Fancm has dual roles in the limiting of meiotic crossovers and germ cell maintenance in mammals

Vanessa Tsui, Ruqian Lyu, Stevan Novakovic, Jessica M. Stringer, Jessica E.M. Dunleavy, Elissah Granger, Tim Semple, Anna Leichter, Luciano G. Martelotto, D. Jo Merriner, Ruijie Liu, Lucy McNeill, Nadeen Zerafa, Eva R. Hoffmann, Moira K. O'Bryan, Karla Hutt, Andrew J. Deans, Jörg Heierhorst, Davis J. McCarthy, Wayne Crismani

Research output: Contribution to journalArticleResearchpeer-review

3 Citations (Scopus)

Abstract

Meiotic crossovers are required for accurate chromosome segregation and producing new allelic combinations. Meiotic crossover numbers are tightly regulated within a narrow range, despite an excess of initiating DNA double-strand breaks. Here, we reveal the tumor suppressor FANCM as a meiotic anti-crossover factor in mammals. We use unique large-scale crossover analyses with both single-gamete sequencing and pedigree-based bulk-sequencing datasets to identify a genome-wide increase in crossover frequencies in Fancm-deficient mice. Gametogenesis is heavily perturbed in Fancm loss-of-function mice, which is consistent with the reproductive defects reported in humans with biallelic FANCM mutations. A portion of the gametogenesis defects can be attributed to the cGAS-STING pathway after birth. Despite the gametogenesis phenotypes in Fancm mutants, both sexes are capable of producing offspring. We propose that the anti-crossover function and role in gametogenesis of Fancm are separable and will inform diagnostic pathways for human genomic instability disorders.

Original languageEnglish
Article number100349
Number of pages27
JournalCell Genomics
Volume3
Issue number8
DOIs
Publication statusPublished - 9 Aug 2023

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