Human MLH1/3 variants causing aneuploidy, pregnancy loss, and premature reproductive aging.
Human MLH1/3 variants causing aneuploidy, pregnancy loss, and premature reproductive aging.
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DOI：
10.1038/s41467-021-25028-1
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发表时间：
2021-08-18
影响因子：
16.6
通讯作者：
Schimenti JC
中科院分区：
文献类型：
--
作者：
Singh P;Fragoza R;Blengini CS;Tran TN;Pannafino G;Al-Sweel N;Schimenti KJ;Schindler K;Alani EA;Yu H;Schimenti JC
胚胎的非整倍体是由于减数分裂过程中染色体的错误分离而导致的，导致妊娠丢失。同源染色体的正确分离需要错配修复(MMR)基因MLH1和MLH3，这对小鼠的生育是必不可少的。这些基因的变异会增加患结直肠癌的风险，但对生殖的影响尚不清楚。为了确定人类群体中的MLH1/3单核苷酸多态(SNPs)是否会导致生殖异常，我们使用了计算预测、酵母双杂交分析以及酵母中的MMR和重组分析，通过基因组编辑选择了9个MLH1和MLH3变体在小鼠身上建模。我们确定了七个导致小鼠生殖缺陷的等位基因，包括雌性不育和雄性不育。值得注意的是，在雌性中，这些等位基因会导致产仔数随年龄的减少和胚胎吸收的增加，这可能是由于减数分裂中期I的交叉增加了单价体的结果。我们的数据表明，减数分裂重组基因的亚型等位基因可能使雌性更容易因配子非整倍体而导致怀孕损失的发生率增加。正确的减数分裂染色体分离需要错配修复基因MLH1和MLH3，这两个基因的变异体出现在人类群体中。在这里，作者使用计算预测和酵母菌分析来选择人类MLH1/3变体在小鼠身上建模，观察异常水平的交换造成的生殖缺陷。
Embryonic aneuploidy from mis-segregation of chromosomes during meiosis causes pregnancy loss. Proper disjunction of homologous chromosomes requires the mismatch repair (MMR) genes MLH1 and MLH3, essential in mice for fertility. Variants in these genes can increase colorectal cancer risk, yet the reproductive impacts are unclear. To determine if MLH1/3 single nucleotide polymorphisms (SNPs) in human populations could cause reproductive abnormalities, we use computational predictions, yeast two-hybrid assays, and MMR and recombination assays in yeast, selecting nine MLH1 and MLH3 variants to model in mice via genome editing. We identify seven alleles causing reproductive defects in mice including female subfertility and male infertility. Remarkably, in females these alleles cause age-dependent decreases in litter size and increased embryo resorption, likely a consequence of fewer chiasmata that increase univalents at meiotic metaphase I. Our data suggest that hypomorphic alleles of meiotic recombination genes can predispose females to increased incidence of pregnancy loss from gamete aneuploidy. Proper meiotic chromosome segregation requires mismatch repair genes MLH1 and MLH3, of which variants occur in the human population. Here, the authors use computational predictions and yeast assays to select human MLH1/3 variants for modelling in mice, observing reproductive defects from abnormal levels of crossing over.
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