate m RNAs, which means about 100,000 expressed genes. This number is still lower than the capacity of the unique DNA fraction in an organi

Figure 1Intron sequences contain some common features. Most introns begin with the sequence GT (GU in RNA) and end with the sequence AG.

Otherwise, very little similarity exists among them. Intron sequences may be large relative to coding sequences; in some genes, over 90 percent of the sequence between the 5′ and 3′ ends of the m RNA is introns.

RNA polymerase transcribes intron sequences. This means that eukaryotic m RNA precursors must be processed to remove introns as well as to add the caps at the 5′ end and polyadenylic acid (poly A) sequences at the 3′ end. Eukaryotic genes may be clustered (for example, genes for a metabolic pathway may occur on the same region of a chromosome) but are independently controlled.

Operons or polycistronic m RNAs do not exist in eukaryotes. This contrasts with prokaryotic genes, where a single control gene often acts on a whole cluster (for example, lac I controls the synthesis of β‐galactosidase, permease, and acetylase).

One well‐studied example of a clustered gene system is the mammalian globin genes. Globins are the protein components of hemoglobin. In mammals, specialized globins exist that are expressed in embryonic or fetal circulation. These have a higher oxygen affinity than adult hemoglobins and thus serve to “capture” oxygen at the placenta, moving it from the maternal circulation to that of the developing embryo or fetus.

After birth, the familiar mature hemoglobin (which consists of two alpha and two beta subunits) replaces these globins.

Two globin clusters exist in humans: the alpha cluster on chromosome 16, and the beta cluster on chromosome 11, as shown in Figure 2. Figure 2These clusters, and the gene for the related protein myoglobin, probably arose by duplication of a primoridial gene that encoded a single heme‐containing, oxygen‐binding protein.

Within each cluster is a gene designated with the Greek letter Ψ. These are pseudogenes —DNA sequences related to a functional gene but containing one or more mutations so that it isn't expressed. The information problem of eukaryotic gene expression therefore consists of several components: gene recognition, gene transcription, and m RNA processing. These problems have been approached biochemically by analyzing the enzyme systems involved in each step.

y? RNA splicing is the cutting out of the introns from the m RNA strand that was transcribed & putting back together of exons to be translated. It is necessary so the cell is more efficient by removing unnecessary coding

Biology

34 terms joepeso02Biology Learn Flashcards Write Spell Test Match Gravity Advertisement Upgrade to remove ads Like this study set? Create a free account to save it. Create a free account Maybe later Sort1. Where do genetic differences between organisms originate? Mutations2. How is a mutation different from a mutagen? Mutagens are the substances that cause mutations or changes in the genetic material What are the three possible outcomes of a mutation?

beneficial, harmful, no effect What is a point mutation? Change in a single nucleotide. What are the two types of frameshift mutations? Insert mutations and deletion mutations Are all mutations inheritable? No, only if the mutations occur in gametes What is the difference between a silent mutation, a missense mutation, a nonsense mutation, and a frameshift mutation?

Silent mutations - are caused by a point mutation & have no effect of the function because they code for the same amino acid Missense mutations - are caused by a point mutation & result in a different amino acid to be placed in the protein Nonsense mutations - a caused by a point mutation & cause a stop where there should not be one Frameshift mutations - are caused by an insertion or deletion of a nucleotide causing the reading frame to shift & the protein to be too long or too short How is a chromosomal deletion different from a chromosomal duplication?

Chromosomal deletion - a piece of chromosome is lost Chromosomal duplication - a piece of chromosome remains attached to its original chromosome & then caries both genes What is the difference between an inversion and a translocation?

Inversion - a piece of chromosome reattaches in the reverse direction Translocation - a piece of chromosome ends up on a non-homologous chromosome How is a nondisjuction different from a polyploidy? How is it the same? give an example of each? Nondisjunction- differences: happen when a homologous pair or sister chromatids do not separate properly Example - Down's Syndrome (Trisomy 21) Polyploidy - differences: happens when all chromosomes fail to separate Example - plants Similarities - both involve failure to separate during meiosis What is the cause of down syndrome?

Nondisjunction of the 21st chromosome Trisomy 21What is gene regulation and why is it important? the system in place that controls which genes are expressed and when it's important so not all genes are expressed at the same time What role does genetics play in gene expression? Tells the cell when to turn on and off a certain gene List and describe the sequence that occurse when your body takes in lactose.

1. You drink milk 2. lac operon turns on 3. The gene is expressed for the protein that digests lactose 4. When no lactose is present the lac operon turns off. How is gene expression different in prokaryotes and eukaryotes? Prokaryotes_ Simple and regulated by operons Eukaryotes- more complex with 3 stages What are transcription factors? Proteins that are involved in gene regulation in eukaryotes Activator-turns on RNa polymerase Reprossers- turnokk RNa polymerase What are operons? Segments of DNA that controls gene expression in prokaryotic cells What is RNA splicing? Why is it neccesar

What is the difference between an intron and an exon? Introns are segments of DNA that do not code of any specific amino acid they stay in the nucleus Exons are segments of DNA that do code for amino acids (protein) & leave the nucleus to be translated What is a genome? How is it measured? Genome- all the DNA that an organisn or species has. It is measured as amount of DNA or the number of genes Why do scientists study genomes?

To compare organisms and see their relatedness Why is the genetic code said to be universal? It is the same in all organisms except bacteria Give three expample of DNA that is not a part of a gene or a chromosome. Plasmids-small, round segments that can be replicated and transferred Introns-noncoding DNA segments Cell Organelles- have their own genome for specific functions (mitochondria and chloroplasts)Describe the endosymbiotic theory.

Which two organisms does it apply to? Organelles originated from bacteria (prokaryotes) & were engulfed by larger cells that did not break them down. Explains Mitochondria & chloroplasts having their own genome6. What does MGE stand for? What are they? Mobile Genetic Elements - they are units of DNA or RNA that are not part of the genome & can moved/transposed as a functional unit7.

Give three examples of MGEs and describe each. Plasmids - small round segments that can be replicated & transferred between cells Transposons - jumping genes, transposed randomly causing a gene to become inactive Viruses - small nonliving particles that consist of DNA/RNA inside a protein coating & infect host8.

What is the cause of antibiotic resistance? Bacteria plasmids transposing & changing the bacteria so it does not respond to the antibiotics because of overuse9. What is cell differentiation? Cells are modified & specialized as they multiply to form a body & is caused by different genes being expressed10. What are homeotic genes? What is a homeobox? Homeotic genes - genes that regulate cell differentiation of cells. Homeobox - is part of homeotic gene that codes for a DNA binding domain11. What is a hox gene? What if it was mutated?

The hox gene direct development relative to body position. If it is mutated body parts will develop where they are not suppose too.12.

Which two proteins control the cell cycle? CDK - regulates the speed of the cell cycle Cyclin - regulates the movement from 1 stage to the next13. What can occur of the cell cycle is not properly regulated? Cancer14. What is apoptosis? Why is this an important function?

Programmed cell death. This is important because it kills unhealthy cells15. What are telomeres? What happens to them as an organism ages? Noncoding ends of the chromosomes. As the organisms ages they are broken off are lost & chromosomes get shorter. Advertisement Upgrade to remove ads Features Quizlet Live Quizlet Learn Diagrams Flashcards Mobile Help Sign up Help Center Honor Code Community Guidelines Students Teachers About Company Press Jobs Privacy Terms Follow us Language© 2018 Quizlet Inc.

it. The transcription unit contains both introns and exons, which are coded into RNA by the enzyme RNA polymerase. After the m RNA strand has been produced, and before it is translated into a protein, the introns are removed from the RNA.

What Is a Transcription Unit?

"Transcription is a process that occurs in all living cells. During transcription, strands of RNA are created based on the DNA found within the cells. When a strand of messenger RNA (m RNA) is created, it is then used to produce proteins during translation. A whole strand of DNA is not usually transcribed into m RNA, but instead specific sections of the DNA are, which are called transcription units.

Throughout the strands of DNA found within cells, there are sequences of nucleotides that code for starts and stops. The enzymes that carry out transcription use these codes to begin and end producing RNA strands. A transcription unit is the chain of nucleotides in a strand of DNA that begins at a start code and continues to the end code.

When referring to the stretch of DNA that is transcribed into RNA, many scientists use the term ""transcription unit"" rather than ""gene.""

This change in terminology has come about because research has shown that the DNA that is transcribed contains a lot of extra nucleotides that are not used to form the protein. The sections of DNA that are not used to code a protein are called introns and the sections that do code for the protein are called exons. Ad Often, there are many more non-coding introns found within a strand of DNA than there are exons.

A gene is the term used to describe the sequence of DNA nucleotides that codes for a protein. It was thought that it was continuous, but research has shown that genes are not continuous strands but are broken up into exons throughout the DNA transcription un

Splicing cuts the introns from the strand of m RNA and then joins the remaining pieces together to form the final strand that will be used for translation. The final strand of m RNA that is created after splicing has occurred may not always be the same. Alternative splicing refers to the fact that the same introns can be removed from a strand of m RNA, but the exons can join together in different ways.

This means that a single transcription unit can in fact code for different proteins, due to the fact that the final sequence of the m RNA strand can be different based on what exons are joined together and in what order.

Ad You might also Like Recommended Related wise GEEK Articles What Is the Transcription Process? What Is Eukaryotic Transcription?

What Is the Role of DNA in Protein Synthesis? What is Transcriptional Regulation? What is the Relationship Between DNA and RNA? What are the Different Genetics Jobs? What is Genetic Research? Ad Discuss this Article Post your comments Post Anonymously Loginusernamepasswordforgot password? Registerusernamepasswordconfirmemail "

ome The sum total of the exons in a genome, which comprise about 1% of human DNA. The exome is regarded as the most functionally relevant DNA, as it encodes proteins and geneproducts.

exome

Correct all you're your grammar errors instantly. Try it now.exome Also found in: Dictionary, Wikipedia .exome (ĕk′sōm′)n. The complete set of protein-coding sequences (exons) of a genome. The American Heritage® Medical Dictionary Copyright © 2007, 2004 by Houghton Mifflin Company. Published by Houghton Mifflin Company. All rights reserved.ex

Segen's Medical Dictionary. © 2012 Farlex, Inc. All rights reserved.exome (ek′sōm″) [ ex (on) + -ome] All of the exons in the DNA of an organism.

It is all of the DNA sequences that are transcribed intoproteins, not including introns. Medical Dictionary, © 2009 Farlex and Partners Want to thank TFD for its existence? Tell a friend about us, add a link to this page, or visit the webmaster's page for free fun content .

Link to this page: Facebook Twitter Finally, Farlex brings you all the rules of English grammar, all in one place, explained in simple terms. The Farlex Grammar Bookis available now in paperback and e Book formats.

Eukaryotic genes are split up into parts that are expressed as RNA products and parts that are not. The parts that are expressed are called exons. They appear in short sequences scattered throughout the gene. Exons are the parts of a eukaryotic gene that are expressed through transcription and translation.

