Prdm9 Deficiency of Rat Oocytes Causes Synapsis Among Non-homologous Chromosomes and Aneuploidy

Overview

Journal Mamm Genome

Specialty Genetics

Date 2022 May 20

PMID 35596034

Authors

Srdjan Gasic

Ondrej Mihola

Zdenek Trachtulec

Affiliations

Soon will be listed here.

Abstract

Aneuploidy (abnormal chromosome number) accompanies reduced ovarian function in humans and mice, but the reasons behind this concomitance remain underexplored. Some variants in the human gene encoding histone-3-lysine-4,36-trimethyltransferase PRDM9 are associated with aneuploidy, and other variants with ovarian function reduced by premature ovarian failure (POF), but no link between POF and aneuploidy has been revealed. SHR/OlaIpcv rat females lacking PRDM9 manifest POF-a reduced follicle number, litter size, and reproductive age. Here, we explored this model to test how POF relates to oocyte euploidy. The mutant rat females displayed increased oocyte aneuploidy and embryonic death of their offspring compared to controls. Because rat PRDM9 positions meiotic DNA breaks, we investigated the repair of these breaks. Fertile control rodents carry pachytene oocytes with synapsed homologous chromosomes and repaired breaks, while sterile Prdm9-deficient mice carry pachytene-like oocytes with many persisting breaks and asynapsed chromosomes. However, most PRDM9-lacking rat oocytes displayed a few persisting breaks and non-homologous synapsis (NHS). HORMAD2 protein serves as a barrier to sister-chromatid repair and a signal for the synapsis and DNA repair checkpoints. NHS but not asynapsis was associated with HORMAD2 levels similar to the levels on rat pachytene chromosomes with homologous synapsis. NHS was accompanied by crossing-over decreased below the minimum that is essential for euploidy. We argue that the increased mutant rat aneuploidy is due to NHS, which allows some oocytes to pass meiotic checkpoints without one crossing-over per chromosomal pair, leading to segregation errors, and thereby NHS links POF to aneuploidy.

Citing Articles

Plasma-derived exosomal miRNA profiles reveal potential epigenetic pathogenesis of premature ovarian failure.

Lin J, Wu Z, Zheng Y, Shen Z, Gan Z, Ma S Hum Genet. 2023; 143(9-10):1021-1034.

PMID: 38054996 DOI: 10.1007/s00439-023-02618-1.

References

Almanzar D, Gordon S, Rog O . Meiotic sister chromatid exchanges are rare in C. elegans. Curr Biol. 2021; 31(7):1499-1507.e3. PMC: 8051885. DOI: 10.1016/j.cub.2020.11.018. View

Balcova M, Faltusova B, Gergelits V, Bhattacharyya T, Mihola O, Trachtulec Z . Hybrid Sterility Locus on Chromosome X Controls Meiotic Recombination Rate in Mouse. PLoS Genet. 2016; 12(4):e1005906. PMC: 4841592. DOI: 10.1371/journal.pgen.1005906. View

Baudat F, Buard J, Grey C, Fledel-Alon A, Ober C, Przeworski M . PRDM9 is a major determinant of meiotic recombination hotspots in humans and mice. Science. 2010; 327(5967):836-40. PMC: 4295902. DOI: 10.1126/science.1183439. View

Baudat F, Manova K, Yuen J, Jasin M, Keeney S . Chromosome synapsis defects and sexually dimorphic meiotic progression in mice lacking Spo11. Mol Cell. 2000; 6(5):989-98. DOI: 10.1016/s1097-2765(00)00098-8. View

Bishop D, Zickler D . Early decision; meiotic crossover interference prior to stable strand exchange and synapsis. Cell. 2004; 117(1):9-15. DOI: 10.1016/s0092-8674(04)00297-1. View

Bolcun-Filas E, Schimenti J . Genetics of meiosis and recombination in mice. Int Rev Cell Mol Biol. 2012; 298:179-227. DOI: 10.1016/B978-0-12-394309-5.00005-5. View

