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Comparative genomics.

Hardison RC - PLoS Biol. (2003)

View Article: PubMed Central - PubMed

Affiliation: Center for Comparative Genomics and Bioinformatics at The Pennsylvania State University in University Park, Pennsylvania, USA. rch8@psu.edu <rch8@psu.edu>

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A complete genome sequence of an organism can be considered to be the ultimate genetic map, in the sense that the heritable characteristics are encoded within the DNA and that the order of all the nucleotides along each chromosome is known... However, knowledge of the DNA sequence does not tell us directly how this genetic information leads to the observable traits and behaviors (phenotypes) that we want to understand... Over such very large distances, the order of genes and the sequences regulating their expression are generally not conserved... At moderate phylogenetic distances (roughly 70–100 million years of divergence), both functional and nonfunctional DNA is found within the conserved DNA... These regions of conserved synteny have many genes from one human chromosome that match genes on a mouse chromosome, often in very similar orders... In most cases, the intron-exon structures are highly conserved... This extensive conservation in protein-coding regions may be expected, because many biochemical functions of humans should also be found in mouse... One class, occupying about 24% of the genome, is comprised of the repetitive elements that arose by transposition only on the human lineage... These particular insertions did not occur in mice, and thus they cannot align between human and mouse... As genome sequences from additional species are determined, the various possible explanations for this nonaligning, nonrepetitive DNA can be tested... The list includes several yeast species to compare with Saccharomyces cerevisiae, another Drosophila species and Anopheles to compare with Drosophila melanogaster, mouse to compare with human, and now C. briggsae to compare with C. elegans... Other approaches using multiple sequences from more closely related species substantially improve the resolving power of comparative genomics... Researchers may reasonably expect in the near future to have results of this comparative analysis readily available... By calibrating these results, such as estimated likelihoods of being under selection, likelihood of being a coding exon, etc., against known functional elements, the power of the comparative approaches should improve.

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Examples of UCSC Genome Browser Views of Genes and AlignmentsThe unc-52 gene in C. elegans (A) and part of its homolog HSPG2 in human (B) are shown, with rectangles for exons and lines for introns; arrows along the introns show the direction of transcription. Both genes encode a chondroitin sulfate proteoglycan. The gene in C. elegans is much smaller (about 29 kb) than the gene in humans (about 180 kb; only the 5′ portion is shown in [B]). The positions of alignments between C. elegans and C. briggsae are shown by the purple rectangles in (A). The probability that alignments between human and mouse result from purifying selection are plotted along the Human Cons track in (B). Note that in both comparisons, substantial amounts of intronic and flanking regions align, and several peaks of likely-selected DNA are seen for the human-mouse alignments in the noncoding regions. Among these are candidates for regulatory elements.
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pbio.0000058-g002: Examples of UCSC Genome Browser Views of Genes and AlignmentsThe unc-52 gene in C. elegans (A) and part of its homolog HSPG2 in human (B) are shown, with rectangles for exons and lines for introns; arrows along the introns show the direction of transcription. Both genes encode a chondroitin sulfate proteoglycan. The gene in C. elegans is much smaller (about 29 kb) than the gene in humans (about 180 kb; only the 5′ portion is shown in [B]). The positions of alignments between C. elegans and C. briggsae are shown by the purple rectangles in (A). The probability that alignments between human and mouse result from purifying selection are plotted along the Human Cons track in (B). Note that in both comparisons, substantial amounts of intronic and flanking regions align, and several peaks of likely-selected DNA are seen for the human-mouse alignments in the noncoding regions. Among these are candidates for regulatory elements.

Mentions: Regions of noncoding DNA with a particularly high similarity among species have long been recognized as good candidates for functional regions (Hardison et al. 1997; Pennacchio and Rubin 2001), and several have been confirmed as gene regulatory sequences (e.g., Loots et al. 2000). However, the appropriate threshold for the level of sequence similarity that is diagnostic for functional sequences has not been established, and investigators use a variety of such thresholds. What is needed is a robust assessment of the likelihood that a particular alignment results from purifying selection rather than evolutionary drift. The analysis is complicated by the variable rate of neutral evolution within species, but solutions have been developed and are being improved. Comparison of the rates of within-species polymorphism and between-species divergence has proven effective for monitoring selection in nucleotides sequences from Drosophila species (Hudson et al. 1987). This method uses the intraspecies polymorphism measurements as a monitor of neutral evolution, and deviations from neutrality, measured as significantly less interspecies change than expected, are indicators of selection. For the human-mouse genome comparisons, the local neutral rate was estimated from the divergence of aligned ancestral repeats, and similarity scores were adjusted accordingly. By evaluating the distribution of these similarity scores in likely-neutral DNA and in DNA inferred as being under selection, a probability that any human-mouse alignment reflects purifying selection can be computed (Figure 2), and such scores are available genome-wide on the UCSC Genome Browser.


Comparative genomics.