Instructor: April Koch April teaches high school science and holds a master's degree in education. In this lesson, we'll explore the unique considerations for gene regulation in the eukaryotic cell.

After all, we humans don't have operons. Humans, remember, are eukaryotes. Unlike the prokaryotic bacteria, eukaryotes don't have clusters of related genes.

Our genes are scattered throughout the genome over multiple chromosomes. Also, our cells contain a nucleus, meaning that we have to perform transcription and translation separately. Transcription has to happen in the nucleus, but translation must occur in the cytoplasm. So, unlike prokaryotes, eukaryotes undergo an RNA processing step right after transcription and before translation.

RNA processing is a challenge that's unique to eukaryotes because only eukaryotic cells have a nucleus. In this lesson, we'll walk through the most important aspects of RNA processing. Introns and Exons

You can think of them like the 'meat' of the gene; they're typically considered the actual coding regions that specify our proteins.

In between all the exons lie the other segments, called introns. Introns are the intervening sequences that are removed from a gene before the RNA product is made. Introns and exons alternate with each other along the length of a gene. Introns are usually considered non-coding regions because they don't seem to code for any enzymes or structural proteins.

However, scientists are still learning about the importance of introns. One thing we do know is that introns are removed from an RNA sequence right after transcription. They exist in DNA, they're transcribed into RNA, but then they're taken out before the RNA has a chance to make any products. Introns are removed from the RNA sequence after transcription RNA Splicing and Spliceosomes So, exons hold the important coding regions of our genes, and introns aren't much more than extra fluff.

How do we get hold of only the good stuff? How do we separate the wheat from the cha

ff? The RNA strand is processed so that its introns are removed and the exons are pushed together to make a continuous, shorter strand. This process is called RNA splicing. It produces a 'final draft' of the m RNA before translation gets under way.

s”Type of:cistron, factor, gene (genetics) a segment of DNA that is involved in producing a polypeptide chain; it can include regions preceding and following the coding DNA as well as introns between the exons; it is considered a unit of heredity

dominant gene

dominant gene Thesaurus Definitions of dominant gene1n gene that produces the same phenotype in the organism whether or not its allele identical“the dominant gene for brown eye

Word Family Usage Examples

"cistron, gene, factor - (genetics) a segment of DNA that is involved in producing a polypeptide chain; it can include regions preceding and following the coding DNA as well as introns between the exons; it is considered a unit of heredity; ""genes were formerlycalled factors"

dominant gene

"dominant gene Also found in: Thesaurus, Medical, Encyclopedia, Wikipedia . Thesaurus Antonyms Related Words Synonyms Legend: Switch to new thesaurus Noun 1. dominant gene - gene that produces the same phenotype in theorganism whether or not its allele identical; ""the dominant gene for brown eyes"

"Based on Word Net 3.0, Farlex clipart collection. © 2003-2012 Princeton University, Farlex Inc. Want to thank TFD for its existence? Tell a friend about us, add a link to this page, or visit the webmaster's page for free fun content . Link to this page: Facebook Twitter "

Also, with regards to ""B"", whether or not the gene coding for a protein has introns or not is pretty much irrelevant to the strength of an amino acid based phylogenetic tree, since only the exons (coding regions) are reflected in the AA sequence anyway.

What do phylogenetic trees represent?

"Science & Mathematics Botany What do phylogenetic trees represent? A) anatomical similarity B) the pattern of continental drift C)the evolutionary relationships among organisms D) the degree of similarity in the habitats occupied by different organisms E)None of the above Which E is not the answer so it's A-D Please help. Follow 2 answers Answers Relevance Rating Newest Oldest Best Answer: C. They are showing how organisms are related one to another.

They are developed mainly by examining similarities in morphology and function but this has become enhanced in recent years by the used of genetic mapping. Some species originally though to be closely related are found to be actually more distant based on what we now know about rates of genetic change. Other species have been found to be more closely related by the same token even though outward appearances show them to be quite different.

Even though answer A) may seem to be correct, many organisms have very similar body structures due to evolutionary convergence. A big example here is the structure of the eyes of cephalopods (octopus and squid) and vertebrates (fish, amphibians, lizards, birds, mammals). Their eyes are VERY similar but there is no way that these two groups are closely related. Source (s): Biology degree and study.

Rick K · 9 years ago2 0 Comment Asker's rating For the best answers, search on this site https://shorturl.im/av IX7 I would say D. Both A and B are a similar line of reasoning, that is how many mutations have occurred in sequences derived from the same ancestral sequence over time.

Depending on the gene mutation rate, and how distant the taxonomic relationships examined the strength of the resulting tree will vary. However, as with any hypothesis, being able to support it with multiple, independent lines of evidence provides the strongest support for the hypothesis.

? · 2 years ago0 0 Comment This Site Might Help You. RE: What do phylogenetic trees represent? A) anatomical similarity B) the pattern of continental drift C)the evolutionary relationships among organisms D) the degree of similarity in the habitats occupied by different organisms E)None of the above Which E is not the answer so it's A-D Please help.

Source (s):phylogenetic trees represent: https://bitly.im/QU2Nt Mariel · 3 years ago0 0 Commentb. they are based on amino acid sequences from homologous proteins, as long as the genes that code for such proteins contain no introns.

Linda · 2 years ago0 0 Comment Maybe you would like to learn more about one of these? Portfolio Management Options Time for a Caribbean cruise? Get a Master's Degreee Online Need debt consolidation loans? "

How Spliceosomes Process RNAWhat is the purpose of introns? DNA is composed of sections known as exons and introns. The exons are the portions that eventually exit the nucleus in the form of m RNA and are used in translation. The introns are removed from the m RNA shortly after transcription. There are a number of hypotheses about the function of introns.

Biology, Eighth Edition (Raven)

Biology, Eighth Edition (Raven)Chapter 15: Genes and How They Work

One hypothesis is that alternative splicing may allow a single gene to code for more than one version of a protein.

In other words a piece of the gene may be an intron in one case and an exon in another case. Another possible explanation is that each exon codes for a module of a protein. Spatially separating the exons may allow for the evolution of proteins by removing, adding, or replacing entire modules.

View the animation below, then complete the quiz to test your knowledge of the concept.1. The sn RNPs are also called A) smurfs. B) snurps. C) snores. D) snippets. E) splits.2. Which of the following do sn RNPs bind to? A) exon only B) exon and the 5' end of the intron C) 5' end of the intron only D) 3' end of the intron only E) 5' and 3' ends of the intron3.

Which of the following statements about RNA splicing is FALSE? A) it removes the introns B) it is performed by the spliceosome C) it shortens the RNA molecule D) it always occurs in the nucleus E) all of the above statements are true4. The cutting out of the intron involves the formation of a loop in the m RNA. A) True B) False5. Only a few eukaryotic genes contain introns. A) True B) False

ent Genes contain exons which are regions coding for proteins and which are interrupted by the unused sequences called introns. Exons have been found to include both sequences coding for amino acids and untranslated sequences. The introns are removed and the exons are joined together to form the final functional m RNA.

Exon

Exonnavigation search Definitionnoun, plural: exons (molecular biology)1. The protein -coding region in the DNA .2. The nucleic acid sequence in the DNA, or RNA transcript following genetic splicing . Supplem

Related forms: exonic ( adjective ). Compare: intron . See also: DNA, RNA, translation, m RNA, protein synthesis . User Contributions / Comme

nts: The base sequences that appear in eukaryotic DNA and are used to make m RNA for a specific protein are the exons of a gene.

For the first estimate, the average protein contains a few hundred amino acids and each amino acid requires three nucleotides of code, so the average gene would take up about 1,000 nucleotides of exon space (an exon is the protein-coding part of a gene).

Mutations: evolutionâs engine becomes evolutionâs end!

This article is from Journal of Creation 22 (2) :60–66—August 2008 Browse our latest digital issue Subscribe Mutations: evolution’s engine becomes evolution’s end!by Alex Williams In neo-Darwinian theory, mutations are uniquely biological events that provide the engine of natural variation for all the diversity of life. However, recent discoveries show that mutation is the purely physical result of the universal mechanical damage that interferes with all molecular machinery. Life’s error correction, avoidance and repair mechanisms themselves suffer the same damage and decay.

The consequence is that all multicellular life on earth is undergoing inexorable genome decay. Mutation rates are so high that they are clearly evident within a single human lifetime, and all individuals suffer, so natural selection is powerless to weed them out. The effects are mostly so small that natural selection cannot ‘see’ them anyway, even if it could remove their carriers. Our reproductive cells are not immune, as previously thought, but are just as prone to damage as our body cells.

Irrespective of whether creationists or evolutionists do the calculations, somewhere between a few thousand and a few million mutations are enough to drive a human lineage to extinction, and this is likely to occur over a time scale of only tens to hundreds of thousands of years.

This is far short of the supposed evolutionary time scales. Mutations destroy Photo stock.xchng Ever since Hugo de Vries discovered mutations in the 1890s they have been given a central role in evolutionary theory.

De Vries was so enamoured with mutations that he developed an anti-Darwinian saltationist theory of evolution via mutation alone. 1 But as more became known, mutations of large effect were found to be universally lethal, so only mutations of small effect could be credibly considered as of value to evolution, and de Vries’ saltationist theory waned.

When the Neo-Darwinian Synthesis emerged in the 1930s and 1940s, mutations were said to provide the natural variations that natural selection worked on to produce all new forms of life. However, directly contradicting mutation’s central role in life’s diversity, we have seen growing experimental evidence that mutations destroy life. In medical circles, mutations are universally regarded as deleterious. They are a fundamental cause of ageing, 2, 3 cancer 4, 5 and infectious diseases.

6Even among evolutionary apologists who search for examples of mutations that are beneficial, the best they can do is to cite damaging mutations that have beneficial side effects (e.g.

sickle-cell trait, 7 a 32-base-pair deletion in a human chromosome that confers HIV resistance to homozygotes and delays AIDS onset in heterozygotes, 8 CCR5–delta32 mutation, 9 animal melanism, 10 and stickleback pelvic spine suppression 11 ).

Such results are not at all surprising in the light of the discovery that DNA undergoes up to a million damage and repair events per cell per day. 12Mutation physics Neo-Darwinian theory represents mutations as uniquely biological events that constitute the ‘engine’ of biological variation. However, now that we can see life working in molecular detail, it becomes obvious that mutations are not uniquely biological events—they are purely physical events.

All multi-cellular life on earth is undergoing inexorable genome decay because the deleterious mutation rates are so high … and natural selection is ineffective in removing the damage. Life works via the constant (often lightning-fast) movement of molecular machinery in cells. Cells are totally filled with solids and liquids—there are no free spaces. The molecular machines and the cell architecture and internal structures are made up of long-chain organic polymers (e.g.

proteins, DNA, RNA, carbohydrates, lipids) while the liquid is mostly water. All forms of movement are subject to the laws of motion, yet the consequences of this simple physical fact have been almost universally ignored in biology.

