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Evolutionary processes acting on candidate cis-regulatory regions in humans inferred from patterns of polymorphism and divergence.

Torgerson DG, Boyko AR, Hernandez RD, Indap A, Hu X, White TJ, Sninsky JJ, Cargill M, Adams MD, Bustamante CD, Clark AG - PLoS Genet. (2009)

Bottom Line: Candidate cis-regulatory regions spanning more than 15,000 genes in 15 African Americans and 20 European Americans were re-sequenced and aligned to the chimpanzee genome in order to identify potentially functional polymorphism and to characterize and quantify departures from neutral evolution.Extensions of the McDonald-Kreitman test identified candidate cis-regulatory regions with high probabilities of positive and negative selection near many known human genes, the biological characteristics of which exhibit genome-wide trends that differ from patterns observed in protein-coding regions.Overall we find that natural selection has played an important role in the evolution of candidate cis-regulatory regions throughout hominid evolution.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York, USA. dara@uchicago.edu

ABSTRACT
Analysis of polymorphism and divergence in the non-coding portion of the human genome yields crucial information about factors driving the evolution of gene regulation. Candidate cis-regulatory regions spanning more than 15,000 genes in 15 African Americans and 20 European Americans were re-sequenced and aligned to the chimpanzee genome in order to identify potentially functional polymorphism and to characterize and quantify departures from neutral evolution. Distortions of the site frequency spectra suggest a general pattern of selective constraint on conserved non-coding sites in the flanking regions of genes (CNCs). Moreover, there is an excess of fixed differences that cannot be explained by a Gamma model of deleterious fitness effects, suggesting the presence of positive selection on CNCs. Extensions of the McDonald-Kreitman test identified candidate cis-regulatory regions with high probabilities of positive and negative selection near many known human genes, the biological characteristics of which exhibit genome-wide trends that differ from patterns observed in protein-coding regions. Notably, there is a higher probability of positive selection in candidate cis-regulatory regions near genes expressed in the fetal brain, suggesting that a larger portion of adaptive regulatory changes has occurred in genes expressed during brain development. Overall we find that natural selection has played an important role in the evolution of candidate cis-regulatory regions throughout hominid evolution.

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Correlation in estimates of γ at different classes of sites within a gene.There is a significant, yet weak positive correlation between estimates of γ in candidate cis-regulatory regions and nonsynonymous sites in both African Americans (top left) (Kendall's tau = 0.055, p = 1.8×10−11), and European Americans (top right) (tau = 0.043, p = 2.9×10−7). There is a slightly stronger correlation between synonymous and nonsynonymous sites in both African Americans (bottom left) (tau = 0.096, p<10−16), and European Americans (bottom right) (tau = 0.087, p<10−16). Candidate cis-regulatory, synonymous, and nonsynonymous sites were run in a single, concurrent run of mkprf.
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pgen-1000592-g004: Correlation in estimates of γ at different classes of sites within a gene.There is a significant, yet weak positive correlation between estimates of γ in candidate cis-regulatory regions and nonsynonymous sites in both African Americans (top left) (Kendall's tau = 0.055, p = 1.8×10−11), and European Americans (top right) (tau = 0.043, p = 2.9×10−7). There is a slightly stronger correlation between synonymous and nonsynonymous sites in both African Americans (bottom left) (tau = 0.096, p<10−16), and European Americans (bottom right) (tau = 0.087, p<10−16). Candidate cis-regulatory, synonymous, and nonsynonymous sites were run in a single, concurrent run of mkprf.

Mentions: First we looked for a correlation between selection acting on coding and candidate cis-regulatory regions, and observe what appears to be a complex relationship (Figure 4). In AAs we find a weak yet significant rank correlation between nonsynonymous and non-coding regions for both the probability of positive (Kendall's tau = 0.055, p = 1.6×10−11) and negative selection (tau = 0.056, p = 9.6×10−12), and between synonymous and non-coding regions (positive selection: tau = 0.060, p = 2.1×10−13; negative selection: tau = 0.060, p = 4.1×10−13). The correlation between synonymous and nonsynonymous sites appears to be slightly stronger (positive selection: tau = 0.098, p<10−16; negative selection: tau = 0.096, p<10−16), as expected due to increased linkage disequilibrium from a closer proximity between sites. Results from the EA sample are similar. However, given the small values of tau, identifying genes with evidence for selection in coding regions may be a poor predictor of whether a gene will show evidence for selection in the same direction as candidate cis-regulatory regions. A recent study has found that genes with patterns of expression consistent with any direction of selection (either positive or negative) exhibit reduced rates of protein evolution on nonsynonymous sites [25], which is consistent with only a weak correlation in the probability of selection between sites. The lack of a strong correlation in the mode of selection also suggests that the effect of linkage between candidate cis-regulatory and protein coding regions may be small, increasing the probability that we are detecting signatures of selection that are specific to non-coding regions.


