Amnon Koren

Genetic variation in human DNA replication timing

Genomic DNA replicates in a choreographed temporal order that impacts the distribution of mutations along the genome. We show that DNA replication timing is shaped by genetic polymorphisms that act in cis upon megabase-scale DNA segments. In genome sequences from proliferating cells, fluctuations in read depth along chromosomes reflected DNA replication activity. 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 a replication timing quantitative trait loci (rtQTLs). rtQTLs involved the differential use of DNA replication origins, exhibited allele-specific effects on replication timing, and associated with gene expression variation at megabase scales. An rtQTL at the Janus Kinase 2 (JAK2) gene was associated with early activation of an adjacent origin of replication, leading to interference with JAK2 transcription and increased rates of JAK2 mutations that cause myeloproliferative neoplasms and leukemia. Our results show replication timing to be shaped by genetic polymorphism, identify a means by which inherited polymorphism regulates the mutability of nearby sequences, and reveal a new way by which non-coding genetic variation can influence phenotype.