1. A predicted deleterious allele of the essential meiosis gene MND1, present in ~3% of East Asians, does not disrupt reproduction in mice
- Author
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Julianna Martinez, Tina N. Tran, and John C. Schimenti
- Subjects
0301 basic medicine ,Male ,Embryology ,Cell Cycle Proteins ,030105 genetics & heredity ,Mice ,0302 clinical medicine ,Gene Frequency ,Pregnancy ,Original Research ,Genetics ,0303 health sciences ,education.field_of_study ,Reproduction ,Obstetrics and Gynecology ,3. Good health ,Meiosis ,Models, Animal ,Female ,Infertility ,Asia ,Population ,Single-nucleotide polymorphism ,Mice, Transgenic ,Biology ,Polymorphism, Single Nucleotide ,03 medical and health sciences ,Asian People ,Species Specificity ,medicine ,SNP ,Animals ,Humans ,Allele ,education ,Molecular Biology ,Gene ,Allele frequency ,Alleles ,030304 developmental biology ,Chromosome ,Cell Biology ,medicine.disease ,Mice, Inbred C57BL ,030104 developmental biology ,Reproductive Medicine ,030217 neurology & neurosurgery ,Developmental Biology - Abstract
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.
- Published
- 2019
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