Meiotic crossovers analysis using single sperm and bulk DNA sequencing of Fancm mice. Fancm regulates meiotic double-strand break repair pathway choice in mammals

Meiotic crossovers are required for accurate chromosome segregation and to produce new allelic combinations. Meiotic crossover numbers are tightly regulated within a narrow range, despite an excess of initiating DNA double-strand breaks. Here, we describe the tumour suppressor FANCM as a meiotic anti-crossover factor in mammals. Crossover analyses with single-gamete and pedigree datasets both reveal 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. Despite the gametogenesis phenotypes in Fancm mutants both sexes were 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.

减数分裂交换（meiotic crossovers）对于染色体的精准分离以及新等位基因组合的形成至关重要。尽管细胞会产生过量的起始性DNA双链断裂（DNA double-strand break），减数分裂交换的数目仍被严格限定在狭窄的波动区间内。本研究证实肿瘤抑制因子范可尼贫血互补组M蛋白（FANCM）是哺乳动物中的减数分裂抗交换因子。通过单配子与家系数据集开展的交换分析均显示，Fancm基因缺陷小鼠的全基因组交换频率显著升高。Fancm功能缺失型小鼠的配子发生过程受到严重干扰，这与携带双等位FANCM突变人群所报道的生殖缺陷表型一致。部分配子发生缺陷可归因于cGAS-STING通路。尽管Fancm突变体存在配子发生相关表型，但雌雄两性均能产生可育后代。本研究提出，Fancm的抗交换功能与其在配子发生中的作用相互独立，该发现可为人类基因组不稳定相关疾病的诊断路径提供重要参考。