Newton’s first law of motion says that a physical body will remain at rest, or continue to move at a constant velocity, unless an external force acts upon it. Think of a message molecule that is sent from one part of a cell to another. Since the cell is full of other molecules, with no empty spaces, the message molecule will soon hit other molecules and either slow down or stop altogether.

This is the universal problem known as friction . Friction events can result from many causes, but can be crudely divided into two types: one is referred to as ploughing and the other is shearing . Ploughing involves the physical displacement of materials to facilitate the motion of an object, while shearing arises from the disruption of adhesive interactions between adjacent surfaces.

13Molecular machines in cells owe a great deal of their structure to hydrogen bonds, but these are rather weak and fairly easily broken. For example, most proteins are long, strongly-bonded chains of amino acids, but these long chains are coiled up into 3-dimensional machine components, and the 3-dimensional structures are held together by hydrogen bonds.

14 When such structures suffer mechanical impacts, the transfer of momentum can distort or break the hydrogen bonds and critically damage the molecule’s function. The inside of a cell has a density and viscosity somewhat similar to yogurt (figure 1). The stewed fruit (dark colour) added to the yogurt during manufacture can be seen swirling out into the white yogurt.

The fruit has not continued to disperse throughout the yogurt. It was completely stopped by the initial friction. This is like what happens in a cell—any movement is quickly dampened by friction forces of all kinds coming from all directions. Figure 1. A transparent carton of fruit yogurt illustrates how friction in the viscous fluid stopped the motion initiated by mixing the fruit (dark colour) with the yogurt (white colour).

How do cells cope with this friction? In at least five different ways. First, there are motor proteins available all over the cell that attach to mobile molecules and carry them along the filaments and tubules that make up the cytoskeleton of the cell.

Second, these motor proteins are continually re-energized after friction collisions by energy inputs packaged in the form of ATP molecules. Third, there are ‘address labels’ attached to mobile molecules to ensure they are delivered to the correct destination (friction effects continually divert mobile molecules from their course).

Fourth, thin films of water cover all the molecular components of cells and provide both a protective layer and a lubricant that reduces the frequency and severity of friction collisions. Fifth, there is a wide range of maintenance and repair mechanisms available to repair the damage that friction causes. The friction problem—and the damage that results from it—is orders of magnitude greater in cells than it is in larger mechanical systems.

Biomolecules are very spiky objects with extremely rough and highly adhesive surfaces. They cannot be manufactured and honed to the smoothness that we achieve in our vehicle engine components such as pistons and flywheel pivots, nor can ball-bearings be inserted to reduce the surface contact area, such as we do in wheel axles.

As a biological example, consider the rotary motor that drives the bacterial flagellum. The major wear surfaces are on the rotor (attached to the flagellum) and the stator (the housing for the rotor, attached to the cell wall). The stator consists of 22 molecules, set in 11 pairs. The wear rate is so great that the average residence time for a stator molecule in the stator is only about 30 seconds.

15 The cell’s maintenance system keeps a pool of about 200 stator molecules in reserve to cope with this huge turnover rate.

Finding suitable lubricants to overcome friction is a major focus in the nanotechnology industry. A special technique called ‘friction force microscopy’ has been developed to quantitatively evaluate potential lubricants. 16This shows that the laws of physics, operating among the viscous components of the cell, both predict and explain the high rate of molecular damage that we observe in DNA.

Between 50% and 80% of the DNA in a cell is continually consulted for the information necessary for everyday metabolism. This consultation requires numerous steps that each involve physical deformation of the DNA—moving around within the nucleus, winding and unwinding of the chromatin structures, unzipping the double-helix, binding and unbinding of the transcription machinery, re-zipping the double-helix, rewinding the chromatin structures and shuffling around within the nucleus.

Each step of motion is powered by ATP discharges and inevitably causes mechanical damage among the components.

While most of this damage is repaired, the repair mechanisms are not 100% perfect because they suffer mechanical damage themselves. 17Mutations rapidly destroy Within neo-Darwinian theory, natural selection is supposed to be the guardian of our genomes because it weeds out unwanted deleterious mutations and favours beneficial ones.

Not so, according to genetics expert Professor John Sanford. 18 Natural selection can only weed out mutations that have a significant negative effect upon fitness (number of offspring produced). But such ‘fitness’ is affected by a huge variety of factors, and the vast majority of mutations have too small an effect for natural selection to be able to detect and remove them.

Furthermore, if the average mutation rate per person per generation is around 1 or more, then everyone is a mutant and no amount of selection can stop degeneration of the whole population. As it turns out, the mutation rate in the human population is very much greater than 1. Sanford estimates at least 100, probably about 300, and possibly more.

All multicellular life suffers Two recent reviews of the mutation literature not only confirm Sanford’s claims, but extend them to all multi-cellular life . In a review of the distribution of fitness effects (DFE) of mutations, 19 the authors are unable to give any examples of beneficial mutations for humans.

In their calculations regarding the rate of deleterious mutations ( MD) and neutral mutations ( MN ), they use the equalities MD = 1 – MN and MN = 1 – MD which both imply that the rate of beneficial mutations is zero. They do give a few non-zero values for beneficial mutation rates in some experimental organisms, but qualify these results by noting the interference of other variables.

In a review of mutation rate variations in eukaryotes, 20 the authors admit that all multicellular organisms are undergoing inexorable genome decay from mutations because natural selection cannot remove the damage.

21 Their Box 2 and Table 1 list deleterious mutation rates for a wide range of multicellular organisms, noting they are all underestimates, with the possible exception of those for the fruit fly Drosophila melanogaster with a value of 1.2. The value given for humans is ‘~3’. Thus, all multicellular life on earth is undergoing inexorable genome decay because the deleterious mutation rates are so high, the effects of the most individual mutations are so small, there are no compensatory beneficial mutations, and natural selection is ineffective in removing the damage.

The wheels have come off the neo-Darwinian juggernaut!How long to extinction? How long could multicellular life survive in the face of universal genetic degradation?

This is a very important question, and I will attempt to answer it by using several different lines of evidence. Human ageing and cancer We have recently discovered that there is a common biology in cancer and ageing—both are the result of accumulating molecular damage in cells. 22 This confirms the arguments outlined above, that for purely physical reasons molecular machinery suffers extremely high damage rates, clearly evident within the lifespan of a single human.

Every cell has a built-in time clock to limit this damage and minimize the chance of it becoming cancerous.

At every cell division, each telomere (the caps on both ends of a chromosome that stop the double-helix from unravelling) is shortened by a small amount, until they reach the Hayflick Limit —discovered in 1965 to be a little over 50 cell divisions.

The cells then stop dividing and they are dismantled and their parts are recycled. By adding the enzyme telomerase, the telomere shortening problem can be circumvented, but that then exposes the cell to a greater risk of becoming cancerous because of accumulating damage elsewhere in the cell. The overall balance between protection from damage and the need for longevity determines fitness (reproductive success) and life span.

23 The body’s normal reaction to increasing genome damage is to kill off the damaged cells via programmed senescence (of which the telomere clock with its Hayflick limit is but one part). But cells become malignant (cancerous) when mutation disables the senescence mechanism itself, which then enables the damaged cells to proliferate without limit. 22 The Hayflick limit of around 50 cell divisions for humans seems to provide the optimum balance.

Fifty human generations of 20 years each gives us only 1,000 years as a timescale over which a human lineage would begin to experience a significant mutation load in its genome. This is alarmingly rapid compared with the supposed evolutionary time scale of millions and billions of years. Reproductive cells Figure 2. Schematic representation of human life expectancy (—), male fertility (∙∙∙), and risk of fetal abnormality with mother’s age (---).

Despite the protective Hayflick limit on cell divisions and life expectancy, very significant molecular damage accumulates in humans even during the most productive years of life.

Mutations do even more damage than the Hayflick limit and associated cancer rates suggest. Ever since August Weismann published The Germ-Plasm: A Theory of Heredity 24 in 1893, a discrete separation has been shown to exist between body cells (the soma) and germ-line cells ( germplasm ).

Germ-line cells were thought to be more protected from mutation than other body cells. However, another recently discovered cause of ageing is that our stem cells grow old as a result of heritable DNA damage and degeneration of their supporting niches (the special ‘nest’ areas in most organs and tissues of the body where stem cells grow and are nurtured and protected).

The telomere shortening mechanism—intended to reduce cancer incidence—appears to also induce the unwanted side-effect of a decline in the replicative capacity of certain stem-cell types with advancing age. This decreased regenerative capacity has led to a ‘stem-cell hypothesis’ for human age-associated degenerative conditions. 25Human fertility problems suggest that the decline in niche protection of stem cells also applies to our gametes (eggs and sperm). For males, fertility—as measured by sperm count, sperm vigor and chance of conception—begins to decline significantly by age 40 and the rate of certain paternal-associated birth defects increases rapidly during the 30s (figure 2).

26 For females, the chance of birth defects increases rapidly from around the mid-30s, particularly because of chromosome abnormalities (figure 2).

In the middle of the most productive part of our lives, our bodies are therefore showing clear evidence of decline through accumulation of molecular damage in our genomes. Do germ-line cells really suffer less damage? When DNA was discovered to be the carrier of inheritance, Weissman’s germ-plasm theory gave rise to the ‘immortal strand hypothesis.’ When the DNA of an embryonic stem cell replicates itself, it was thought that the ‘old’ strand would remain with the self-renewing ‘mother’ stem cell, while the newly constructed daughter strand proceeds down the path of differentiation into a body cell.

In this way, the ‘old’ strand would remain error free—because it has not suffered any copying errors—and thus becomes effectively immortal.

However, a research team at the Howard Hughes Memorial Institute recently tested this theory using the stem cells that produce blood, and found that they segregate their chromosomes randomly. 27 That is, the ‘immortal strand hypothesis’ is wrong. If stem cells are not given this kind of preferential treatment then it is reasonable to conclude that germ-line cells are also subject to the same molecular damage as somatic cells.

This is confirmed by the observation that human fertility exhibits damage long before age-related diseases take over.

A single human lifetime is enough to show very significant mutation damage, even in our reproductive cells. Haldane’s dilemma The severe contradictions that these findings pose for neo-Darwinian theory corroborate what has become known as Haldane’s dilemma.

J. B. S. Haldane was one of the architects of neo-Darwinism who pioneered its application to population biology. He realized that it would take a long time for natural selection to fix an advantageous mutation in a population—fixation is when every member has two copies of an allele, having inherited it from both mother and father.

He estimated that for vertebrates, about 300 generations would be required, on average, where the selective advantage is 10%.

In humans, with a 20-year generation time and about 6 million years since our last common ancestor with the chimpanzee, only about 1,000 such advantageous mutations could have been fixed. Haldane believed that substitution of about 1,000 alleles would be enough to create a new species, but it is not nearly enough to explain the observed differences between us and our closest supposed relatives.

The measured difference between the human and chimpanzee genomes amounts to about 125 million nucleotides, which are thought to have arisen from about 40 million mutation events.

28 If only 1000 of these mutations could have been naturally selected to produce the new (human) species, it means the other 39,999,000 mutations were deleterious, which is completely consistent with the reviews showing that the vast majority of mutations are deleterious.

