Genetic Variation in Human DNA Replication Timing

被引：111

作者：

Koren, Amnon ^{[1
,2
,3
]}

Handsaker, Robert E. ^{[1
,2
,3
,4
]}

Kamitaki, Nolan ^{[1
,2
,3
,4
]}

Karlic, Rosa ^{[5
]}

Ghosh, Sulagna ^{[1
,2
,3
,4
,6
]}

Polak, Paz ^{[3
,7
,8
,9
]}

Eggan, Kevin ^{[3
,4
,6
]}

McCarroll, Steven A. ^{[1
,2
,3
,4
]}

机构：

[1] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA

[2] MIT, Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA

[3] Harvard, Cambridge, MA 02142 USA

[4] MIT, Broad Inst, Stanley Ctr Psychiat Res, Cambridge, MA 02142 USA

[5] Univ Zagreb, Fac Sci, Div Biol, Bioinformat Grp, Zagreb 10000, Croatia

[6] Harvard Univ, Harvard Stem Cell Inst, Howard Hughes Med Inst, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA

[7] MIT, Broad Inst, Canc Program, Cambridge, MA 02142 USA

[8] Harvard Univ, Sch Med, Dept Med, Ctr Canc, Boston, MA 02114 USA

[9] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA

来源：

CELL | 2014年 / 159卷 / 05期

关键词：

JAK2; HAPLOTYPE; HUMAN MUTATION; INITIATION; CANCER; WAVES; DYNAMICS; SNP;

D O I：

10.1016/j.cell.2014.10.025

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：1015 / 1026

页数：12

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