Human MLH1/3 variants causing aneuploidy, pregnancy loss, and premature reproductive aging
| Autor: | Eric A. Alani, Priti Singh, Haiyuan Yu, Najla Al-Sweel, John C. Schimenti, Karen Schindler, Cecilia S. Blengini, Robert Fragoza, Kerry J. Schimenti, Tina N. Tran, Gianno Pannafino |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Male
Litter Size Science DNA mismatch repair General Physics and Astronomy Aneuploidy Reproductive biology Single-nucleotide polymorphism MLH3 Saccharomyces cerevisiae Biology MLH1 General Biochemistry Genetics and Molecular Biology Article Mice Meiosis Pregnancy Developmental biology medicine Homologous chromosome Animals Humans Crossing Over Genetic Homologous Recombination Alleles Genetics Multidisciplinary Reproduction Medical genetics Meiotic metaphase I General Chemistry medicine.disease digestive system diseases Abortion Spontaneous MutL Proteins Embryo Loss Female Homologous recombination MutL Protein Homolog 1 |
| Zdroj: | Nature Communications Nature Communications, Vol 12, Iss 1, Pp 1-12 (2021) |
| ISSN: | 2041-1723 |
| Popis: | 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. Proper meiotic chromosome segregation requires mismatch repair genes MLH1 and MLH3, of which variants occur in the human population. Here, the authors use computational predictions and yeast assays to select human MLH1/3 variants for modelling in mice, observing reproductive defects from abnormal levels of crossing over. |
| Databáze: | OpenAIRE |
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