Consequently, we must have degenerated from the apes, which is an absurd conclusion. According to Kirschner and Gerhart’s facilitated variation theory, 29 life consists of two main components— conserved core processes (the structure and machinery in cells) and modular regulatory processes (the signalling circuits and switches that operate the machinery and provide a built-in source of natural variation).

The 40 million ‘mutation’ differences between humans and chimps are therefore much more reasonably explained as 40 million modular differences between the design of chimps and the design of humans.

Quantitative estimates of time to extinction There are a number of different ways to estimate the time it would take for relentlessly accumulating mutations to send our species to extinction. Binomial estimates Some very rough estimates can be derived from the Binomial distribution, which can predict the likelihood of multiple mutations accumulating in an essential genetic functional module. A binomial model of a mutating genome could consist of the cell’s DNA being divided into N functional modules, of which N e are essential; that is, the lineage fails to reproduce if any of the essential modules are disabled. For any given mutational event, p = 1/ N is the probability of being ‘hit’, q is the probability of being ‘missed’, and p q = 1. What is the likely value of N? We can derive two estimates from the knowledge that there are about 25,000 genes, plus the discovery from the pilot study report of the ENCODE project that virtually the whole human genome is functional. 30

For the first estimate, the average protein contains a few hundred amino acids and each amino acid requires three nucleotides of code, so the average gene would take up about 1,000 nucleotides of exon space (an exon is the protein-coding part of a gene).

There are about 3 billion nucleotides in the whole human genome, so if we assume that the average protein represents an average functional unit then N = 3 million. The second estimate comes from the ENCODE report that gene regions produce on average 5 RNA transcripts per nucleotide, and the untranslated regions produce on average 7 RNA transcripts per nucleotide.

There are about 33 times as many nucleotides in the untranslated regions as in the genic regions. Assuming that transcript size is approximately equal in each region, then there are 25,000 x 5 = 125,000 gene transcripts and 25,000 x 33 x 7 = 5,775,000 untranslated transcripts, making N = 5,900,000 in total.

Our two estimates of N are therefore 3 to 6 million in round figures. What is the likely value of Ne? Experiments with mice indicate that 85% of genes can be knocked out one at a time without lethal effects. 31 This is due to the robustness and failure-tolerance through fallback processes built into the genomic designs. That means any one of those remaining 15% genes will be fatal if disabled. Multiple mutations occur however, so the likely value of Ne when exposed to multiple mutations will be much higher than 15%.

The maximum possible value is 100%. In a study of 2,823 human metabolic pathways, 96% produced disease conditions when disrupted by mutation, 32 so if we take an average between this value and the minimum 15% then we get about 60% of functional units being essential.

How many random mutations are required on average to disable an essential functional module? In rare cases, a single mutation is enough to disable a person’s ability to reproduce.

A two-hit model is common in cancer. In a study of cell signalling networks, these two hits usually knocked out: (i) the programmed death system for dealing with damaged (cancerous) cells, and (ii) the normal controls on cell proliferation—so the damaged cancer cells can proliferate without limit. The proportion of cancer-associated genes was also found to increase with the number of linkages between genes. When a healthy gene is linked to more than 6 mutated genes, ~80% of all genes in the network are cancerous. Extrapolating from this, we find that by the time a normal gene is linked to about 10 mutated genes, then the whole network has become cancerous.

33Almost 70% of known human genes can be causal agents of cancer when mutated. 34 Cancers can result from as little as a single mutation in a stem cell, or multiple mutations in somatic cells.

35 The minimum possible value of 1 is known to be rare, so the more common occurrence of the 2-hit model makes it a reasonable best-estimate minimum. But it may require 10 modules to receive two hits each for the whole network to become dysfunctional.

The maximum number of hits required to disable a single module may be 100 or more, but if the average functional module only contains 1,000 nucleotides then this figure, at 10% of the whole, seems rather large. An order-of-magnitude average is perhaps more likely to be 10 random mutations per functional module. To provide some context for these estimates, recent work shows that the cell-cycle checkpoint damage repair system is activated when 10 to 20 double-strand breaks accumulate in a cell undergoing division.

36 That is, life will tolerate only 10 to 20 DNA breaks per cell before it starts repair work, whereas we are examining scenarios in which there are thousands and millions of damage events per cell. Our numbers are clearly up in a region where the cell’s repair mechanisms are working at their hardest.

What then is the likelihood of accumulating either 2 hits in 10 modules, or 10 hits in one module, in any one of either 15% or 60% of the 3 to 6 million functional modules?

The binomial distribution in Microsoft Excel was used to make the following calculations, making the further assumption that the likelihood of the unit being a critical one must exceed 50% for extinction to be more likely than not in the next generation.

Assuming 60% essentiality, only one functional module needs to be disabled for the probability of its essential status to exceed 50%. For the 2-hit model, about 6,000 to 12,000 mutations are required to disable ten of the 3 to 6 million functional modules. For the 10-hit model, 3 to 6 million mutations are required to disable one functional module. Assuming 15% essentiality, four modules need to be disabled before the probability of at least one of them being essential exceeds 50%.

For the 2-hit model, 250,000 to 500,000 mutations are required to disable ten modules with four mutations each among the 3 to 6 million functional modules. For the 10-hit model, 3.7 to 7.5 million mutations are required to disable four functional modules.

If every individual produces 100 new mutations every generation (assuming a generation time of 20 years) and these mutations are spread among 3 to 6 million functional modules across the whole genome, then the average time to extinction is:1,200 to 2,400 years for the 2-hits in 10 modules model and 60% essentiality50,000 to 100,000 years for the 2-hits in 10 modules model and 15% essentiality600,000 to 1,200,000 years for the 10-hit model and 60% essentiality740,000 to 1,500,000 years for the 10-hit model and 15% essentiality. Truncation selection Evolutionary geneticist Dr James Crow argued that humans are probably protected by ‘truncation selection’. 26 Truncation occurs when natural selection preferentially deletes individuals with the highest mutation loads.

Plant geneticist John Sanford put Crow’s claims to the test by developing a computer simulation of truncation. His assumptions were: 100 individuals in the population, 100 mutations per person per generation, 4 offspring per female, 25% non-genetic random deaths per generation, and 50% selection against the most mutant offspring per generation. He assumed an average fitness loss per mutation of 1 in 10,000. His species became extinct in only 300 generations.

With a generation time of 20 years this corresponds to 6,000 years. 37Sanford’s assumptions are somewhat unrealistic, but there are other ways to approach the problem. Mutations are pure chance events that follow a Poisson distribution, and this behaves like the normal curve when the average expected value is greater than about 30.

38 In a Poisson distribution, the variance is equal to the average expected value, and the standard deviation is the square root of the variance.

When the expected average value is 100, the standard deviation will be 10. The normal curve now tells us the following: Half the people will suffer about 100 mutations or more, and half the people will suffer about 100 mutations or less. About 84% of people will suffer 110 mutations or less, and so the remaining 16% of people will suffer 110 or more mutations.

Alternatively, about 16% of people will suffer 90 or less. About 97.7% of the population will experience 120 mutations or less, and the remaining 2.3% will suffer 120 mutations or more.

Alternatively, 2.3% will suffer 80 or less. About 99.9% of the population will suffer 130 mutations or less, and the remaining 0.1% will suffer 130 or more mutations. Alternatively, 0.1% will suffer 70 or less. If we remove the most mutant—those above 130 mutations per person per generation—then we will only remove 0.1% of the population and it will make virtually no difference.

If we removed the most mutant 50% of the population that would not solve the problem either, for two reasons. First, the great majority of the remaining people still suffer between 70 and 100 mutations per person per generation, far above the value of 1 that ensures inexorable decline. Second, removing half the population each generation would send it extinct in a few dozen generations. Table 1. Estimated number of generations and years to extinction for populations of various sizes, when fitness declines by 1.5% in each generation.

Synergistic epistasis and population size None of the above models include the effect of synergistic epistasis (if one gene is mutated, its impact is ameliorated by the coordinated activity of other genes) or of population size.

We can include these by using Crow’s estimate that the fitness of the human race is currently degenerating at a rate of about 1 to 2% per generation. If we use an average value of 1.5% then only 98.5% of the next generation will produce reproductively viable offspring. The next generation after that will only have 98.5% of those survivors able to produce reproductively viable offspring, and so on.

For any given stable population size N, the size of the next generation that can produce reproductively viable offspring will be 98.5% of N , and for any given number of generations G, the number of survivors able to produce reproductively viable offspring will be (98.5%) G of N. Table 1 shows the approximate numbers of generations after which the population degenerates to extinction (only one individual is left, so breeding cannot continue). No population can sustain a continual loss of viability of 1.5%. Like rust eating away the steel in a bridge, mutations are eating away our genomes and there is nothing we can do to stop them.

The above model assumes that right from the beginning there will be 1.5% loss of fitness each generation. However, the binomial simulations earlier showed that individuals can tolerate somewhere between a few thousand to a few million mutations before the damage critically interferes with their ability to reproduce.

This means that synergistic epistasis is a real phenomenon—life is robust in the face of mutational assault. Instead of the immediate loss of 1.5% every generation, the general population would remain apparently healthy for a much longer time before the damage became apparent.

However, the rate at which mutations accumulate will remain the same because the cause remains the same—mechanical damage. This means that most people will be apparently healthy, but then approach the threshold of dysfunction over a much shorter period, creating a population crash rather than a slow decline. Either way, however, the time scales will be approximately the same because the rate of damage accumulation remains approximately the same.

Summary Mutations are not uniquely biological events that provide an engine of natural variation for natural selection to work upon and produce all the variety of life. Mutation is the purely physical result of the all-pervading mechanical damage that accompanies all molecular machinery.

As a consequence, all multicellular life on earth is undergoing inexorable genome decay because the deleterious mutation rates are so high, the effects of the individual mutations are so small, there are no compensatory beneficial mutations and natural selection is ineffective in removing the damage.

So much damage occurs that it is clearly evident within a single human lifetime. Our reproductive cells are not immune, as previously thought, but are just as prone to mechanical damage as our body cells. Somewhere between a few thousand and a few million mutations are enough to drive a human lineage to extinction, and this is likely to occur over a time scale of only tens to hundreds of thousands of years.

This is far short of the supposed evolutionary time scales. Like rust eating away the steel in a bridge, mutations are eating away our genomes and there is nothing we can do to stop them.

Evolution’s engine, when properly understood, becomes evolution’s end. Related Articles Antifreeze protein evolution: turning wrenches into hammers The limits of Neo-Darwinism Is information a ‘false metaphor’ for DNA? An information-gaining mutation in HIV? Genetics: no friend of evolution Gain-of-function mutations: at a loss to explain molecules-to-man evolution Squirrel evolution?

