Human MLH1/3 variants causing aneuploidy, pregnancy loss, and premature reproductive aging

Abstract Embryonic aneuploidy from mis-segregation of chromosomes during meiosis causes pregnancy loss. Proper disjunction homologous requires the mismatch repair (MMR) genes MLH1 and MLH3 , essential in mice for fertility. Variants these can increase colorectal cancer risk, yet reproductive impacts are unclear. To determine if MLH1/3 single nucleotide polymorphisms (SNPs) human populations could cause abnormalities, we use computational predictions, yeast two-hybrid assays, MMR recombination assays yeast, selecting nine variants to model via genome editing. We identify seven alleles causing defects including female subfertility male infertility. Remarkably, females age-dependent decreases litter size increased embryo resorption, likely a consequence fewer chiasmata that univalents at meiotic metaphase I. Our data suggest hypomorphic predispose incidence loss gamete aneuploidy.