Species: mouse
Mutation name: None
type: null mutation
fertility: subfertile
Comment: Genetic Evidence that Synaptonemal Complex Axial Elements Govern Recombination Pathway Choice in Mice. Li XC et al. Chiasmata resulting from interhomolog recombination are critical for proper chromosome segregation at meiotic metaphase I, thus preventing aneuploidy and consequent deleterious effects. Recombination in meiosis is driven by programmed induction of double strand breaks (DSBs), and the repair of these breaks occurs primarily by recombination between homologous chromosomes, not sister chromatids. Almost nothing is known about the basis for recombination partner choice in mammals. We addressed this problem using a genetic approach. Since meiotic recombination is coupled with synaptonemal complex (SC) morphogenesis, we explored the role of axial elements - precursors to the lateral element in the mature SC - in recombination partner choice, DSB repair pathways, and checkpoint control. Female mice lacking the SC axial element protein SYCP3 produce viable, but often aneuploid, oocytes. We describe genetic studies indicating that while DSB-containing Sycp3(-/-) oocytes can be eliminated efficiently, those that survive have completed repair before the execution of an intact DNA damage checkpoint. We find that the requirement for DMC1 and TRIP13, proteins normally essential for recombination repair of meiotic DSBs, is substantially bypassed in Sycp3 and Sycp2 mutants. This bypass requires RAD54, a functionally conserved protein that promotes intersister recombination in yeast meiosis and mammalian mitotic cells. Immunocytological and genetic studies indicated that the bypass in Sycp3(-/-) Dmc1(-/-) oocytes was linked to increased DSB repair. These experiments lead us to hypothesize that axial elements mediate the activities of recombination proteins to favor interhomolog, rather than intersister recombinational repair of genetically programmed DSBs in mice. The elimination of this activity in SYCP3- or SYCP2-deficient oocytes may underlie the aneuploidy in derivative mouse embryos and spontaneous abortions in women.

Species: human
Mutation name:
type: None
fertility: None
Comment: Objective: The goal of this study was to determine whether mutations of meiotic genes, such as disrupted meiotic cDNA (DMC1), MutS homolog (MSH4), MSH5, and S. cerevisiae homolog (SPO11), were associated with premature ovarian failure (POF). Design: Case–control study. Methods: Blood sampling, karyotype, hormonal dosage, ultrasound, and ovarian biopsy were carried out on most patients. However, the main outcome measure was the sequencing of genomic DNA from peripheral blood samples of 41 women with POF and 36 fertile women (controls). Results: A single heterozygous missense mutation, substitution of a cytosine residue with thymidine in exon 2 of MSH5, was found in two Caucasian women in whom POF developed at 18 and 36 years of age. Thismutation resulted in replacement of a non-polar amino acid (proline)with a polar amino acid (serine) at position 29 (P29S). Neither 36 control women nor 39 other patients with POF possessed this genetic perturbation.Another POF patient ofAfrican origin showed a homozygous nucleotide change in the tenth of DMC1 gene that led to an alteration of the amino acid composition of the protein (M200V). Conclusions: The symptoms of infertility observed in the DMC1 homozygote mutation carrier and in both patientswith a heterozygous substitution in exon 2 of theMSH5 gene provide indirect evidence of the role of genes involved in meiotic recombination in the regulation of ovarian function. MSH5 and DMC1 mutations may be one explanation for POF, albeit uncommon. https://doi.org/10.1530/eje-07-0400

Species: mouse
Mutation name:
type: naturally occurring
fertility: subfertile
Comment: Genetic insights into biological mechanisms governing human ovarian ageing. Ruth KS et al. (2021) Reproductive longevity is essential for fertility and influences healthy ageing in women^1,2, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations³. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.////////////////// Earlier research showed that feeding pregnant mice a high-fat, high-sugar diet results in their female offspring having a lowered reproductive potential (reduced ovarian reserve)11. Ruth et al. observed changes in the expression of 2 of 35 assessed DRR-related genes (Dmc1 and Brsk1) in ovarian tissue from the female offspring of mice on this diet, suggesting that maternal diet can affect DNA repair in offspring.

Species: mouse
Mutation name: DMC1 null mutation
type: null mutation
fertility: infertile - ovarian defect
Comment: Pittman et al. (1998) generated a null mutation in the Dmc1 gene in mice and showed that homozygous mutant males and females are sterile, with arrest of gametogenesis in the first meiotic prophase. Chromosomes in mutant spermatocytes failed to synapse, despite the formation of axial elements that are the precursor to the synaptonemal complexes. The strong similarity of phenotypes in Dmc1-deficient mice and yeast suggests that meiotic mechanisms have been highly conserved through evolution. The DMC1 protein was detected in leptotene-to-zygotene spermatocytes, when homolog pairing likely initiates. Targeted gene disruption in the male mouse showed an arrest of meiosis of germ cells at the early zygotene stage, followed by apoptosis. In female mice lacking the Dmc1 gene, normal differentiation of oogenesis was aborted in embryos, and germ cells disappeared in the adult ovary. Meiotic chromosome analysis of Dmc1-deficient mouse spermatocytes revealed random spread of univalent axial elements without correct pairing between homologs. In rare cases, however, we observed complex pairing among nonhomologs. Thus, the mouse Dmc1 gene is required for homologous synapsis of chromosomes in meiosis (Yoshida et al., 1998).