DNA mismatch repair (MMR) proteins play an important role in maintaining genome stability, both in somatic and in germline cells. Loss of MLH1, a central MMR protein, leads to infertility and to microsatellite instability (MSI) in spermatocytes, however, the effect of Mlh1 heterozygosity on germline genome stability remains unexplored. To test the effect of Mlh1 heterozygosity on MSI in mature sperm, we combined mouse genetics with single-molecule PCR that detects allelic changes at unstable microsatellites. We discovered 4.5% and 5.9% MSI in sperm of 4- and 12-month-old Mlh1+/− mice, respectively, and that Mlh1 promoter methylation in Mlh1+/− sperm correlated with higher MSI. No such elevated MSI was seen in non-proliferating somatic cells. Additionally, we show contrasting dynamics of deletions versus insertions at unstable microsatellites (mononucleotide repeats) in sperm.

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Mlh1 杂合性和启动子甲基化与小鼠精子中的微卫星不稳定性相关

DNA 错配修复 (MMR) 蛋白在维持体细胞和生殖细胞中的基因组稳定性方面发挥着重要作用。中枢 MMR 蛋白 MLH1 的缺失会导致不育和精母细胞中的微卫星不稳定性 (MSI)，然而，Mlh1 杂合性对种系基因组稳定性的影响仍未得到探索。为了测试 Mlh1 杂合性对成熟精子 MSI 的影响，我们将小鼠遗传学与单分子 PCR 相结合，以检测不稳定微卫星的等位基因变化。我们分别在 4 和 12 个月大的 Mlh1+/- 小鼠的精子中发现了 4.5% 和 5.9% 的 MSI，并且 Mlh1+/- 精子中的 Mlh1 启动子甲基化与更高的 MSI 相关。在非增殖体细胞中没有观察到这种升高的 MSI。此外，