AI Article Synopsis
- Mis-segregation of chromosomes during meiosis can lead to embryonic aneuploidy, a major cause of pregnancy loss, and the MMR genes MLH1 and MLH3 are essential for proper chromosome separation in mice.
- Variants (SNPs) in MLH1 and MLH3 are linked to fertility issues and colorectal cancer, prompting research using yeast and mouse models to investigate their effect on reproduction.
- The study discovered that seven specific alleles lead to reproductive defects in mice, including decreased litter size and increased embryo resorption, indicating that certain gene variants may heighten the risk of pregnancy loss due to chromosomal abnormalities in females.
Article Abstract
Embryonic 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.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8373927 | PMC |
| http://dx.doi.org/10.1038/s41467-021-25028-1 | DOI Listing |
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