BORUM K . Oogenesis in the mouse. A study of the meiotic prophase. Exp Cell Res. 1961; 24:495-507. DOI: 10.1016/0014-4827(61)90449-9. View

Brick K, Smagulova F, Khil P, Camerini-Otero R, Petukhova G . Genetic recombination is directed away from functional genomic elements in mice. Nature. 2012; 485(7400):642-5. PMC: 3367396. DOI: 10.1038/nature11089. View

Chernus J, Allen E, Zeng Z, Hoffman E, Hassold T, Feingold E . A candidate gene analysis and GWAS for genes associated with maternal nondisjunction of chromosome 21. PLoS Genet. 2019; 15(12):e1008414. PMC: 6932832. DOI: 10.1371/journal.pgen.1008414. View

10.

Chiang T, Duncan F, Schindler K, Schultz R, Lampson M . Evidence that weakened centromere cohesion is a leading cause of age-related aneuploidy in oocytes. Curr Biol. 2010; 20(17):1522-8. PMC: 2939204. DOI: 10.1016/j.cub.2010.06.069. View

11.

Chiang T, Schultz R, Lampson M . Meiotic origins of maternal age-related aneuploidy. Biol Reprod. 2011; 86(1):1-7. PMC: 3313661. DOI: 10.1095/biolreprod.111.094367. View

12.

Coulam C, Adamson S, Annegers J . Incidence of premature ovarian failure. Obstet Gynecol. 1986; 67(4):604-6. View

13.

de Vries S, Baart E, Dekker M, Siezen A, de Rooij D, de Boer P . Mouse MutS-like protein Msh5 is required for proper chromosome synapsis in male and female meiosis. Genes Dev. 1999; 13(5):523-31. PMC: 316502. DOI: 10.1101/gad.13.5.523. View

14.

Di Giacomo M, Barchi M, Baudat F, Edelmann W, Keeney S, Jasin M . Distinct DNA-damage-dependent and -independent responses drive the loss of oocytes in recombination-defective mouse mutants. Proc Natl Acad Sci U S A. 2005; 102(3):737-42. PMC: 545532. DOI: 10.1073/pnas.0406212102. View

15.

Diagouraga B, Clement J, Duret L, Kadlec J, de Massy B, Baudat F . PRDM9 Methyltransferase Activity Is Essential for Meiotic DNA Double-Strand Break Formation at Its Binding Sites. Mol Cell. 2018; 69(5):853-865.e6. DOI: 10.1016/j.molcel.2018.01.033. View

16.

Dresser M, Ewing D, Harwell S, Coody D, Conrad M . Nonhomologous synapsis and reduced crossing over in a heterozygous paracentric inversion in Saccharomyces cerevisiae. Genetics. 1994; 138(3):633-47. PMC: 1206214. DOI: 10.1093/genetics/138.3.633. View

17.

Flachs P, Mihola O, Simecek P, Gregorova S, Schimenti J, Matsui Y . Interallelic and intergenic incompatibilities of the Prdm9 (Hst1) gene in mouse hybrid sterility. PLoS Genet. 2012; 8(11):e1003044. PMC: 3486856. DOI: 10.1371/journal.pgen.1003044. View

18.

Flachs P, Bhattacharyya T, Mihola O, Pialek J, Forejt J, Trachtulec Z . Prdm9 incompatibility controls oligospermia and delayed fertility but no selfish transmission in mouse intersubspecific hybrids. PLoS One. 2014; 9(4):e95806. PMC: 3995920. DOI: 10.1371/journal.pone.0095806. View

19.

Forejt J, Jansa P, Parvanov E . Hybrid sterility genes in mice (Mus musculus): a peculiar case of PRDM9 incompatibility. Trends Genet. 2021; 37(12):1095-1108. DOI: 10.1016/j.tig.2021.06.008. View

20.

Fu X, Cheng J, Hou Y, Zhu S . The association between the oocyte pool and aneuploidy: a comparative study of the reproductive potential of young and aged mice. J Assist Reprod Genet. 2013; 31(3):323-31. PMC: 3947073. DOI: 10.1007/s10815-013-0160-5. View