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Cell. 2014 Nov 20;159(5):1015-1026. doi: 10.1016/j.cell.2014.10.025. Epub 2014 Nov 13.

Genetic variation in human DNA replication timing.

Author information

1
Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
2
Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
3
Bioinformatics Group, Division of Biology, Faculty of Science, Zagreb University, 10000 Zagreb, Croatia.
4
Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Stem Cell and Regenerative Biology, The Howard Hughes Medical Institute, Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
5
Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medicine, Cancer Center and Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
6
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Stem Cell and Regenerative Biology, The Howard Hughes Medical Institute, Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
7
Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: mccarroll@genetics.med.harvard.edu.

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.

PMID:
25416942
PMCID:
PMC4359889
DOI:
10.1016/j.cell.2014.10.025
[Indexed for MEDLINE]
Free PMC Article

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