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The Impact of Recombination on Nucleotide Substitutions in the Human Genome

Unraveling the evolutionary forces responsible for variations of neutral substitution patterns among taxa or along genomes is a major issue for detecting selection within sequences. Mammalian genomes show large-scale regional variations of GC-content (the isochores), but the substitution processes a...

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Autores principales: Duret, Laurent, Arndt, Peter F.
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2008
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2346554/
https://www.ncbi.nlm.nih.gov/pubmed/18464896
http://dx.doi.org/10.1371/journal.pgen.1000071
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author Duret, Laurent
Arndt, Peter F.
author_facet Duret, Laurent
Arndt, Peter F.
author_sort Duret, Laurent
collection PubMed
description Unraveling the evolutionary forces responsible for variations of neutral substitution patterns among taxa or along genomes is a major issue for detecting selection within sequences. Mammalian genomes show large-scale regional variations of GC-content (the isochores), but the substitution processes at the origin of this structure are poorly understood. We analyzed the pattern of neutral substitutions in 1 Gb of primate non-coding regions. We show that the GC-content toward which sequences are evolving is strongly negatively correlated to the distance to telomeres and positively correlated to the rate of crossovers (R(2) = 47%). This demonstrates that recombination has a major impact on substitution patterns in human, driving the evolution of GC-content. The evolution of GC-content correlates much more strongly with male than with female crossover rate, which rules out selectionist models for the evolution of isochores. This effect of recombination is most probably a consequence of the neutral process of biased gene conversion (BGC) occurring within recombination hotspots. We show that the predictions of this model fit very well with the observed substitution patterns in the human genome. This model notably explains the positive correlation between substitution rate and recombination rate. Theoretical calculations indicate that variations in population size or density in recombination hotspots can have a very strong impact on the evolution of base composition. Furthermore, recombination hotspots can create strong substitution hotspots. This molecular drive affects both coding and non-coding regions. We therefore conclude that along with mutation, selection and drift, BGC is one of the major factors driving genome evolution. Our results also shed light on variations in the rate of crossover relative to non-crossover events, along chromosomes and according to sex, and also on the conservation of hotspot density between human and chimp.
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spelling pubmed-23465542008-05-09 The Impact of Recombination on Nucleotide Substitutions in the Human Genome Duret, Laurent Arndt, Peter F. PLoS Genet Research Article Unraveling the evolutionary forces responsible for variations of neutral substitution patterns among taxa or along genomes is a major issue for detecting selection within sequences. Mammalian genomes show large-scale regional variations of GC-content (the isochores), but the substitution processes at the origin of this structure are poorly understood. We analyzed the pattern of neutral substitutions in 1 Gb of primate non-coding regions. We show that the GC-content toward which sequences are evolving is strongly negatively correlated to the distance to telomeres and positively correlated to the rate of crossovers (R(2) = 47%). This demonstrates that recombination has a major impact on substitution patterns in human, driving the evolution of GC-content. The evolution of GC-content correlates much more strongly with male than with female crossover rate, which rules out selectionist models for the evolution of isochores. This effect of recombination is most probably a consequence of the neutral process of biased gene conversion (BGC) occurring within recombination hotspots. We show that the predictions of this model fit very well with the observed substitution patterns in the human genome. This model notably explains the positive correlation between substitution rate and recombination rate. Theoretical calculations indicate that variations in population size or density in recombination hotspots can have a very strong impact on the evolution of base composition. Furthermore, recombination hotspots can create strong substitution hotspots. This molecular drive affects both coding and non-coding regions. We therefore conclude that along with mutation, selection and drift, BGC is one of the major factors driving genome evolution. Our results also shed light on variations in the rate of crossover relative to non-crossover events, along chromosomes and according to sex, and also on the conservation of hotspot density between human and chimp. Public Library of Science 2008-05-09 /pmc/articles/PMC2346554/ /pubmed/18464896 http://dx.doi.org/10.1371/journal.pgen.1000071 Text en Duret, Arndt. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Duret, Laurent
Arndt, Peter F.
The Impact of Recombination on Nucleotide Substitutions in the Human Genome
title The Impact of Recombination on Nucleotide Substitutions in the Human Genome
title_full The Impact of Recombination on Nucleotide Substitutions in the Human Genome
title_fullStr The Impact of Recombination on Nucleotide Substitutions in the Human Genome
title_full_unstemmed The Impact of Recombination on Nucleotide Substitutions in the Human Genome
title_short The Impact of Recombination on Nucleotide Substitutions in the Human Genome
title_sort impact of recombination on nucleotide substitutions in the human genome
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2346554/
https://www.ncbi.nlm.nih.gov/pubmed/18464896
http://dx.doi.org/10.1371/journal.pgen.1000071
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