Abstract
AbstractEmbryonic aneuploidy from mis-segregation of chromosomes during meiosis causes pregnancy loss. Proper disjunction of homologous chromosomes requires the mismatch repair (MMR) genes MLH1 and MLH3, essential in mice for fertility. Variants in these genes can increase colorectal cancer risk, yet the reproductive impacts are unclear. To determine if MLH1/3 single nucleotide polymorphisms (SNPs) in human populations could cause reproductive abnormalities, we use computational predictions, yeast two-hybrid assays, and MMR and recombination assays in yeast, selecting nine MLH1 and MLH3 variants to model in mice via genome editing. We identify seven alleles causing reproductive defects in mice including female subfertility and male infertility. Remarkably, in females these alleles cause age-dependent decreases in litter size and increased embryo resorption, likely a consequence of fewer chiasmata that increase univalents at meiotic metaphase I. Our data suggest that hypomorphic alleles of meiotic recombination genes can predispose females to increased incidence of pregnancy loss from gamete aneuploidy.
Funder
U.S. Department of Health & Human Services | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry
Reference78 articles.
1. Silver, R. M. & Branch, D. In Clinical obstetrics: The fetus & mother (eds. Reece, E. A. & Hobbins, J. C.) 143–160 (Blackwell Publishing, 2007).
2. Soler, A. et al. Overview of chromosome abnormalities in first trimester miscarriages: a series of 1,011 consecutive chorionic villi sample karyotypes. Cytogenet. Genome Res. 152, 81–89 (2017).
3. Chiang, T., Duncan, F. E., Schindler, K., Schultz, R. M. & Lampson, M. A. Evidence that weakened centromere cohesion is a leading cause of age-related aneuploidy in oocytes. Curr. Biol. 20, 1522–1528 (2010).
4. Duncan, F. E. et al. Chromosome cohesion decreases in human eggs with advanced maternal age. Aging Cell 11, 1121–1124 (2012).
5. Sullivan, A. E., Silver, R. M., LaCoursiere, D. Y., Porter, T. F. & Branch, D. W. Recurrent fetal aneuploidy and recurrent miscarriage. Obstet. Gynecol. 104, 784–788 (2004).
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