Bacterial mutations plus biblical geology The diminishing returns of beneficial mutations The evolution train’s a-comin’Beneficial mutations: real or imaginary?—part 1Beneficial mutations: real or imaginary?—part 2The mutant ‘feather-duster’ budgie Seeing is believing for evolutionists The Riddle Further Reading Mutations Questions and Answers Related Media A 'mountain of evidence' for evolution? -- Creation Magazine LIVE! (2-18)References De Vries, H., The Mutation Theory, German edition 1900–03, English edition 1910–11; De Vries, H., Species and Varieties: Their Origin by Mutation, 1905, <en.wikipedia.org/wiki/Hugo_de_Vries>, 11 August 2007.

Return to text. Niedernhofer, L. J. et al ., A new progeroid syndrome reveals that genotoxic stress suppresses the somatotroph axis, Nature 444: 1038–1043, 2006. Return to text. Kudlow, B. A., Kennedy, B. K. and Monnat, R. J. Jr, Werner and Hutchinson–Gilford progeria syndromes: mechanistic basis of human progeroid diseases, Nature Reviews Molecular Cell Biology 8 :394–404, 2007.

Return to text. Eccleston, A. and Dhand, R., Signaling in cancer, Nature 441 (7092):423, 2006. Return to text. He, X. C. et al ., PTEN-deficient intestinal stem cells initiate intestinal polyposis, Nature Genetics 39 :189–198, 2007.

Return to text. Casanova, J-L. and Abel, L., Human genetics of infectious diseases: a unified theory, The EMBO Journal26 :915–922, 2007. Return to text. Carroll, S. B., The Making of the Fittest: DNA and the ultimate forensic record of evolution, Norton, New York, pp. 174–179, 2006. Return to text. Guilherme, A. and Pacheco, F., CCR5 receptor gene and HIV infection, <www.cdc.gov/genomics/hugenet/factsheets/FS_CCR5.htm>, 11 August 2007.

Return to text. Lamb, A., CCR5–delta32: a very beneficial mutation, Journal of Creation 20 (1):15, 2006. Return to text. Carroll, S. B., Endless Forms Most Beautiful: The new science of evo devo, Norton, New York, Ch. 9, 2005. Return to text. Carroll, S. B., The Making of the Fittest: DNA and the ultimate forensic record of evolution, Norton, New York, Ch.

8, 2006. Return to text.<en.wikipedia.org/wiki/DNA_repair>, January 29, 2008. Return to text. Leggett, G. J., Brewer, N. J and Chong, K. S. L., Friction force microscopy: towards quantitative analysis of molecular organisation with nanometre spatial resolution, Phys. Chem. Chem. Phys. 7 :1107–1120, 2005. Return to text. Most organic macromolecules contain numerous hydrogen atoms bonded to carbon atoms.

Because hydrogen has only one (negative) electron and one (positive) proton, the ‘cloud’ of electron trajectories tends to be easily skewed towards the stronger electromagnetic fields in the core of the carbon chain, thus giving the hydrogen atom a small net positive force, which is then available to form a ‘hydrogen bond’ with electron-rich (negative) sites on other nearby molecules, or on adjacent folds in its own chain.

Return to text. Leake, M. C. et. al ., Stoichiometry and turnover in single functioning membrane protein complexes, Nature 443 :355–358, 2006. Return to text. Leggett, G. J., Brewer, N. J. and Chong, K. S. L., Friction force microscopy: towards quantitative analysis of molecular organisation with nanometre spatial resolution, Phys. Chem. Chem. Phys. 7 :1107–1120, 2005. Return to text. Copy fidelity varies with the different DNA copying systems that are present in all eukaryote cells, with the different kinds of errors that can occur, and with the different stages at which errors can occur.

A couple of errors in ten million is fairly typical, but mutant cells may produce a hundred to ten thousand times this value.

E.g. Pursell, Z. F., Isoz, I., Landström, E-. L., Johansson, E. and Kunkel, T. A. Regulation of B family DNA polymerase fidelity by a conserved active site residue: characterization of M644W, M644L and M644F mutants of yeast DNA polymerase ε, Nucleic Acids Research 35 (9):3076–3086, 2007. Return to text. Sanford, J. C., Genetic Entropy & The Mystery of the Genome, Elim Publishing, New York, 2005.

Return to text. Humans have lived on earth for about 6,000 years and about 250 generations. For a population size of 1 million people, an average rate of one mutation per 20 people per generation is sufficient to ensure that everyone today is a mutant.

I.e. (0.054) 250 x 1 million people < 1. If the supposed 300,000 generations since the split with apes is assumed, then a rate of only 1 mutation in 21,000 people per generation is enough to ensure that everyone today is a mutant.

Return to text. Eyre.-Walker, A. and Keightley, P. D., The distribution of fitness effects of new mutations, Nature Reviews Genetics 8 :610–618, 2007. Return to text. Baer, C. F., Miyamoto, M. M. and Denver, D. R., Mutation rate variation in multicellular eukaryotes: causes and consequences, Nature Reviews Genetics 8 :619–631, 2007. Return to text. Two important difference between multicellular organisms and bacteria and viruses in this regard are: (a) effective population size (trillions in the latter); (b) the latter have higher tolerance for mutations and are able to actively use them to their own advantage when required.

E.g. Wagner, J. and Nohmi, T., Escherichia coli DNA Polymerase IV mutator activity: genetic requirements and mutational specificity, Journal of Bacteriology 182 (16): 4587–4595, 2000. Return to text. Finkel, T., Serrano, M. and Blasco, M. A., The common biology of cancer and ageing, Nature 448 :767–774, 2007. Return to text. Serrano, M. and Blasco, M. A., Cancer and ageing: convergent and divergent mechanisms, Nature Reviews Molecular Cell Biology 8 :715–722, 2007.

Return to text. Weismann, A., The Germ-Plasm: A Theory of Heredity , Charles Scribner’s Sons, 1893. On-line version: <www.esp.org/books/weismann/germ-plasm/facsimile/>. Sharpless, N. E. and De Pinho, R. A., How stem cells age and why this makes us grow old, Nature Reviews Molecular Cell Biology 8 :703–713, 2007. Return to text. Crow, J. F., The high spontaneous mutation rate: is it a health risk? Proceedings of the National Academy of Science 94 :8380–8386, 1997. Return to text. Kiel, M. J. et al., Haematopoietic stem cells do not asymmetrically segregate chromosomes or retain Brd U, Nature 449 :238–242, 2007. Return to text. De Witt, D. A., Chimp genome sequence very different from man, Journal of Creation 19 (3):4–5, 2005. Return to text. Kirschner, M. W. and Gerhart, J. C., The Plausibility of Life: Resolving Darwin’s Dilemma, Yale University Press, New Haven, CT, 2005. Return to text. Williams, A., Astonishing DNA complexity uncovered. Return to text.<en.wikipedia.org/wiki/Knockout_mouse>, 14 August 2007. Return to text. Ma, H., et al., The Edinburgh human metabolic network reconstruction and its functional analysis, Molecular Systems Biology 3, Article number 135; published online, 2007, <www.molecularsystemsbiology.com>. Return to text. Cui, O. et al., A map of human cancer signaling, Molecular Systems Biology 3, Article number 152, 2007. Return to text. Kim, L., Accumulation of mutations: cancer or molecule-to-man evolution? Journal of Creation 21 (2):77–81, 2007. Return to text. He, X. C. et al ., PTEN-deficient intestinal stem cells initiate intestinal polyposis, Nature Genetics39 (2):189–198, 2007. Return to text. Löbrich, M. and Jeggo, P. A., The impact of a negligent G2/M checkpoint on genomic instability and cancer induction, Nature Reviews Cancer 7 :861–869, 2007. Return to text. Sanford, ref. 18, p. 113. Return to text. Arnold, S. F., Mathematical Statistics, Prentice Hall, NJ, Table 6, 1990. Return to text. View All

Answer An intron is a nucleotide sequence found within the genes and is removed via RNA splicing when a mature RNA molecule is being generated; on the other hand, an exon is a nucleic acid sequence present in a mature messenger RNA molecule.

What Is the Difference Between Exons and Introns?

Science Biology Molecular Biology & DNAQ: What Is the Difference Between Exons and Introns? A: Quick

Basically, introns are DNA bases found in between exons while exons can be described as DNA bases which are translated to m RNA. Continue Reading Keep Learning What Is the Role of the TRNA Anticodon? What Is Gene Splicing? What Do DNA and RNA Have in Common?

Full Answer Both introns and exons are parts of genes. They were independently discovered by Phillip Sharp and Richard Roberts in 1977. Introns are mostly found in multicellular eukaryotes, like humans. They are rarely found in unicellular eukaryotes like yeast.

Since introns are less conserved, their sequence tends to rapidly change over time. Exons are more conserved, meaning their sequence remains unchanged over time or in between the species. An exon is a part of the gene responsible for coding amino acids while introns do not take part in protein coding. Therefore, introns are non-coding areas whereas exons are coding areas. Introns are found within the gene while exons are always found at the ends of a gene.

Exons are the only parts of the gene nucleotide sequence that are expressed in the protein; introns are silent and are not expressed because they interfere with exons.

Learn more about Molecular Biology & DNASources: news-medical.net nih.gov ndsu.edu Related Questions Q: What Is a Nucleic Acid Polymer? A: DNA and RNA are nucleic acid polymers. Nucleic acid is a macromolecule that serves as the binding for these two genetic substances.

It is a staple of all o... Full Answer >Filed Under: Molecular Biology & DNAQ: What Is a Codon and Where Is It Found?

A: A codon is a sequence of three nucleotides in DNA or RNA that either codes for a particular amino acid or tells the cellular machinery to start or stop usi... Full Answer >Filed Under: Molecular Biology & DNAQ: What Are the Roles of DNA and RNA in Protein Synthesis?

A: Deoxyribonucleic acid (DNA) carries the sequence of coded instructions for the synthesis of proteins, which are transcribed into ribonucleic acid (RNA) to ... Full Answer >Filed Under: Molecular Biology & DNAQ: What Is an Anticodon Part Of?

A: An anticodon is part of a transfer RNA molecule abbreviated t RNA for short. The anticodon consists of 3 nucleotides that match the base pairs of a specific... Full Answer >Filed Under: Molecular Biology & DNAYou May Also Like Q: What Are Some Disadvantages of the Human Genome Project? Q: What Materials Can Be Used to Make a DNA Model? Q: What Is the Difference Between Organza and Organdy? Q: What Is the Difference Between a Father and a Dad? Q: What Is the Difference Between Monoecious and Dioecious? Q: What Are Some Interesting Facts About Mitochondria?

To distinguish the two types of DNA, scientists call the coding sequences of genes exons and the pieces in between introns (for intervening sequences). If RNA polymerase were to transcribe DNA from the start of an intron-containing gene to the end, the RNA would be complementary to the introns as well as the exons.

The New Genetics

"Chapter 1: How Genes Work People have known for many years that living things inherit traits from their parents. That common-sense observation led to agriculture, the purposeful breeding and cultivation of animals and plants for desirable characteristics. Firming up the details took quite some time, though. Researchers did not understand exactly how traits were passed to the next generation until the middle of the 20th century.

Now it is clear that genes are what carry our traits through generations and that genes are made of deoxyribonucleic acid (DNA).

