School of Molecular Biosciences, Washington State University, Pullman, WA 99164, USA.
School of Molecular Biosciences, Washington State University, Pullman, WA 99164, USA.
Am J Hum Genet. 2021 Jan 7;108(1):16-24. doi: 10.1016/j.ajhg.2020.11.010. Epub 2020 Dec 10.
Failure of homologous chromosomes to recombine is arguably the most important cause of human meiotic nondisjunction, having been linked to numerous autosomal and sex chromosome trisomies of maternal origin. However, almost all information on these "exchangeless" homologs has come from genetic mapping studies of trisomic conceptuses, so the incidence of this defect and its impact on gametogenesis are not clear. If oocytes containing exchangeless homologs are selected against during meiosis, the incidence may be much higher in developing germ cells than in zygotes. To address this, we initiated studies of exchangeless chromosomes in fetal ovarian samples from elective terminations of pregnancy. In total, we examined more than 7,000 oocytes from 160 tissue samples, scoring for the number of foci per cell of the crossover-associated protein MLH1. We identified a surprisingly high level of recombination failure, with more than 7% of oocytes containing at least one chromosome pair that lacked an MLH1 focus. Detailed analyses indicate striking chromosome-specific differences, with a preponderance of MLH1-less homologs involving chromosomes 21 or 22. Further, the effect was linked to the overall level of recombination in the cell, with the presence of one or two exchangeless chromosomes in a cell associated with a 10%-20% reduction in the total number of crossovers. This suggests individuals with lower rates of meiotic recombination are at an increased risk of producing aneuploid offspring.
同源染色体不重组可以说是人类减数分裂非分离的最重要原因，它与许多母体来源的常染色体和性染色体三体有关。然而，几乎所有关于这些“无交换”同源物的信息都来自于三体胚胎的遗传图谱研究，因此这种缺陷的发生率及其对配子发生的影响尚不清楚。如果在减数分裂过程中选择不含有交换同源物的卵母细胞，那么在正在发育的生殖细胞中，这种缺陷的发生率可能比在受精卵中高得多。为了解决这个问题，我们开始研究来自选择性终止妊娠的胎儿卵巢样本中的无交换染色体。总共，我们检查了 160 个组织样本中的 7000 多个卵母细胞，对与交叉相关的蛋白 MLH1 每个细胞的焦点数量进行了评分。我们发现了一个令人惊讶的高重组失败率，超过 7%的卵母细胞至少有一对染色体缺乏 MLH1 焦点。详细的分析表明存在明显的染色体特异性差异，缺乏 MLH1 的同源物主要涉及 21 号或 22 号染色体。此外，这种效应与细胞中的总体重组水平有关，一个或两个无交换染色体的存在与细胞中交叉总数减少 10%-20%有关。这表明，减数分裂重组率较低的个体产生非整倍体后代的风险增加。
