Genetic variation in human DNA replication timing.

Cell
Authors
Keywords
Abstract

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.

Year of Publication
2014
Journal
Cell
Volume
159
Issue
5
Pages
1015-1026
Date Published
2014 Nov 20
ISSN
1097-4172
URL
DOI
10.1016/j.cell.2014.10.025
PubMed ID
25416942
PubMed Central ID
PMC4359889
Links
Grant list
R01 HG006855 / HG / NHGRI NIH HHS / United States
R01 HG 006855 / HG / NHGRI NIH HHS / United States
Howard Hughes Medical Institute / United States