But genes themselves don't do the actual work. Rather, they serve as instruction books for making functional molecules such as ribonucleic acid (RNA) and proteins, which perform the chemical reactions in our bodies. Proteins do many other things, too. They provide the body's main building materials, forming the cell's architecture and structural components. But one thing proteins can't do is make copies of themselves. When a cell needs more proteins, it uses the manufacturing instructions coded in DNA.

The DNA code of a gene—the sequence of its individual DNA building blocks, labeled A (adenine), T (thymine), C (cytosine) and G (guanine) and collectively called nucleotides — spells out the exact order of a protein's building blocks, amino acids.

Occasionally, there is a kind of typographical error in a gene's DNA sequence. This mistake— which can be a change, gap or duplication—is called a mutation. A mutation can cause a gene to encode a protein that works incorrectly or that doesn't work at all.

Sometimes, the error means that no protein is made. But not all DNA changes are harmful. Some mutations have no effect, and others produce new versions of proteins that may give a survival advantage to the organisms that have them. Over time, mutations supply the raw material from which new life forms evolve (see Chapter 3, ""Life's Genetic Tree"" ).

Genetics in the Garden Beautiful DNADNA Structure Copycat Let's Call It Even Meiosis Getting the Message Nature's Cut-and-Paste Job All Together Now Genetics and You: Nursery Genetics Found in Translation RNA Surprises An Interesting Development The Tools of Genetics: Mighty Microarrays Got It? Genetics in the Garden The monk Gregor Mendel first described how traits are inherited from one generation to the next.

In 1900, three European scientists independently discovered an obscure research paper that had been published nearly 35 years before. Written by Gregor Mendel, an Austrian monk who was also a scientist, the report described a series of breeding experiments performed with pea plants growing in his abbey garden. Mendel had studied how pea plants inherited the two variant forms of easy-to-see traits. These included flower color (white or purple) and the texture of the peas (smooth or wrinkled).

Mendel counted many generations of pea plant offspring and learned that these characteristics were passed on to the next generation in orderly, predictable ratios.

When he cross-bred purple-flowered pea plants with white-flowered ones, the next generation had only purple flowers. But directions for making white flowers were hidden somewhere in the peas of that generation, because when those purple-flowered plants were bred to each other, some of their offspring had white flowers.

What's more, the second-generation plants displayed the colors in a predictable pattern. On average, 75 percent of the second-generation plants had purple flowers and 25 percent of the plants had white flowers. Those same ratios persisted, and were reproduced when the experiment was repeated many times over.

Related Links Four Ways Inheritance Is More Complex Than Mendel Knew from Biomedical Beat Trying to solve the mystery of the missing color blooms, Mendel imagined that the reproductive cells of his pea plants might contain discrete ""factors,"" each of which specified a particular trait, such as white flowers. Mendel reasoned that the factors, whatever they were, must be physical material because they passed from parent to offspring in a mathematically orderly way.

It wasn't until many years later, when the other scientists unearthed Mendel's report, that the factors were named genes. Early geneticists quickly discovered that Mendel's mathematical rules of inheritance applied not just to peas, but also to all plants, animals and people. The discovery of a quantitative rule for inheritance was momentous. It revealed that a common, general principle governed the growth and development of all life on Earth.

Back to top Beautiful DNAUp until the 1950s, scientists knew a good deal about heredity, but they didn't have a clue what DNA looked like. In order to learn more about DNA and its structure, some scientists experimented with using X rays as a form of molecular photography. In 1953, Watson and Crick created their historic model of the shape of DNA: the double helix. COLD SPRING HARBOR LABORATORY ARCHIVESRosalind Franklin, a physical chemist working with Maurice Wilkins at King's College in London, was among the first to use this method to analyze genetic material.

Her experiments produced what were referred to at the time as ""the most beautiful X-ray photographs of any substance ever taken. ""Other scientists, including zoologist James Watson and physicist Francis Crick, both working at Cambridge University in the United Kingdom, were trying to determine the shape of DNA too.

Ultimately, this line of research revealed one of the most profound scientific discoveries of the 20th century: that DNA exists as a double helix. The 1962 Nobel Prize in physiology or medicine was awarded to Watson, Crick and Wilkins for this work. Although Franklin did not earn a share of the prize due to her untimely death at age 38, she is widely recognized as having played a significant role in the discovery.

Rosalind Franklin's original X-ray diffraction photo revealed the physical structure of DNA. OREGON STATE UNIVERSITY LIBRARIES SPECIAL COLLECTIONSThe spiral staircase-shaped double helix has attained global status as the symbol for DNA. But what is so beautiful about the discovery of the twisting ladder structure isn't just its good looks. Rather, the structure of DNA taught researchers a fundamental lesson about genetics. It taught them that the two connected strands—winding together like parallel handrails—were complementary to each other, and this unlocked the secret of how genetic information is stored, transferred and copied.

In genetics, complementary means that if you know the sequence of nucleotide building blocks on one strand, you know the sequence of nucleotide building blocks on the other strand: A always matches up with T and C always links to G ( see drawing ). Long strings of nucleotides form genes, and groups of genes are packaged tightly into structures called chromosomes.

Every cell in your body except for eggs, sperm and red blood cells contains a full set of chromosomes in its nucleus. If the chromosomes in one of your cells were uncoiled and placed end to end, the DNA would be about 6 feet long.

If all the DNA in your body were connected in this way, it would stretch approximately 67 billion miles! That's nearly 150,000 round trips to the Moon. DNA Structure The long, stringy DNA that makes up genes is spooled within chromosomes inside the nucleus of a cell.

(Note that a gene would actually be a much longer stretch of DNA than what is shown here. )DNA consists of two long, twisted chains made up of nucleotides. Each nucleotide contains one base, one phosphate molecule and the sugar molecule deoxyribose. The bases in DNA nucleotides are adenine, thymine, cytosine and guanine. Back to top Copycat Humans have 23 pairs of chromosomes. Male DNA (pictured here) contains an X and a Y chromosome, whereas female DNA contains two X chromosomes. CYTOGENETICS LABORATORY, BRIGHAM AND WOMEN'S HOSPITALIt's astounding to think that your body consists of trillions of cells.

But what's most amazing is that it all starts with one cell. How does this massive expansion take place? As an embryo progresses through development, its cells must reproduce. But before a cell divides into two new, nearly identical cells, it must copy its DNA so there will be a complete set of genes to pass on to each of the new cells. To make a copy of itself, the twisted, compacted double helix of DNA has to unwind and separate its two strands.

Each strand becomes a pattern, or template, for making a new strand, so the two new DNA molecules have one new strand and one old strand. The copy is courtesy of a cellular protein machine called DNA polymerase, which reads the template DNA strand and stitches together the complementary new strand. The process, called replication, is astonishingly fast and accurate, although occasional mistakes, such as deletions or duplications, occur.

Fortunately, a cellular spell-checker catches and corrects nearly all of these errors. When DNA polymerase makes an error while copying a gene's DNA sequence, the mistake is called a mutation.

In this example, the nucleotide G has been changed to an A. During DNA replication, each strand of the original molecule acts as a template for the synthesis of a new, complementary DNA strand. Mistakes that are not corrected can lead to diseases such as cancer and certain genetic disorders. Some of these include Fanconi anemia, early aging diseases and other conditions in which people are extremely sensitive to sunlight and some chemicals.

DNA copying is not the only time when DNA damage can happen. Prolonged, unprotected sun exposure can cause DNA changes that lead to skin cancer, and toxins in cigarette smoke can cause lung cancer. It may seem ironic, then, that many drugs used to treat cancer work by attacking DNA. That's because these chemotherapy drugs disrupt the DNA copying process, which goes on much faster in rapidly dividing cancer cells than in other cells of the body.

The trouble is that most of these drugs do affect normal cells that grow and divide frequently, such as cells of the immune system and hair cells. Understanding DNA replication better could be a key to limiting a drug's action to cancer cells only.

Let's Call It Even After copying its DNA, a cell's next challenge is getting just the right amount of genetic material into each of its two offspring.

Most of your cells are called diploid (""di"" means two, and ""ploid"" refers to sets of chromosomes) because they have two sets of chromosomes (23 pairs).

Eggs and sperm are different; these are known as haploid cells. Each haploid cell has only one set of 23 chromosomes so that at fertilization the math will work out: A haploid egg cell will combine with a haploid sperm cell to form a diploid cell with the right number of chromosomes: 46.

Chromosomes are numbered 1 to 22, according to size, with 1 being the largest chromosome. The 23rd pair, known as the sex chromosomes, are called X and Y. In humans, abnormalities of chromosome number usually occur during meiosis, the time when a cell reduces its chromosomes from diploid to haploid in creating eggs or sperm.

What happens if an egg or a sperm cell gets the wrong number of chromosomes, and how often does this happen? Trisomy, the hallmark of Down syndrome, results when a baby is born with three copies of chromosome 21 instead of the usual two. Molecular biologist Angelika Amon of the Massachusetts Institute of Technology in Cambridge says that mistakes in dividing DNA between daughter cells during meiosis are the leading cause of human birth defects and miscarriages.

Current estimates are that 10 percent of all embryos have an incorrect chromosome number. Most of these don't go to full term and are miscarried.

In women, the likelihood that chromosomes won't be apportioned properly increases with age. One of every 18 babies born to women over 45 has three copies of chromosome 13, 18 or 21 instead of the normal two, and this improper balancing can cause trouble. For example, three copies of chromosome 21 lead to Down syndrome. To make her work easier, Amon—like many other basic scientists—studies yeast cells, which separate their chromosomes almost exactly the same way human cells do, except that yeast do it much faster.

A yeast cell copies its DNA and produces daughter cells in about 1 1/2 hours, compared to a whole day for human cells. The yeast cells she uses are the same kind bakeries use to make bread and breweries use to make beer!Amon has made major progress in understanding the details of meiosis.

Her research shows how, in healthy cells, gluelike protein complexes called cohesins release pairs of chromosomes at exactly the right time.

This allows the chromosomes to separate properly. These findings have important implications for understanding and treating infertility, birth defects and cancer. Meiosis Back to top Getting the Message So, we've described DNA—its basic properties and how our bodies make more of it.

But how does DNA serve as the language of life? How do you get a protein from a gene? There are two major steps in making a protein. The first is transcription, where the information coded in DNA is copied into RNA. The RNA nucleotides are complementary to those on the DNA: a C on the RNA strand matches a G on the DNA strand.1.

RNA polymerase transcribes DNA to make messenger RNA (m RNA). 2. The m RNA sequence (dark red strand) is complementary to the DNA sequence (blue strand). 3. On ribosomes, transfer RNA (t RNA) helps convert m RNA into protein. 4. Amino acids link up to make a protein.

The only difference is that RNA pairs a nucleotide called uracil (U), instead of a T, with an A on the DNA. A protein machine called RNA polymerase reads the DNA and makes the RNA copy. This copy is called messenger RNA, or m RNA, because it delivers the gene's message to the protein-producing machinery.

