Tsui Vanessa, Lyu Ruqian, Novakovic Stevan, Stringer Jessica M, Dunleavy Jessica E M, Granger Elissah, Semple Tim, Leichter Anna, Martelotto Luciano G, Merriner D Jo, Liu Ruijie, McNeill Lucy, Zerafa Nadeen, Hoffmann Eva R, O'Bryan Moira K, Hutt Karla, Deans Andrew J, Heierhorst Jörg, McCarthy Davis J, Crismani Wayne
DNA Repair and Recombination Laboratory, St Vincent's Institute of Medical Research, Fitzroy, VIC, Australia.
The Faculty of Medicine, Dentistry and Health Science, The University of Melbourne, Parkville, VIC, Australia.
Cell Genom. 2023 Jun 29;3(8):100349. doi: 10.1016/j.xgen.2023.100349. eCollection 2023 Aug 9.
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 -deficient mice. Gametogenesis is heavily perturbed in loss-of-function mice, which is consistent with the reproductive defects reported in humans with biallelic mutations. A portion of the gametogenesis defects can be attributed to the cGAS-STING pathway after birth. Despite the gametogenesis phenotypes in mutants, both sexes are capable of producing offspring. We propose that the anti-crossover function and role in gametogenesis of are separable and will inform diagnostic pathways for human genomic instability disorders.
减数分裂交叉对于准确的染色体分离和产生新的等位基因组合是必需的。尽管起始DNA双链断裂过量，但减数分裂交叉数在狭窄范围内受到严格调控。在这里，我们揭示了肿瘤抑制因子FANCM作为哺乳动物减数分裂中的抗交叉因子。我们使用独特的大规模交叉分析，结合单配子测序和基于家系的批量测序数据集，来确定Fancm缺陷小鼠全基因组交叉频率的增加。在Fancm功能丧失的小鼠中，配子发生受到严重干扰，这与双等位基因Fancm突变的人类所报道的生殖缺陷一致。一部分配子发生缺陷可归因于出生后的cGAS-STING途径。尽管Fancm突变体存在配子发生表型，但两性都能够产生后代。我们提出，Fancm的抗交叉功能及其在配子发生中的作用是可分离的，这将为人类基因组不稳定疾病的诊断途径提供信息。
