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Hotspots of biased nucleotide substitutions in human genes.

Berglund J, Pollard KS, Webster MT - PLoS Biol. (2009)

Bottom Line: We next analyzed genes with significantly elevated ratios of nonsynonymous to synonymous rates of base substitution (dN/dS) along the human lineage, and those with an excess of amino acid replacement substitutions relative to human polymorphism.These findings indicate that a recombination-associated process, such as biased gene conversion (BGC), is driving fixation of GC alleles in the human genome.This process can lead to accelerated evolution in coding sequences and excess amino acid replacement substitutions, thereby generating significant results for tests of positive selection.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.

ABSTRACT
Genes that have experienced accelerated evolutionary rates on the human lineage during recent evolution are candidates for involvement in human-specific adaptations. To determine the forces that cause increased evolutionary rates in certain genes, we analyzed alignments of 10,238 human genes to their orthologues in chimpanzee and macaque. Using a likelihood ratio test, we identified protein-coding sequences with an accelerated rate of base substitutions along the human lineage. Exons evolving at a fast rate in humans have a significant tendency to contain clusters of AT-to-GC (weak-to-strong) biased substitutions. This pattern is also observed in noncoding sequence flanking rapidly evolving exons. Accelerated exons occur in regions with elevated male recombination rates and exhibit an excess of nonsynonymous substitutions relative to the genomic average. We next analyzed genes with significantly elevated ratios of nonsynonymous to synonymous rates of base substitution (dN/dS) along the human lineage, and those with an excess of amino acid replacement substitutions relative to human polymorphism. These genes also show evidence of clusters of weak-to-strong biased substitutions. These findings indicate that a recombination-associated process, such as biased gene conversion (BGC), is driving fixation of GC alleles in the human genome. This process can lead to accelerated evolution in coding sequences and excess amino acid replacement substitutions, thereby generating significant results for tests of positive selection.

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Venn Diagram Showing Overlap between Three Different Subsets of Fast-Evolving GenesGenes with evidence for accelerated dN/dS on the human lineage based on a LRT p<0.05 using a chi-squared test are shown in one circle. Genes containing exons with evidence for accelerated evolutionary rate in humans based on simulations with a FDR p < 0.05 are in the second circle. Genes with evidence for a significant McDonald-Kreitman test [39] with p < 0.05 are in the third circle.
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pbio-1000026-g005: Venn Diagram Showing Overlap between Three Different Subsets of Fast-Evolving GenesGenes with evidence for accelerated dN/dS on the human lineage based on a LRT p<0.05 using a chi-squared test are shown in one circle. Genes containing exons with evidence for accelerated evolutionary rate in humans based on simulations with a FDR p < 0.05 are in the second circle. Genes with evidence for a significant McDonald-Kreitman test [39] with p < 0.05 are in the third circle.

Mentions: Figure 5 indicates the overlap between the main sets of fast-evolving genes we have identified. Fourteen genes with accelerated dN/dS on the human lineage at the p < 0.05 level also contain accelerated exons. This is significantly higher than the 3.9 genes expected purely by chance (binomial test p = 3.0 × 10−5), although it is not surprising that genes with evidence for acceleration in the relative rate of nonsynonymous substitutions also show evidence for acceleration in evolutionary rates overall. Eleven of the genes with accelerated dN/dS also show evidence for an excess of amino acid substitutions using the MK test [39] at the p < 0.05 level, which is larger than the 5.9 expected, but not significant (p = 0.051). Five of the genes with significant MK tests also contain accelerated exons, which is larger than the 2.0 expected, but not significant (p = 0.054). The three different tests therefore have a tendency to identify some of the same genes, but in general they appear to target genes with different evolutionary histories.


Hotspots of biased nucleotide substitutions in human genes.

Berglund J, Pollard KS, Webster MT - PLoS Biol. (2009)

Venn Diagram Showing Overlap between Three Different Subsets of Fast-Evolving GenesGenes with evidence for accelerated dN/dS on the human lineage based on a LRT p<0.05 using a chi-squared test are shown in one circle. Genes containing exons with evidence for accelerated evolutionary rate in humans based on simulations with a FDR p < 0.05 are in the second circle. Genes with evidence for a significant McDonald-Kreitman test [39] with p < 0.05 are in the third circle.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2631073&req=5

pbio-1000026-g005: Venn Diagram Showing Overlap between Three Different Subsets of Fast-Evolving GenesGenes with evidence for accelerated dN/dS on the human lineage based on a LRT p<0.05 using a chi-squared test are shown in one circle. Genes containing exons with evidence for accelerated evolutionary rate in humans based on simulations with a FDR p < 0.05 are in the second circle. Genes with evidence for a significant McDonald-Kreitman test [39] with p < 0.05 are in the third circle.
Mentions: Figure 5 indicates the overlap between the main sets of fast-evolving genes we have identified. Fourteen genes with accelerated dN/dS on the human lineage at the p < 0.05 level also contain accelerated exons. This is significantly higher than the 3.9 genes expected purely by chance (binomial test p = 3.0 × 10−5), although it is not surprising that genes with evidence for acceleration in the relative rate of nonsynonymous substitutions also show evidence for acceleration in evolutionary rates overall. Eleven of the genes with accelerated dN/dS also show evidence for an excess of amino acid substitutions using the MK test [39] at the p < 0.05 level, which is larger than the 5.9 expected, but not significant (p = 0.051). Five of the genes with significant MK tests also contain accelerated exons, which is larger than the 2.0 expected, but not significant (p = 0.054). The three different tests therefore have a tendency to identify some of the same genes, but in general they appear to target genes with different evolutionary histories.

Bottom Line: We next analyzed genes with significantly elevated ratios of nonsynonymous to synonymous rates of base substitution (dN/dS) along the human lineage, and those with an excess of amino acid replacement substitutions relative to human polymorphism.These findings indicate that a recombination-associated process, such as biased gene conversion (BGC), is driving fixation of GC alleles in the human genome.This process can lead to accelerated evolution in coding sequences and excess amino acid replacement substitutions, thereby generating significant results for tests of positive selection.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.

ABSTRACT
Genes that have experienced accelerated evolutionary rates on the human lineage during recent evolution are candidates for involvement in human-specific adaptations. To determine the forces that cause increased evolutionary rates in certain genes, we analyzed alignments of 10,238 human genes to their orthologues in chimpanzee and macaque. Using a likelihood ratio test, we identified protein-coding sequences with an accelerated rate of base substitutions along the human lineage. Exons evolving at a fast rate in humans have a significant tendency to contain clusters of AT-to-GC (weak-to-strong) biased substitutions. This pattern is also observed in noncoding sequence flanking rapidly evolving exons. Accelerated exons occur in regions with elevated male recombination rates and exhibit an excess of nonsynonymous substitutions relative to the genomic average. We next analyzed genes with significantly elevated ratios of nonsynonymous to synonymous rates of base substitution (dN/dS) along the human lineage, and those with an excess of amino acid replacement substitutions relative to human polymorphism. These genes also show evidence of clusters of weak-to-strong biased substitutions. These findings indicate that a recombination-associated process, such as biased gene conversion (BGC), is driving fixation of GC alleles in the human genome. This process can lead to accelerated evolution in coding sequences and excess amino acid replacement substitutions, thereby generating significant results for tests of positive selection.

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