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Cell DOI:10.1016/j.cell.2014.10.025

Genetic variation in human DNA replication timing.

Publication TypeJournal Article
Year of Publication2014
AuthorsKoren, A, Handsaker, RE, Kamitaki, N, Karlić, R, Ghosh, S, Polak, P, Eggan, K, McCarroll, SA
Date Published2014 Nov 20
KeywordsDNA Replication Timing, Genetics, Population, Genome, Human, Genome-Wide Association Study, Humans, Janus Kinase 2, Myeloproliferative Disorders, Polymorphism, Genetic, Quantitative Trait Loci, Replication Origin

Genomic DNA replicates in a choreographed temporal order that impacts the distribution of mutations along the genome. We show here that DNA replication timing is shaped by genetic polymorphisms that act in cis upon megabase-scale DNA segments. In genome sequences from proliferating cells, read depth along chromosomes reflected DNA replication activity in those cells. We used this relationship to analyze variation in replication timing among 161 individuals sequenced by the 1000 Genomes Project. Genome-wide association of replication timing with genetic variation identified 16 loci at which inherited alleles associate with replication timing. We call these "replication timing quantitative trait loci" (rtQTLs). rtQTLs involved the differential use of replication origins, exhibited allele-specific effects on replication timing, and associated with gene expression variation at megabase scales. Our results show replication timing to be shaped by genetic polymorphism and identify a means by which inherited polymorphism regulates the mutability of nearby sequences.


Alternate JournalCell
PubMed ID25416942
PubMed Central IDPMC4359889
Grant ListR01 HG006855 / HG / NHGRI NIH HHS / United States
R01 HG 006855 / HG / NHGRI NIH HHS / United States
/ / Howard Hughes Medical Institute / United States