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Human mutation rate associated with DNA replication timing

Published on Apr 1, 2009in Nature Genetics25.455
路 DOI :10.1038/ng.363
John A. Stamatoyannopoulos80
Estimated H-index: 80
(UW: University of Washington),
Ivan Adzhubei15
Estimated H-index: 15
(Brigham and Women's Hospital)
+ 3 AuthorsShamil R. Sunyaev67
Estimated H-index: 67
(Brigham and Women's Hospital)
Abstract
Eukaryotic DNA replication is highly stratified, with different genomic regions shown to replicate at characteristic times during S phase. Here we observe that mutation rate, as reflected in recent evolutionary divergence and human nucleotide diversity, is markedly increased in later-replicating regions of the human genome. All classes of substitutions are affected, suggesting a generalized mechanism involving replication time-dependent DNA damage. This correlation between mutation rate and regionally stratified replication timing may have substantial evolutionary implications.
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The major DNA repair pathways operate on damage in double-strand DNA because they use the intact strand as a template after damage removal. Therefore, lesions in transient single-strand stretches of chromosomal DNA are expected to be especially threatening to genome stability. To test this hypothesis, we designed systems in budding yeast that could generate many kilobases of persistent single-strand DNA next to double-strand breaks or uncapped telomeres. The systems allowed controlled restoratio...
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