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Am J Hum Genet DOI:10.1016/j.ajhg.2012.10.018

Differential relationship of DNA replication timing to different forms of human mutation and variation.

Publication TypeJournal Article
Year of Publication2012
AuthorsKoren, A, Polak, P, Nemesh, J, Michaelson, JJ, Sebat, J, Sunyaev, SR, McCarroll, SA
JournalAm J Hum Genet
Date Published2012 Dec 07
KeywordsBase Composition, Cell Line, DNA Copy Number Variations, DNA Replication Timing, Female, Genetic Variation, Genome, Human, High-Throughput Nucleotide Sequencing, Humans, Male, Meiosis, Mutation, Point Mutation, Polymorphism, Single Nucleotide, Recombination, Genetic, Sex Factors

Human genetic variation is distributed nonrandomly across the genome, though the principles governing its distribution are only partially known. DNA replication creates opportunities for mutation, and the timing of DNA replication correlates with the density of SNPs across the human genome. To enable deeper investigation of how DNA replication timing relates to human mutation and variation, we generated a high-resolution map of the human genome's replication timing program and analyzed its relationship to point mutations, copy number variations, and the meiotic recombination hotspots utilized by males and females. DNA replication timing associated with point mutations far more strongly than predicted from earlier analyses and showed a stronger relationship to transversion than transition mutations. Structural mutations arising from recombination-based mechanisms and recombination hotspots used more extensively by females were enriched in early-replicating parts of the genome, though these relationships appeared to relate more strongly to the genomic distribution of causative sequence features. These results indicate differential and sex-specific relationship of DNA replication timing to different forms of mutation and recombination.


Alternate JournalAm. J. Hum. Genet.
PubMed ID23176822
PubMed Central IDPMC3516607
Grant ListR01 MH076431 / MH / NIMH NIH HHS / United States