Evolutionary processes acting on candidate cis-regulatory regions in humans inferred from patterns of polymorphism and divergence.

Torgerson DG, Boyko AR, Hernandez RD, Indap A, Hu X, White TJ, Sninsky JJ, Cargill M, Adams MD, Bustamante CD, Clark AG - PLoS Genet. (2009)

Correlation in estimates of γ at different classes of sites within a gene.There is a significant, yet weak positive correlation between estimates of γ in candidate cis-regulatory regions and nonsynonymous sites in both African Americans (top left) (Kendall's tau = 0.055, p = 1.8×10−11), and European Americans (top right) (tau = 0.043, p = 2.9×10−7). There is a slightly stronger correlation between synonymous and nonsynonymous sites in both African Americans (bottom left) (tau = 0.096, p<10−16), and European Americans (bottom right) (tau = 0.087, p<10−16). Candidate cis-regulatory, synonymous, and nonsynonymous sites were run in a single, concurrent run of mkprf.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2714078&req=5

pgen-1000592-g004: Correlation in estimates of γ at different classes of sites within a gene.There is a significant, yet weak positive correlation between estimates of γ in candidate cis-regulatory regions and nonsynonymous sites in both African Americans (top left) (Kendall's tau = 0.055, p = 1.8×10−11), and European Americans (top right) (tau = 0.043, p = 2.9×10−7). There is a slightly stronger correlation between synonymous and nonsynonymous sites in both African Americans (bottom left) (tau = 0.096, p<10−16), and European Americans (bottom right) (tau = 0.087, p<10−16). Candidate cis-regulatory, synonymous, and nonsynonymous sites were run in a single, concurrent run of mkprf.
Mentions: First we looked for a correlation between selection acting on coding and candidate cis-regulatory regions, and observe what appears to be a complex relationship (Figure 4). In AAs we find a weak yet significant rank correlation between nonsynonymous and non-coding regions for both the probability of positive (Kendall's tau = 0.055, p = 1.6×10−11) and negative selection (tau = 0.056, p = 9.6×10−12), and between synonymous and non-coding regions (positive selection: tau = 0.060, p = 2.1×10−13; negative selection: tau = 0.060, p = 4.1×10−13). The correlation between synonymous and nonsynonymous sites appears to be slightly stronger (positive selection: tau = 0.098, p<10−16; negative selection: tau = 0.096, p<10−16), as expected due to increased linkage disequilibrium from a closer proximity between sites. Results from the EA sample are similar. However, given the small values of tau, identifying genes with evidence for selection in coding regions may be a poor predictor of whether a gene will show evidence for selection in the same direction as candidate cis-regulatory regions. A recent study has found that genes with patterns of expression consistent with any direction of selection (either positive or negative) exhibit reduced rates of protein evolution on nonsynonymous sites [25], which is consistent with only a weak correlation in the probability of selection between sites. The lack of a strong correlation in the mode of selection also suggests that the effect of linkage between candidate cis-regulatory and protein coding regions may be small, increasing the probability that we are detecting signatures of selection that are specific to non-coding regions.

Bottom Line: Candidate cis-regulatory regions spanning more than 15,000 genes in 15 African Americans and 20 European Americans were re-sequenced and aligned to the chimpanzee genome in order to identify potentially functional polymorphism and to characterize and quantify departures from neutral evolution.Extensions of the McDonald-Kreitman test identified candidate cis-regulatory regions with high probabilities of positive and negative selection near many known human genes, the biological characteristics of which exhibit genome-wide trends that differ from patterns observed in protein-coding regions.Overall we find that natural selection has played an important role in the evolution of candidate cis-regulatory regions throughout hominid evolution.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York, USA. dara@uchicago.edu

ABSTRACT
Analysis of polymorphism and divergence in the non-coding portion of the human genome yields crucial information about factors driving the evolution of gene regulation. Candidate cis-regulatory regions spanning more than 15,000 genes in 15 African Americans and 20 European Americans were re-sequenced and aligned to the chimpanzee genome in order to identify potentially functional polymorphism and to characterize and quantify departures from neutral evolution. Distortions of the site frequency spectra suggest a general pattern of selective constraint on conserved non-coding sites in the flanking regions of genes (CNCs). Moreover, there is an excess of fixed differences that cannot be explained by a Gamma model of deleterious fitness effects, suggesting the presence of positive selection on CNCs. Extensions of the McDonald-Kreitman test identified candidate cis-regulatory regions with high probabilities of positive and negative selection near many known human genes, the biological characteristics of which exhibit genome-wide trends that differ from patterns observed in protein-coding regions. Notably, there is a higher probability of positive selection in candidate cis-regulatory regions near genes expressed in the fetal brain, suggesting that a larger portion of adaptive regulatory changes has occurred in genes expressed during brain development. Overall we find that natural selection has played an important role in the evolution of candidate cis-regulatory regions throughout hominid evolution.

Show MeSH
Related in: MedlinePlus