Multiscale Regulation of Meiotic Recombination in Mammals

Abstract Meiotic recombination is a multilayered process that shapes genetic diversity while safeguarding genome stability. In mammals, the final distribution of crossovers and non-crossovers emerges from the integration of sequence-specific hotspot specification, chromosome architecture, replication timing, and crossover patterning mechanisms. PRDM9 directs most double-strand break formation to short (typically 1-2 kb), rapidly evolving hotspots by depositing histone marks and remodeling chromatin, whereas in PRDM9-independent contexts, breaks are redirected toward accessible promoters and CpG islands. Yet hotspot marking alone is insufficient: double-strand break formation requires assembly of the SPO11-TOPOVIBL catalytic machinery together with accessory proteins on the chromosome axis, linking recombination initiation to loop-axis organization. Broader regional biases are further imposed by meiotic replication timing, which favors early replicating domains. Downstream, only a small fraction of breaks matures into crossovers through ZMM-dependent stabilization, HEI10/RNF212-mediated dynamics, crossover interference, and the obligate crossover rule. These mechanisms result in sex-specific recombination landscapes, with structural differences in axis length and synapsis dynamics contributing to heterochiasmy. Disruption at any of these control layers can compromise homolog segregation and promote infertility, aneuploidy, recurrent pregnancy loss, or structural genomic disorders. Together, these findings support a hierarchical model in which meiotic recombination is best understood as the integrated output of DNA sequence, chromatin state, chromosome architecture, and choice of repair pathway-based patterning.