Cell https://doi.org/10.1016/j.cell.2021.06.025 (2021)
Sperm and eggs are produced by meiosis, a specialized cell division involving a single round of DNA replication followed by two rounds of cell division. In meiosis, homologous chromosomes pair, recombine and segregate to produce haploid gametes. Recombination initiates at programmed DNA double-strand breaks (DSBs) along individual chromosomes to form interhomologue crossovers that enable genetic exchange and ensure accurate chromosome pairing and segregation. Writing in Cell, Carmerini-Otero and colleagues show that DNA replication in meiotic S-phase shapes the distribution of meiotic DNA breaks and thus the recombination landscape. The authors use a novel ori-SSDS (origin-derived single-stranded DNA sequencing) approach to map ~11,500 meiotic replication origins in mouse testis and profile replication timing in meiotic S-phase nuclei by whole-genome sequencing and in silico modeling. Germline replication initiates at origins that coincide with CpG islands. Origins cluster in early- and late-replicating regions of open chromatin distinguished by high and low origin density, respectively. The authors find that recombination is elevated in early replicating regions. Assays to monitor the presence or activity of the protein factors that introduce DSBs or mediate homologous recombination consistently show that meiotic DNA breaks and interhomologue DNA repair preferentially occur in regions of high origin density, revealing a tight association between replication timing and meiotic recombination. Moreover, the positive correlation between early replication timing and meiotic DSB patterns is also observed in the human male germline: GC-rich subtelomeric regions of human chromosomes that replicate early in S-phase cells from human testes are enriched in both DSBs and crossovers, but early subtelomeric DNA replication is not a consistent feature in somatic cells. We look forward to the elucidation of the mechanism that spatially and temporally couples meiotic recombination to DNA replication in mammalian germlines.
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