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PRDM9 directs most double-strand break formation to short (typically 1-2\u00a0kb), 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 (Zip1-4, Msh4-5, Mer3, Spo16)-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.<\/jats:p>","DOI":"10.1093\/biolre\/ioag204","type":"journal-article","created":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T11:38:46Z","timestamp":1790077126000},"source":"Crossref","is-referenced-by-count":0,"title":["Multiscale regulation of meiotic recombination in mammals"],"prefix":"10.1093","author":[{"given":"Najma","family":"Shaheen","sequence":"first","affiliation":[{"name":"Genetics and Biochemistry Branch, NIDDK, National Institutes of Health , Bethesda, MD ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Marton Menendez","sequence":"additional","affiliation":[{"name":"Genetics and Biochemistry Branch, NIDDK, National Institutes of Health , Bethesda, MD ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9678-8044","authenticated-orcid":false,"given":"Florencia","family":"Pratto","sequence":"additional","affiliation":[{"name":"Genetics and Biochemistry Branch, NIDDK, National Institutes of Health , Bethesda, MD ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,9,22]]},"reference":[{"key":"2026100713365095700_ref1","doi-asserted-by":"publisher","first-page":"a016618","DOI":"10.1101\/cshperspect.a016618","article-title":"Meiotic recombination: the essence of heredity","volume":"7","author":"Hunter","year":"2015","journal-title":"Cold Spring Harb Perspect Biol"},{"key":"2026100713365095700_ref2","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1038\/s41437-022-00523-3","article-title":"Gene conversion: a non-mendelian process integral to meiotic recombination","volume":"129","author":"Lorenz","year":"2022","journal-title":"Heredity"},{"key":"2026100713365095700_ref3","doi-asserted-by":"publisher","first-page":"369","DOI":"10.1146\/annurev-genet-072820-033609","article-title":"Errors of the egg: the establishment and progression of human aneuploidy research in the maternal germline","volume":"56","author":"Gruhn","year":"2022","journal-title":"Annu Rev Genet"},{"key":"2026100713365095700_ref4","doi-asserted-by":"publisher","first-page":"584","DOI":"10.1002\/pd.5910","article-title":"Missed connections: recombination and human aneuploidy","volume":"41","author":"Hassold","year":"2021","journal-title":"Prenat Diagn"},{"key":"2026100713365095700_ref5","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1146\/annurev.genom.3.032802.120023","article-title":"Molecular mechanisms for genomic disorders","volume":"3","author":"Inoue","year":"2002","journal-title":"Annu Rev Genomics Hum Genet"},{"key":"2026100713365095700_ref6","doi-asserted-by":"publisher","first-page":"118","DOI":"10.1002\/ajpa.24713","article-title":"Genomic structural variation: A complex but important driver of human evolution","volume":"181","author":"Soto","year":"2023","journal-title":"Am J Biol Anthropol"},{"key":"2026100713365095700_ref7","doi-asserted-by":"publisher","first-page":"a016634","DOI":"10.1101\/cshperspect.a016634","article-title":"Mechanism and regulation of meiotic recombination initiation","volume":"7","author":"Lam","year":"2014","journal-title":"Cold Spring Harb Perspect Biol"},{"key":"2026100713365095700_ref8","doi-asserted-by":"publisher","first-page":"563","DOI":"10.1146\/annurev-genet-110711-155423","article-title":"Initiation of meiotic recombination: how and where? 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