Hardison RC - PLoS Biol. (2003)

Examples of UCSC Genome Browser Views of Genes and AlignmentsThe unc-52 gene in C. elegans (A) and part of its homolog HSPG2 in human (B) are shown, with rectangles for exons and lines for introns; arrows along the introns show the direction of transcription. Both genes encode a chondroitin sulfate proteoglycan. The gene in C. elegans is much smaller (about 29 kb) than the gene in humans (about 180 kb; only the 5′ portion is shown in [B]). The positions of alignments between C. elegans and C. briggsae are shown by the purple rectangles in (A). The probability that alignments between human and mouse result from purifying selection are plotted along the Human Cons track in (B). Note that in both comparisons, substantial amounts of intronic and flanking regions align, and several peaks of likely-selected DNA are seen for the human-mouse alignments in the noncoding regions. Among these are candidates for regulatory elements.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC261895&req=5

pbio.0000058-g002: Examples of UCSC Genome Browser Views of Genes and AlignmentsThe unc-52 gene in C. elegans (A) and part of its homolog HSPG2 in human (B) are shown, with rectangles for exons and lines for introns; arrows along the introns show the direction of transcription. Both genes encode a chondroitin sulfate proteoglycan. The gene in C. elegans is much smaller (about 29 kb) than the gene in humans (about 180 kb; only the 5′ portion is shown in [B]). The positions of alignments between C. elegans and C. briggsae are shown by the purple rectangles in (A). The probability that alignments between human and mouse result from purifying selection are plotted along the Human Cons track in (B). Note that in both comparisons, substantial amounts of intronic and flanking regions align, and several peaks of likely-selected DNA are seen for the human-mouse alignments in the noncoding regions. Among these are candidates for regulatory elements.
Mentions: Regions of noncoding DNA with a particularly high similarity among species have long been recognized as good candidates for functional regions (Hardison et al. 1997; Pennacchio and Rubin 2001), and several have been confirmed as gene regulatory sequences (e.g., Loots et al. 2000). However, the appropriate threshold for the level of sequence similarity that is diagnostic for functional sequences has not been established, and investigators use a variety of such thresholds. What is needed is a robust assessment of the likelihood that a particular alignment results from purifying selection rather than evolutionary drift. The analysis is complicated by the variable rate of neutral evolution within species, but solutions have been developed and are being improved. Comparison of the rates of within-species polymorphism and between-species divergence has proven effective for monitoring selection in nucleotides sequences from Drosophila species (Hudson et al. 1987). This method uses the intraspecies polymorphism measurements as a monitor of neutral evolution, and deviations from neutrality, measured as significantly less interspecies change than expected, are indicators of selection. For the human-mouse genome comparisons, the local neutral rate was estimated from the divergence of aligned ancestral repeats, and similarity scores were adjusted accordingly. By evaluating the distribution of these similarity scores in likely-neutral DNA and in DNA inferred as being under selection, a probability that any human-mouse alignment reflects purifying selection can be computed (Figure 2), and such scores are available genome-wide on the UCSC Genome Browser.

View Article: PubMed Central - PubMed

Affiliation: Center for Comparative Genomics and Bioinformatics at The Pennsylvania State University in University Park, Pennsylvania, USA. rch8@psu.edu <rch8@psu.edu>

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

A complete genome sequence of an organism can be considered to be the ultimate genetic map, in the sense that the heritable characteristics are encoded within the DNA and that the order of all the nucleotides along each chromosome is known... However, knowledge of the DNA sequence does not tell us directly how this genetic information leads to the observable traits and behaviors (phenotypes) that we want to understand... Over such very large distances, the order of genes and the sequences regulating their expression are generally not conserved... At moderate phylogenetic distances (roughly 70–100 million years of divergence), both functional and nonfunctional DNA is found within the conserved DNA... These regions of conserved synteny have many genes from one human chromosome that match genes on a mouse chromosome, often in very similar orders... In most cases, the intron-exon structures are highly conserved... This extensive conservation in protein-coding regions may be expected, because many biochemical functions of humans should also be found in mouse... One class, occupying about 24% of the genome, is comprised of the repetitive elements that arose by transposition only on the human lineage... These particular insertions did not occur in mice, and thus they cannot align between human and mouse... As genome sequences from additional species are determined, the various possible explanations for this nonaligning, nonrepetitive DNA can be tested... The list includes several yeast species to compare with Saccharomyces cerevisiae, another Drosophila species and Anopheles to compare with Drosophila melanogaster, mouse to compare with human, and now C. briggsae to compare with C. elegans... Other approaches using multiple sequences from more closely related species substantially improve the resolving power of comparative genomics... Researchers may reasonably expect in the near future to have results of this comparative analysis readily available... By calibrating these results, such as estimated likelihoods of being under selection, likelihood of being a coding exon, etc., against known functional elements, the power of the comparative approaches should improve.

Show MeSH