Abstract
DNA replication follows a strict spatiotemporal program that intersects with chromatin structure but has a poorly understood genetic basis. To systematically identify genetic regulators of replication timing, we exploited inter-individual variation in human pluripotent stem cells from 349 individuals. We show that the human genome’s replication program is broadly encoded in DNA and identify 1,617 cis-acting replication timing quantitative trait loci (rtQTLs) – sequence determinants of replication initiation. rtQTLs function individually, or in combinations of proximal and distal regulators, and are enriched at sites of histone H3 trimethylation of lysines 4, 9, and 36 together with histone hyperacetylation. H3 trimethylation marks are individually repressive yet synergistically associate with early replication. We identify pluripotency-related transcription factors and boundary elements as positive and negative regulators of replication timing, respectively. Taken together, human replication timing is controlled by a multi-layered mechanism with dozens of effectors working combinatorially and following principles analogous to transcription regulation.
Highlights
DNA replication follows a strict spatiotemporal program that intersects with chromatin structure but has a poorly understood genetic basis
DNA replication timing leads to variation in DNA copy number along chromosomes among S phase cells, causing read depth fluctuations in the sequencing data[18] (Supplementary Fig. 1a)
We leveraged population-scale replication timing and genetic polymorphism data to perform the equivalent of millions of surgical genetic interrogations of replication timing determinants
Summary
DNA replication follows a strict spatiotemporal program that intersects with chromatin structure but has a poorly understood genetic basis. We previously showed that replication timing is variable among individuals, that it can be studied at fine-scale on a population level by sequencing the genomes of proliferating cells, and that genotype information from the same genome sequences can be used to associate replication timing variation with specific genetic polymorphisms This results in the identification of replication timing quantitative trait loci (rtQTLs), DNA sequences that act in cis to affect replication initiation[18]. We identify 1,617 cis-rtQTLs and analyze their locations and allelic differences These analyses delineate the architecture of human replication timing as a quantitative trait involving combinatorial regulation by several layers of epigenetic mechanisms rooted in cis-acting DNA sequences
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