At this point you may be wondering why all of the cells in the human body aren't exactly alike, since they all contain the same DNA. What makes a liver cell different from a brain cell? How do the cells in the heart make the organ contract, but those in skin allow us to sweat? Cells can look and act differently, and do entirely different jobs, because each cell ""turns on,"" or expresses, only the genes appropriate for what it needs to do.

RNA polymerase (green) and one end of a DNA strand (blue) are attached to clear beads pinned down in two optical traps. As RNA polymerase moves along the DNA, it creates an RNA copy of a gene, shown here as a pink strand.

STEVEN BLOCKThat's because RNA polymerase does not work alone, but rather functions with the aid of many helper proteins. While the core part of RNA polymerase is the same in all cells, the helpers vary in different cell types throughout the body.

You'd think that for a process so essential to life, researchers would know a lot about how transcription works. While it's true that the basics are clear—biologists have been studying gene transcribing by RNA polymerases since these proteins were first discovered in 1960— some of the details are actually still murky.

The biggest obstacle to learning more has been a lack of tools. Until recently, researchers were unable to get a picture at the atomic level of the giant RNA polymerase protein assemblies inside cells to understand how the many pieces of this amazing, living machine do what they do, and do it so well.

But our understanding is improving fast, thanks to spectacular technological advances. We have new X-ray pictures that are far more sophisticated than those that revealed the structure of DNA.

Roger Kornberg of Stanford University in California used such methods to determine the structure of RNA polymerase.

This work earned him the 2006 Nobel Prize in chemistry. In addition, very powerful microscopes and other tools that allow us to watch one molecule at a time provide a new look at RNA polymerase while it's at work reading DNA and producing RNA. For example, Steven Block, also of Stanford, has used a physics technique called optical trapping to track RNA polymerase as it inches along DNA.

Block and his team performed this work by designing a specialized microscope sensitive enough to watch the real-time motion of a single polymerase traveling down a gene on one chromosome. The researchers discovered that molecules of RNA polymerase behave like battery-powered spiders as they crawl along the DNA ladder, adding nucleotides one at a time to the growing RNA strand. The enzyme works much like a motor, Block believes, powered by energy released during the chemical synthesis of RNA. Back to top Nature's Cut-and-Paste Job Genes are often interrupted by stretches of DNA (introns, blue) that do not contain instructions for making a protein.

The DNA segments that do contain protein-making instructions are known as exons (green). Several types of RNA play key roles in making a protein. The gene transcript (the m RNA) transfers information from DNA in the nucleus to the ribosomes that make protein. Ribosomal RNA forms about 60 percent of the ribosomes. Lastly, transfer RNA carries amino acids to the ribosomes. As you can see, all three types of cellular RNAs come together to produce new proteins. But the journey from gene to protein isn't quite as simple as we've just made it out to be.

After transcription, several things need to happen to m RNA before a protein can be made. For example, the genetic material of humans and other eukaryotes (organisms that have a nucleus) includes a lot of DNA that doesn't encode proteins. Some of this DNA is stuck right in the middle of genes.

To distinguish the two types of DNA, scientists call the coding sequences of genes exons and the pieces in between introns (for intervening sequences). If RNA polymerase were to transcribe DNA from the start of an intron-containing gene to the end, the RNA would be complementary to the introns as well as the exons.

To get an m RNA molecule that yields a working protein, the cell needs to trim out the intron sections and then stitch only the exon pieces together (see drawing). This process is called RNA splicing. Arranging exons in different patterns, called alternative splicing, enables cells to make different proteins from a single gene. Splicing has to be extremely accurate. An error in the splicing process, even one that results in the deletion of just one nucleotide in an exon or the addition of just one nucleotide in an intron, will throw the whole sequence out of alignment.

The result is usually an abnormal protein—or no protein at all. One form of Alzheimer's disease, for example, is caused by this kind of splicing error.

Molecular biologist Christine Guthrie of the University of California, San Francisco, wants to understand more fully the mechanism for removing intron RNA and find out how it stays so accurate. She uses yeast cells for these experiments. Just like human DNA, yeast DNA has introns, but they are fewer and simpler in structure and are therefore easier to study.

Guthrie can identify which genes are required for splicing by finding abnormal yeast cells that mangle splicing. So why do introns exist, if they're just going to be chopped out? Without introns, cells wouldn't need to go through the splicing process and keep monitoring it to be sure it's working right.

As it turns out, splicing also makes it possible for cells to create more proteins. Think about all the exons in a gene. If a cell stitches together exons 1, 2 and 4, leaving out exon 3, the m RNA will specify the production of a particular protein.

But instead, if the cell stitches together exons 1, 2 and 3, this time leaving out exon 4, then the m RNA will be translated into a different protein ( see drawing ). By cutting and pasting the exons in different patterns, which scientists call alternative splicing, a cell can create different proteins from a single gene.

Alternative splicing is one of the reasons why human cells, which have about 20,000 genes, can make hundreds of thousands of different proteins. Back to top All Together Now Until recently, researchers looked at genes, and the proteins they encode, one at a time.

Now, they can look at how large numbers of genes and proteins act, as well as how they interact. This gives them a much better picture of what goes on in a living organism.

Already, scientists can identify all of the genes that are transcribed in a cell—or in an organ, like the heart. And although researchers can't tell you, right now, what's going on in every cell of your body while you read a book or walk down the street, they can do this sort of ""whole-body"" scan for simpler, single-celled organisms like yeast.

Using a technique called genome-wide location analysis, Richard Young of the Massachusetts Institute of Technology unraveled a ""regulatory code"" of living yeast cells, which have more than 6,000 genes in their genome. Young's technique enabled him to determine the exact places where RNA polymerase's helper proteins sit on DNA and tell RNA polymerase to begin transcribing a gene.

Since he did the experiment with the yeast exposed to a variety of different conditions,Young was able to figure out how transcription patterns differ when the yeast cell is under stress (say, in a dry environment) or thriving in a sugary-rich nutrient solution.

Done one gene at a time, using methods considered state-of-the-art just a few years ago, this kind of analysis would have taken hundreds of years.

After demonstrating that his technique worked in yeast, Young then took his research a step forward. He used a variation of the yeast method to scan the entire human genome in small samples of cells taken from the pancreases and livers of people with type 2 diabetes. He used the results to identify genes that aren't transcribed correctly in people with the disease.

This information provides researchers with an important tool for understanding how diabetes and other diseases are influenced by defective genes. By building models to predict how genes respond in diverse situations, researchers may be able to learn how to stop or jump-start genes on demand, change the course of a disease or prevent it from ever happening.

Genetics and You: Nursery Genetics While most genetic research uses lab organisms, test tubes and petri dishes, the results have real consequences for people. Your first encounter with genetic analysis probably happened shortly after you were born, when a doctor or nurse took a drop of blood from the heel of your tiny foot. Lab tests performed with that single drop of blood can diagnose certain rare genetic disorders as well as metabolic problems like phenylketonuria (PKU).

Screening newborns in this way began in the 1960s in Massachusetts with testing for PKU, a disease affecting 1 in 14,000 people. PKU is caused by an enzyme that doesn't work properly due to a genetic mutation. Those born with this disorder cannot metabolize the amino acid phenylalanine, which is present in many foods.

Left untreated, PKU can lead to mental retardation and neurological damage, but a special diet can prevent these outcomes.

Testing for this condition has made a huge difference in many lives. Newborn screening is governed by individual states. This means that the state in which a baby is born determines the genetic conditions for which he or she will be screened. Currently, states test for between 28 and 54 conditions. All states test for PKU. Although expanded screening for genetic diseases in newborns is advocated by some, others question the value of screening for conditions that are currently untreatable.

Another issue is that some children with mild versions of certain genetic diseases may be treated needlessly. In 2006, the Advisory Committee on Heritable Disorders in Newborns and Children, which assists the Secretary of the U. S. Department of Health and Human Services, recommended a standard, national set of newborn tests for 29 conditions, ranging from relatively common hearing problems to very rare metabolic diseases.

Back to top Found in Translation A ribosome consists of large and small protein subunits with transfer RNAs nestled in the middle.

RIBOSOME STRUCTURE COURTESY OF JAMIE CATE, MARAT YUSUPOV, GULNARA YUSUPOVA, THOMAS EARNEST AND HARRY NOLLER. GRAPHIC COURTESY OF ALBION BAUCOM, UNIVERSITY OF CALIFORNIA, SANTA CRUZ. After a gene has been read by RNA polymerase and the RNA is spliced, what happens next in the journey from gene to protein? The next step is reading the RNA information and fitting the building blocks of a protein together.

This is called translation, and its principal actors are the ribosome and amino acids. Ribosomes are among the biggest and most intricate structures in the cell. The ribosomes of bacteria contain not only huge amounts of RNA, but also more than 50 different proteins.

Human ribosomes have even more RNA and between 70 and 80 different proteins!Harry Noller of the University of California, Santa Cruz, has found that a ribosome performs several key jobs when it translates the genetic code of m RNA. As the messenger RNA threads through the ribosome protein machine, the ribosome reads the m RNA sequence and helps recognize and recruit the correct amino acid-carrying transfer RNA to match the m RNA code.

The ribosome also links each additional amino acid into a growing protein chain ( see drawing ). For many years, researchers believed that even though RNAs formed a part of the ribosome, the protein portion of the ribosome did all of the work. Noller thought, instead, that maybe RNA, not proteins, performed the ribosome's job. His idea was not popular at first, because at that time it was thought that RNA could not perform such complex functions.

Some first-aid ointments contain the antibiotic neomycin, which treats infections by attacking ribosomes in bacteria. Some time later, however, the consensus changed. Sidney Altman of Yale University in New Haven, Connecticut, and Thomas Cech, who was then at the University of Colorado in Boulder, each discovered that RNA can perform work as complex as that done by protein enzymes. Their ""RNA-as-an-enzyme"" discovery turned the research world on its head and earned Cech and Altman the 1989 Nobel Prize in chemistry.

Noller and other researchers have continued the painstaking work of understanding ribosomes. In 1999, he showed how different parts of a bacterial ribosome interact with one another and how the ribosome interacts with molecules involved in protein synthesis. These studies provided near proof that the fundamental mechanism of translation is performed by RNA, not by the proteins of the ribosome. Back to top RNA Surprises But which ribosomal RNAs are doing the work? Most scientists assumed that RNA nucleotides buried deep within the ribosome complex—the ones that have the same sequence in every species from bacteria to people—were the important ones for piecing the growing protein together.

However, recent research by Rachel Green, who worked with Noller before moving to Johns Hopkins University in Baltimore, Maryland, showed that this is not the case. Green discovered that those RNA nucleotides are not needed for assembling a protein. Instead, she found, the nucleotides do something else entirely: They help the growing protein slip off the ribosome once it's finished.

Noller, Green and hundreds of other scientists work with the ribosomes of bacteria. Why should you care about how bacteria create proteins from their genes?

One reason is that this knowledge is important for learning how to disrupt the actions of disease-causing microorganisms. For example, antibiotics like erythromycin and neomycin work by attacking the ribosomes of bacteria, which are different enough from human ribosomes that our cells are not affected by these drugs.

