Infertility is a major health problem affecting ~15% of couples worldwide. Except for cases involving readily detectable chromosome aberrations, confident identification of a causative genetic defect is problematic. Despite the advent of genome sequencing for diagnostic purposes, the preponderance of segregating genetic variants complicates identification of culprit genetic alleles or mutations. Many algorithms have been developed to predict the effects of 'variants of unknown significance', typically single nucleotide polymorphisms (SNPs), but these predictions are not sufficiently accurate for clinical action. As part of a project to identify population variants that impact fertility, we have been generating clustered regularly interspaced short palindromic repeats-Cas9 edited mouse models of suspect SNPs in genes that are known to be required for fertility in mice. Here, we present data on a non-synonymous (amino acid altering) SNP (rs140107488) in the meiosis gene Mnd1, which is predicted bioinformatically to be deleterious to protein function. We report that when modeled in mice, this allele (MND1K85M), which is present at an allele frequency of ~ 3% in East Asians, has no discernable effect upon fertility, fecundity or gametogenesis, although it may cause sex skewing of progeny from homozygous males. In sum, assuming the mouse model accurately reflects the impact of this variant in humans, rs140107488 appears to be a benign allele that can be eliminated or de-prioritized in clinical genomic analyses of infertility patients.

中文翻译：

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大约3％的东亚人中存在着基本减数分裂基因MND1的预计有害等位基因，不会破坏小鼠的繁殖。

不孕是一个重大的健康问题，影响着全球约15％的夫妇。除了涉及容易检测到的染色体畸变的情况之外，对引起原因的遗传缺陷的可靠鉴定是有问题的。尽管出于诊断目的进行基因组测序的出现，但是分离遗传变异体的优势使得使罪魁祸首遗传等位基因或突变的鉴定复杂化。已经开发出许多算法来预测“重要性不明的变异”的影响，通常是单核苷酸多态性（SNP），但这些预测对于临床作用而言不够准确。作为确定影响生育力的人口变异的项目的一部分，我们已经产生了成簇的规则间隔的短回文重复-Cas9编辑的可疑SNPs小鼠模型，这些基因已知是小鼠生育力所必需的。在这里，我们介绍了减数分裂基因Mnd1中非同义（氨基酸改变）SNP（rs140107488）的数据，该基因在生物信息学上预计对蛋白质功能有害。我们报告说，在小鼠中建模时，该等位基因（MND1K85M）在东亚地区的等位基因频率为〜3％，对生育力，繁殖力或配子发生没有明显影响，尽管它可能导致纯合子代的性别偏斜男性。总而言之，假设小鼠模型能够准确反映该变体对人类的影响，则rs140107488似乎是一个良性等位基因，可以在不育症患者的临床基因组分析中消除或取消优先级。