A predicted deleterious allele of the essential meiosis gene MND1, present in ~ 3% of East Asians, does not disrupt reproduction in mice.
A predicted deleterious allele of the essential meiosis gene MND1, present in ~ 3% of East Asians, does not disrupt reproduction in mice.
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A%20预测%20有害%20等位基因%20of%20the%20essential%20减数分裂%20基因%20MND1,%20present%20in%20~–3%%20of%20东方%20亚洲人,%20does%20not%20disrupt%20reproductive%20in%
DOI：
10.1093/molehr/gaz048
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发表时间：
2019
影响因子：
4
通讯作者：
Schimenti,JohnC
中科院分区：
文献类型：
--
作者：
Tran,TinaN;Martinez,Julianna;Schimenti,JohnC
不孕症是一个主要的健康问题，影响到全世界约15%的夫妇。除了涉及容易检测到的染色体畸变的情况下，有把握地鉴定致病性遗传缺陷是有问题的。尽管出现了用于诊断目的的基因组测序，但分离遗传变体的优势使鉴定罪魁祸首遗传等位基因或突变复杂化。已经开发了许多算法来预测“未知意义的变体”的影响，通常是单核苷酸多态性（SNP），但这些预测对于临床行动不够准确。作为鉴定影响生育力的群体变异的项目的一部分，我们一直在生成已知小鼠生育力所需基因中可疑SNP的成簇的规律间隔的短回文重复序列-Cas9编辑的小鼠模型。在这里，我们提出了一个非同义（氨基酸改变）SNP（rs 140107488）的减数分裂基因Mnd 1，这是预测生物信息学是有害的蛋白质功能的数据。我们报告说，当在小鼠中建模时，这种等位基因（MND 1 K85 M），这是在东亚人中的等位基因频率约为3%，对生育力，生殖力或配子发生没有明显的影响，虽然它可能会导致纯合子男性后代的性别偏斜。总之，假设小鼠模型准确地反映了这种变异在人类中的影响，rs 140107488似乎是一种良性等位基因，可以在不孕症患者的临床基因组分析中消除或降低优先级。
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 geneMnd1, 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.