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Chromatin structure and evolution in the human genome

BACKGROUND: Evolutionary rates are not constant across the human genome but genes in close proximity have been shown to experience similar levels of divergence and selection. The higher-order organisation of chromosomes has often been invoked to explain such phenomena but previously there has been i...

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Autores principales: Prendergast, James GD, Campbell, Harry, Gilbert, Nick, Dunlop, Malcolm G, Bickmore, Wendy A, Semple, Colin AM
Formato: Texto
Lenguaje:English
Publicado: BioMed Central 2007
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1876461/
https://www.ncbi.nlm.nih.gov/pubmed/17490477
http://dx.doi.org/10.1186/1471-2148-7-72
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author Prendergast, James GD
Campbell, Harry
Gilbert, Nick
Dunlop, Malcolm G
Bickmore, Wendy A
Semple, Colin AM
author_facet Prendergast, James GD
Campbell, Harry
Gilbert, Nick
Dunlop, Malcolm G
Bickmore, Wendy A
Semple, Colin AM
author_sort Prendergast, James GD
collection PubMed
description BACKGROUND: Evolutionary rates are not constant across the human genome but genes in close proximity have been shown to experience similar levels of divergence and selection. The higher-order organisation of chromosomes has often been invoked to explain such phenomena but previously there has been insufficient data on chromosome structure to investigate this rigorously. Using the results of a recent genome-wide analysis of open and closed human chromatin structures we have investigated the global association between divergence, selection and chromatin structure for the first time. RESULTS: In this study we have shown that, paradoxically, synonymous site divergence (dS) at non-CpG sites is highest in regions of open chromatin, primarily as a result of an increased number of transitions, while the rates of other traditional measures of mutation (intergenic, intronic and ancient repeat divergence as well as SNP density) are highest in closed regions of the genome. Analysis of human-chimpanzee divergence across intron-exon boundaries indicates that although genes in relatively open chromatin generally display little selection at their synonymous sites, those in closed regions show markedly lower divergence at their fourfold degenerate sites than in neighbouring introns and intergenic regions. Exclusion of known Exonic Splice Enhancer hexamers has little affect on the divergence observed at fourfold degenerate sites across chromatin categories; however, we show that closed chromatin is enriched with certain classes of ncRNA genes whose RNA secondary structure may be particularly important. CONCLUSION: We conclude that, overall, non-CpG mutation rates are lowest in open regions of the genome and that regions of the genome with a closed chromatin structure have the highest background mutation rate. This might reflect lower rates of DNA damage or enhanced DNA repair processes in regions of open chromatin. Our results also indicate that dS is a poor measure of mutation rates, particularly when used in closed regions of the genome, as genes in closed regions generally display relatively strong levels of selection at their synonymous sites.
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spelling pubmed-18764612007-05-23 Chromatin structure and evolution in the human genome Prendergast, James GD Campbell, Harry Gilbert, Nick Dunlop, Malcolm G Bickmore, Wendy A Semple, Colin AM BMC Evol Biol Research Article BACKGROUND: Evolutionary rates are not constant across the human genome but genes in close proximity have been shown to experience similar levels of divergence and selection. The higher-order organisation of chromosomes has often been invoked to explain such phenomena but previously there has been insufficient data on chromosome structure to investigate this rigorously. Using the results of a recent genome-wide analysis of open and closed human chromatin structures we have investigated the global association between divergence, selection and chromatin structure for the first time. RESULTS: In this study we have shown that, paradoxically, synonymous site divergence (dS) at non-CpG sites is highest in regions of open chromatin, primarily as a result of an increased number of transitions, while the rates of other traditional measures of mutation (intergenic, intronic and ancient repeat divergence as well as SNP density) are highest in closed regions of the genome. Analysis of human-chimpanzee divergence across intron-exon boundaries indicates that although genes in relatively open chromatin generally display little selection at their synonymous sites, those in closed regions show markedly lower divergence at their fourfold degenerate sites than in neighbouring introns and intergenic regions. Exclusion of known Exonic Splice Enhancer hexamers has little affect on the divergence observed at fourfold degenerate sites across chromatin categories; however, we show that closed chromatin is enriched with certain classes of ncRNA genes whose RNA secondary structure may be particularly important. CONCLUSION: We conclude that, overall, non-CpG mutation rates are lowest in open regions of the genome and that regions of the genome with a closed chromatin structure have the highest background mutation rate. This might reflect lower rates of DNA damage or enhanced DNA repair processes in regions of open chromatin. Our results also indicate that dS is a poor measure of mutation rates, particularly when used in closed regions of the genome, as genes in closed regions generally display relatively strong levels of selection at their synonymous sites. BioMed Central 2007-05-09 /pmc/articles/PMC1876461/ /pubmed/17490477 http://dx.doi.org/10.1186/1471-2148-7-72 Text en Copyright © 2007 Prendergast et al; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( (http://creativecommons.org/licenses/by/2.0) ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Prendergast, James GD
Campbell, Harry
Gilbert, Nick
Dunlop, Malcolm G
Bickmore, Wendy A
Semple, Colin AM
Chromatin structure and evolution in the human genome
title Chromatin structure and evolution in the human genome
title_full Chromatin structure and evolution in the human genome
title_fullStr Chromatin structure and evolution in the human genome
title_full_unstemmed Chromatin structure and evolution in the human genome
title_short Chromatin structure and evolution in the human genome
title_sort chromatin structure and evolution in the human genome
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1876461/
https://www.ncbi.nlm.nih.gov/pubmed/17490477
http://dx.doi.org/10.1186/1471-2148-7-72
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