准确的染色体分离和产生新等位基因组合需要减数分裂交互重组。尽管有过多的DNA双链断裂起始，但减数分裂交互重组数目在一定范围内得到严格调控。在这里，我们揭示了肿瘤抑制因子FANCM在哺乳动物中作为减数分裂抗交换因子。我们使用独特的大规模交互重组分析，结合单配子测序和家系为基础的批量测序数据集，发现Fancm缺陷小鼠中基因组范围内交互重组频率增加。在Fancm功能丧失小鼠中，生殖发育严重受到干扰，这与患有双等位基因FANCM突变的人类的生殖缺陷一致。部分生殖发育缺陷可以归因于出生后的cGAS-STING通路。尽管Fancm突变体出现生殖发育表型，但两性都能够繁殖后代。我们提出Fancm的抗交互重组功能和生殖发育角色是可以分离的，并将为人类基因组不稳定性障碍的诊断路径提供信息。© 2023 作者们

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.© 2023 The Authors.