As researchers gain new information about bacterial translation, the knowledge may lead to more antibiotics for people. New antibiotics are urgently needed because many bacteria have developed resistance to the current arsenal. This resistance is sometimes the result of changes in the bacteria's ribosomal RNA. It can be difficult to find those small, but critical, changes that may lead to resistance, so it is important to find completely new ways to block bacterial translation.

Green is working on that problem too. Her strategy is to make random mutations to the genes in a bacterium that affect its ribosomes. But what if the mutation disables the ribosome so much that it can't make proteins? Then the bacterium won't grow, and Green wouldn't find it. Using clever molecular tricks, Green figured out a way to rescue some of the bacteria with defective ribosomes so they could grow.

While some of the rescued bacteria have changes in their ribosomal RNA that make them resistant to certain antibiotics (and thus would not make good antibiotic targets) other RNA changes that don't affect resistance may point to promising ideas for new antibiotics.

Back to top An Interesting Development In the human body, one of the most important jobs for proteins is to control how embryos develop. Scientists discovered a hugely important set of proteins involved in development by studying mutations that cause bizarre malformations in fruit flies.

The most famous such abnormality is a fruit fly with a leg, rather than the usual antenna, growing out of its head (see photo). According to Thomas C. Kaufman of Indiana University in Bloomington, the leg is perfectly normal—it's just growing in the wrong place. Normal fruit fly head. Fruit fly head showing the effects of the Antennapedia gene. This fly has legs where its antennae should be. FLYBASE; R. TURNERIn this type of mutation and many others, something goes wrong with the genetic program that directs some of the cells in an embryo to follow developmental pathways, which are a series of chemical reactions that occur in a specific order.

In the antenna-into-leg problem, it is as if the cells growing from the fly's head, which normally would become an antenna, mistakenly believe that they are in the fly's thorax, and therefore ought to grow into a leg. And so they do. Thinking about this odd situation taught scientists an important lesson—that the proteins made by some genes can act as switches.

Switch genes are master controllers that provide each body part with a kind of identification card. If a protein that normally instructs cells to become an antenna is disrupted, cells can receive new instructions to become a leg instead. Scientists determined that several different genes, each with a common sequence, provide these anatomical identification card instructions.

Kaufman isolated and described one of these genes, which became known as Antennapedia, a word that means ""antenna feet. ""Kaufman then began looking a lot more closely at the molecular structure of the Antennapedia gene. In the early 1980s, he and other researchers made a discovery that has been fundamental to understanding evolution as well as developmental biology.

The scientists found a short sequence of DNA, now called the homeobox, that is present not only in Antennapedia but in the several genes next to it and in genes in many other organisms. When geneticists find very similar DNA sequences in the genes of different organisms, it's a good clue that these genes do something so important and useful that evolution uses the same sequence over and over and permits very few changes in its structure as new species evolve.

Researchers quickly discovered nearly identical versions of homeobox DNA in almost every non-bacterial cell they examined—from yeast to plants, frogs, worms, beetles, chickens, mice and people. Hundreds of homeobox-containing genes have been identified, and the proteins they make turn out to be involved in the early stages of development of many species. For example, researchers have found that abnormalities in the homeobox genes can lead to extra fingers or toes in humans.

Back to top The Tools of Genetics: Mighty Microarrays We now have the ability to attach a piece of every gene in a genome (all of an organism's genes) to a postage stamp-sized glass microscope slide. This ordered series of DNA spots is called a DNA microarray, a gene chip or a DNA chip. DNA fragments are attached to glass or plastic, then fluorescently tagged molecules are washed over the fragments.

Some molecules (green) bind to their complementary sequence. These molecules can be identified because they glow under fluorescent light. The resulting pattern of fluorescence indicates which genes are active. Whichever name you prefer, the chip could also be called revolutionary.

This technology has changed the way many geneticists do their work by making it possible to observe the activity of thousands of genes at once. In recent years, microarrays have become standard equipment for modern biologists, but teachers and students are using them, too.

The Genome Consortium for Active Teaching program ( www.bio.davidson.edu/GCAT) provides resources and instructions for high school and college students to do gene-chip experiments in class.

Microarrays are used to get clues about which genes are expressed to control cell, tissue or organ function. By measuring the level of RNA production for every gene at the same time, researchers can learn the genetic programming that makes cell types different and diseased cells different from healthy ones.

The chips consist of large numbers of DNA fragments distributed in rows in a very small space. The arrays are laid out by robots that can position DNA fragments so precisely that more than 20,000 of them can fit on one microscope slide.

Scientists isolate m RNA from cells grown under two conditions and tag the two sources of RNA with different colors of fluorescent molecules. The two colors of RNA are then placed on the chip, where they attach to complementary DNA fragments anchored to the chip's surface.

Next, a scanner measures the amount of fluorescence at each spot on the chip, revealing how active each gene was (how much m RNA each gene produced). A computer analyzes the patterns of gene activity, providing a snapshot of a genome under two conditions ( e.g., healthy or diseased). In December 2004, the U. S. Food and Drug Administration cleared the first gene chip for medical use. The Amplichip CYP450™, made by Roche Molecular Systems Inc. of Pleasanton, California, analyzes variations in two genes that play a major role in the body's processing of many widely prescribed drugs.

This information can help doctors choose the proper dose of certain medicines for an individual patient. Back to top Got It? Why are some infections hard to treat with antibiotics? What are some things researchers might do to solve this public health problem?

How does DNA work as a form of information storage? How can 20,000 human genes provide the instructions for making hundreds of thousands of different proteins? What newborn tests does your area hospital routinely do? Next Chapter "

. These pieces, called exons, are thought to make up 1 percent of a person's genome. Together, all the exons in a genome are known as the exome, and the method of sequencing them is known as whole exome sequencing.

What are whole exome sequencing and whole genome sequencing?

Determining the order of DNA building blocks (nucleotides) in an individual's genetic code, called DNA sequencing, has advanced the study of genetics and is one technique used to test for genetic disorders. Two methods, whole exome sequencing and whole genome sequencing, are increasingly used in healthcare and research to identify genetic variations; both methods rely on new technologies that allow rapid sequencing of large amounts of DNA.

These approaches are known as next-generation sequencing (or next-gen sequencing). The original sequencing technology, called Sanger sequencing (named after the scientist who developed it, Frederick Sanger), was a breakthrough that helped scientists determine the human genetic code, but it is time-consuming and expensive.

The Sanger method has been automated to make it faster and is still used in laboratories today to sequence short pieces of DNA, but it would take years to sequence all of a person's DNA (known as the person's genome). Next-generation sequencing has sped up the process (taking only days to weeks to sequence a human genome) while reducing the cost.

With next-generation sequencing, it is now feasible to sequence large amounts of DNA, for instance all the pieces of an individual's DNA that provide instructions for making proteins

This method allows variations in the protein-coding region of any gene to be identified, rather than in only a select few genes. Because most known mutations that cause disease occur in exons, whole exome sequencing is thought to be an efficient method to identify possible disease-causing mutations.

However, researchers have found that DNA variations outside the exons can affect gene activity and protein production and lead to genetic disorders--variations that whole exome sequencing would miss. Another method, called whole genome sequencing, determines the order of all the nucleotides in an individual's DNA and can determine variations in any part of the genome. While many more genetic changes can be identified with whole exome and whole genome sequencing than with select gene sequencing, the significance of much of this information is unknown.

Because not all genetic changes affect health, it is difficult to know whether identified variants are involved in the condition of interest.

Sometimes, an identified variant is associated with a different genetic disorder that has not yet been diagnosed (these are called incidental or secondary findings). In addition to being used in the clinic, whole exome and whole genome sequencing are valuable methods for researchers.

Continued study of exome and genome sequences can help determine whether new genetic variations are associated with health conditions, which will aid disease diagnosis in the future. For more information about DNA sequencing technologies and their use: Genetics Home Reference discusses whether all genetic changes affect health and development.

A scientist at the Genome Institute at Washington University in St. Louis describes the different sequencing technologies and what the new technologies have meant for the study of the genetic code. An illustration of the decline in the cost of DNA sequencing, including that caused by the introduction of new technologies, is provided by the National Human Genome Research Institute.

The American College of Medical Genetics and Genomics has laid out their policies regarding whole exome and whole genome sequencing (PDF), including when these methods should be used, what results may arise, and what the results might indicate. Gene Reviews compares whole genome sequencing, whole exome sequencing, and the sequencing of a selection of individual genes, particularly their use in the diagnosis of genetic conditions.

The PHG Foundation provides an overview of whole genome sequencing and how it can be used in healthcare. The Mount Sinai School of Medicine Genomics Core Facility describes the techniques used in whole exome sequencing. The Smithsonian National Museum of Natural History's exhibit 'Genome: Unlocking Life's Code' discusses the advancements made in DNA sequencing.

(ĭn'trŏn) A segment of a gene situated between exons that does not function in coding for protein synthesis. After transcription of a gene to messenger RNA, the transcriptions of introns are removed, and the exons are spliced together by enzymes before translation and assembly of amino acids into proteins. Compare exon.

intron

intron [ in -tron]Spell Syllables Word Originnoun, Genetics.1. a noncoding segment in a length of DNA that interrupts a gene-coding sequence or nontranslated sequence, the corresponding segment being removed from the RNA copy before transcription. Expand Also called intervening sequence. Expand Compare exon 2 . Origin of intron Expand1975-19801975-80; perhaps intr (o)- + -on 1Dictionary.com Unabridged Based on the Random House Dictionary, © Random House, Inc. 2018.

Cite This Source British Dictionary definitions for intron Expandintron/ ˈɪntrɒn /noun1. ( biochem) a stretch of DNA that interrupts a gene and does not contribute to the specification of a protein Compare exon 2Word Origin C20: from intr ( agenic) ( regi) on Collins English Dictionary - Complete & Unabridged 2012 Digital Edition © William Collins Sons & Co. Ltd. 1979, 1986 © Harper Collins Publishers 1998, 2000, 2003, 2005, 2006, 2007, 2009, 2012 Cite This Source Word Origin and History for intron Expand1978, from intragenic + -on.

Online Etymology Dictionary, © 2010 Douglas Harper Cite This Sourceintron in Medicine Expandintron in·tron (ĭn'trŏn) n. A segment of a gene situated between exons that does not function in coding for protein synthesis. The American Heritage® Stedman's Medical Dictionary Copyright © 2002, 2001, 1995 by Houghton Mifflin Company. Published by Houghton Mifflin Company. Cite This Sourceintron in Science Expandintron

The American Heritage® Science Dictionary Copyright © 2002. Published by Houghton Mifflin. All rights reserved.

Cite This Sourceintron in Culture Expandintron definition A stretch of DNA in a gene that does not code for proteins.

In eukaryotes, introns in a given gene separate stretches of DNA that contain instructions for constructing proteins. ( Compare exon . )The New Dictionary of Cultural Literacy, Third Edition Copyright © 2005 by Houghton Mifflin Company. Published by Houghton Mifflin Company. All rights reserved. Cite This Source