title: Allele-specific analysis of DNA replication origins in mammalian cells.
abstract: The mechanisms that control the location and timing of firing of replication origins are poorly understood. Using a novel functional genomic approach based on the analysis of SNPs and indels in phased human genomes, we observe that replication asynchrony is associated with small cumulative variations in the initiation efficiency of multiple origins between the chromosome homologues, rather than with the activation of dormant origins. Allele-specific measurements demonstrate that the presence of G-quadruplex-forming sequences does not correlate with the efficiency of initiation. Sequence analysis reveals that the origins are highly enriched in sequences with profoundly asymmetric G/C and A/T nucleotide distributions and are almost completely depleted of antiparallel triplex-forming sequences. We therefore propose that although G4-forming sequences are abundant in replication origins, an asymmetry in nucleotide distribution, which increases the propensity of origins to unwind and adopt non-B DNA structure, rather than the ability to form G4, is directly associated with origin activity.
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA.
authors.forename: Boris
authors.initials: B
authors.lastname: Bartholdy
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA.
authors.forename: Rituparna
authors.initials: R
authors.lastname: Mukhopadhyay
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA.
authors.forename: Julien
authors.initials: J
authors.lastname: Lajugie
authors.affiliation: Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, 37 Convent Drive, Bethesda, Maryland 20892, USA.
authors.forename: Mirit I
authors.initials: MI
authors.lastname: Aladjem
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA.
authors.forename: Eric E
authors.initials: EE
authors.lastname: Bouhassira
mesh_terms: D000483:Alleles; D002875:Chromosomes / Q000648:ultrastructure; D019295:Computational Biology / Q000379:methods*; D018899:CpG Islands; D004247:DNA / Q000032:analysis; D004261:DNA Replication; D015894:Genome, Human; D006801:Humans; D007962:Leukocytes / Q000378:metabolism; D008957:Models, Genetic; D020641:Polymorphism, Single Nucleotide; D018741:Replication Origin; D013997:Time Factors
chemical_list: D004247:DNA