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MLH1/3 variants causing aneuploidy, pregnancy loss, and premature reproductive aging
bioRxiv - Genetics Pub Date : 2021-01-15 , DOI: 10.1101/2021.01.14.426654
Priti Singh , Robert Fragoza , Cecilia S. Blengini , Tina N. Tran , Gianno Pannafino , Najla Al-Sweel , Kerry J. Schimenti , Karen Schindler , Eric A. Alani , Haiyuan Yu , John C. Schimenti

Most spontaneous pregnancy losses are a result of embryonic aneuploidy stemming from mis-segregation of chromosomes during meiosis. Proper disjunction of homologous chromosomes is dependent upon precise control of crossing-over, a process requiring the mismatch repair (MMR) genes MLH1 and MLH3. Both are required for fertility and completion of meiosis in mice. People inheriting variants in these genes are often at high risk for colorectal cancer and Lynch syndrome, yet the potential impacts of variants upon reproduction are unclear. To determine if MLH1/3 variants (namely single nucleotide polymorphisms, or SNPs) in human populations can cause reproductive abnormalities, we used a combination of computational predictions, yeast two-hybrid assays, and assays of MMR and recombination in yeast to select nine MLH1 and MLH3 variants for modeling in mice via genome editing. We identified 7 alleles that caused reproductive defects in mice including subfertility in females, male infertility, reduced sperm counts, and increased spermatocyte apoptosis. Remarkably, these alleles in females caused age-dependent decreases in litter size, and increased resorption of embryos during pregnancy. These outcomes were likely a consequence of reduced meiotic chiasmata, in turn causing an increase in misaligned chromosomes and univalents in meiotic metaphase I (MI). Our data indicate that segregating hypomorphic alleles of meiotic recombination genes in populations can predispose females to increased incidence of pregnancy loss from gamete aneuploidy.

中文翻译:

MLH1 / 3变体会导致非整倍性,妊娠流失和生殖早衰

大多数自然流产是由于减数分裂过程中染色体错误分离引起的胚胎非整倍性。同源染色体的正确分离取决于交叉的精确控制,这一过程需要错配修复(MMR)基因MLH1和MLH3。两者都是小鼠生育力和完成减数分裂所必需的。在这些基因中遗传变异的人经常患结肠直肠癌和林奇综合征的风险很高,但变异对繁殖的潜在影响尚不清楚。为了确定人类人群中的MLH1 / 3变体(即单核苷酸多态性或SNP)是否会导致生殖异常,我们结合了计算预测,酵母双杂交检测,酵母中的MMR和重组检测,以选择9种MLH1和MLH3变体,以通过基因组编辑在小鼠中建模。我们确定了7个等位基因,它们引起了小鼠的生殖缺陷,包括雌性亚生育力,雄性不育,精子数量减少和精细胞凋亡增加。值得注意的是,这些等位基因在雌性动物中导致了随年龄而减少的产仔数,并在怀孕期间增加了胚胎的吸收。这些结果可能是减数分裂性视疲劳减少的结果,进而导致减数分裂中期I(MI)中染色体错位和单价增加。我们的数据表明,在人群中分离减数分裂重组基因的亚等位基因可能使雌性易受配子非整倍性的影响而导致妊娠减少。我们鉴定出了7个等位基因,这些等位基因导致了小鼠的生殖缺陷,包括雌性不育,雄性不育,精子数量减少和精细胞凋亡增加。值得注意的是,这些等位基因在雌性动物中导致了随年龄而减少的产仔数,并在怀孕期间增加了胚胎的吸收。这些结果可能是减数分裂性视疲劳减少的结果,进而导致减数分裂中期I(MI)中染色体错位和单价增加。我们的数据表明,在人群中分离减数分裂重组基因的亚等位基因可能使雌性易受配子非整倍性的影响而导致妊娠流产的发生率增加。我们鉴定出了7个等位基因,这些等位基因导致了小鼠的生殖缺陷,包括雌性不育,雄性不育,精子数量减少和精细胞凋亡增加。值得注意的是,这些等位基因在雌性动物中导致了随年龄而减少的产仔数,并在怀孕期间增加了胚胎的吸收。这些结果可能是减数分裂性视疲劳减少的结果,进而导致减数分裂中期I(MI)中染色体错位和单价增加。我们的数据表明,在人群中分离减数分裂重组基因的亚等位基因可能使雌性易受配子非整倍性的影响而导致妊娠流产的发生率增加。雌性中的这些等位基因导致了产仔数的年龄依赖性减少,并在怀孕期间增加了胚胎的吸收。这些结果可能是减数分裂性视疲劳减少的结果,进而导致减数分裂中期I(MI)中染色体错位和单价增加。我们的数据表明,在人群中分离减数分裂重组基因的亚等位基因可能使雌性易受配子非整倍性的影响而导致妊娠减少。雌性中的这些等位基因导致了产仔数的年龄依赖性减少,并在怀孕期间增加了胚胎的吸收。这些结果可能是减数分裂性视疲劳减少的结果,进而导致减数分裂中期I(MI)中染色体错位和单价增加。我们的数据表明,在人群中分离减数分裂重组基因的亚等位基因可能使雌性易受配子非整倍性的影响而导致妊娠流产的发生率增加。
更新日期:2021-01-16
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