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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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Cumulative Average Human Recombination Rate in the Regions Surrounding the Most Accelerated Exons(A) Cumulative average male (red), female (green), and sex-averaged (black) recombination rates.(B) Cumulative average distance to the nearest recombination hotspot.The dashed line represents the average for the entire dataset.
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pbio-1000026-g004: Cumulative Average Human Recombination Rate in the Regions Surrounding the Most Accelerated Exons(A) Cumulative average male (red), female (green), and sex-averaged (black) recombination rates.(B) Cumulative average distance to the nearest recombination hotspot.The dashed line represents the average for the entire dataset.

Mentions: We investigated the recombination rates of the regions where accelerated exons reside. We find that the most accelerated exons tend to be found in regions with elevated male recombination rates. In the top 20 accelerated exons, the average male recombination rate is 2.65, which is significantly higher than the average of all exons in the dataset (0.92; bootstrap p < 0.001). By contrast, female recombination rate in the top 20 accelerated exons is 1.62, which is not significantly higher than the genomic average of 1.69 (bootstrap p = 0.45). Male recombination rate is therefore highly elevated in the most accelerated exons, whereas female recombination rate remains relatively constant (Figure 4A).


Hotspots of biased nucleotide substitutions in human genes.

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

Cumulative Average Human Recombination Rate in the Regions Surrounding the Most Accelerated Exons(A) Cumulative average male (red), female (green), and sex-averaged (black) recombination rates.(B) Cumulative average distance to the nearest recombination hotspot.The dashed line represents the average for the entire dataset.
© Copyright Policy
Related In: Results  -  Collection

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

pbio-1000026-g004: Cumulative Average Human Recombination Rate in the Regions Surrounding the Most Accelerated Exons(A) Cumulative average male (red), female (green), and sex-averaged (black) recombination rates.(B) Cumulative average distance to the nearest recombination hotspot.The dashed line represents the average for the entire dataset.
Mentions: We investigated the recombination rates of the regions where accelerated exons reside. We find that the most accelerated exons tend to be found in regions with elevated male recombination rates. In the top 20 accelerated exons, the average male recombination rate is 2.65, which is significantly higher than the average of all exons in the dataset (0.92; bootstrap p < 0.001). By contrast, female recombination rate in the top 20 accelerated exons is 1.62, which is not significantly higher than the genomic average of 1.69 (bootstrap p = 0.45). Male recombination rate is therefore highly elevated in the most accelerated exons, whereas female recombination rate remains relatively constant (Figure 4A).

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.

Show MeSH