Human MLH1/3 variants causing aneuploidy, pregnancy loss, and premature reproductive aging.
Priti SinghRobert FragozaCecilia S BlenginiTina N TranGianno PannafinoNajla Al-SweelKerry J SchimentiKaren SchindlerEric A AlaniHaiyuan YuJohn C SchimentiPublished in: Nature communications (2021)
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.
Keyphrases
- genome wide
- genome editing
- copy number
- crispr cas
- endothelial cells
- pregnancy outcomes
- high fat diet induced
- preterm birth
- dna damage
- dna repair
- genome wide identification
- bioinformatics analysis
- high throughput
- induced pluripotent stem cells
- dna methylation
- saccharomyces cerevisiae
- risk factors
- wild type
- type diabetes
- gene expression
- genome wide analysis
- electronic health record
- pregnant women
- transcription factor
- deep learning
- machine learning
- bone loss