title: Genetic variation in human DNA replication timing.
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.
authors.affiliation: 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.
authors.forename: Amnon
authors.initials: A
authors.lastname: Koren
authors.affiliation: 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.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Handsaker
authors.affiliation: 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.
authors.forename: Nolan
authors.initials: N
authors.lastname: Kamitaki
authors.affiliation: Bioinformatics Group, Division of Biology, Faculty of Science, Zagreb University, 10000 Zagreb, Croatia.
authors.forename: Rosa
authors.initials: R
authors.lastname: Karlić
authors.affiliation: 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.
authors.forename: Sulagna
authors.initials: S
authors.lastname: Ghosh
authors.affiliation: 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.
authors.forename: Paz
authors.initials: P
authors.lastname: Polak
authors.affiliation: 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.
authors.forename: Kevin
authors.initials: K
authors.lastname: Eggan
authors.affiliation: 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.
authors.forename: Steven A
authors.initials: SA
authors.lastname: McCarroll
mesh_terms: D042522:DNA Replication Timing; D005828:Genetics, Population; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006801:Humans; D053614:Janus Kinase 2 / Q000378:metabolism; D009196:Myeloproliferative Disorders / Q000235:genetics / Q000378:metabolism; D011110:Polymorphism, Genetic; D040641:Quantitative Trait Loci; D018741:Replication Origin
chemical_list: C507924:JAK2 protein, human; D053614:Janus Kinase 2