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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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Polymorphism and divergence across pooled sites in African and European Americans.
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pgen-1000592-g001: Polymorphism and divergence across pooled sites in African and European Americans.

Mentions: Our non-coding dataset included 6.9 Mb of autosomal conserved non-coding sites (CNCs) resequenced in 15 African Americans (AAs), 20 European Americans (EAs), and aligned to a single chimpanzee (PanTro2), while our coding dataset included 17.5 Mb of autosomal sites resequenced across the same panel of individuals, see [32],[33]. Conserved noncoding sites were defined as strictly non-coding sites that fall within human and mouse conserved sequences (sequences with at least 70% identity and 100 nucleotides in length). We found at least one human polymorphism or fixed difference to the chimpanzee in CNCs flanking a total of 11,334 autosomal genes (75.4%), with 7,826 genes having at least one human polymorphism across the 35 individuals (52.9%). CNCs that are flanking genes tend to have lower divergence and polymorphism compared to those in intergenic regions, however all categories of CNCs exhibit lower polymorphism and divergence as compared to synonymous sites (Figure 1). In AAs, CNCs in 5′ upstream regions have a smaller ratio of divergence to polymorphism when compared to synonymous sites, consistent with the presence of selective constraint in the upstream regions of genes (p = 0.029, Table 1). However, the overall ratio of divergence to polymorphism is generally similar between pooled CNCs and synonymous sites (p>0.05, Table 1), and all categories of CNCs exhibit a higher ratio of divergence to polymorphism when compared to nonsynonymous sites.


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)

Polymorphism and divergence across pooled sites in African and European Americans.
© Copyright Policy
Related In: Results  -  Collection

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

pgen-1000592-g001: Polymorphism and divergence across pooled sites in African and European Americans.
Mentions: Our non-coding dataset included 6.9 Mb of autosomal conserved non-coding sites (CNCs) resequenced in 15 African Americans (AAs), 20 European Americans (EAs), and aligned to a single chimpanzee (PanTro2), while our coding dataset included 17.5 Mb of autosomal sites resequenced across the same panel of individuals, see [32],[33]. Conserved noncoding sites were defined as strictly non-coding sites that fall within human and mouse conserved sequences (sequences with at least 70% identity and 100 nucleotides in length). We found at least one human polymorphism or fixed difference to the chimpanzee in CNCs flanking a total of 11,334 autosomal genes (75.4%), with 7,826 genes having at least one human polymorphism across the 35 individuals (52.9%). CNCs that are flanking genes tend to have lower divergence and polymorphism compared to those in intergenic regions, however all categories of CNCs exhibit lower polymorphism and divergence as compared to synonymous sites (Figure 1). In AAs, CNCs in 5′ upstream regions have a smaller ratio of divergence to polymorphism when compared to synonymous sites, consistent with the presence of selective constraint in the upstream regions of genes (p = 0.029, Table 1). However, the overall ratio of divergence to polymorphism is generally similar between pooled CNCs and synonymous sites (p>0.05, Table 1), and all categories of CNCs exhibit a higher ratio of divergence to polymorphism when compared to nonsynonymous sites.

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