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Prdm9 deficiency of rat oocytes causes synapsis among non-homologous chromosomes and aneuploidy

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.

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Acknowledgements

We thank Dr. T. Kobets for help with the spreads of rat males, M. Fickerová and K. Křivánková for genotyping, animal facility workers for rat keeping, Š. Takáčová for English editing, as well as Drs. J.C. Schimenti, P. Svoboda, J. Forejt, and anonymous reviewers for comments. Images were produced at the Microscopy Centre of the Institute of Molecular Genetics in Prague and BIOCEV in Vestec.

Funding

This work was supported by the Czech Science Foundation (CSF 16-06548S, GA19-06272S), Czech Academy of Sciences (RVO 68378050), Ministry of Education, Youth and Sports of the Czech Republic (LQ1604 NPUII, LM2015040 CCP, LM2015042 CESNET, LM2015062 Czech BioImaging), and European Regional Development Fund (CZ.1.05/1.1.00/02.0109 BIOCEV, CZ.1.05/2.1.00/19.0395, CZ.02.1.01/0.0/0.0/16_013/0001775).

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SG co-designed the study, performed most experiments, analyzed the data, and drafted the manuscript. OM performed analyses of E20-E21 ovaries and CDK2/MLH1 comparison in mouse males, co-supervised all other analyses, and commented the manuscript. ZT co-designed the study, supervised the project, and wrote the manuscript.

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Correspondence to Zdenek Trachtulec.

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The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

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Gasic, S., Mihola, O. & Trachtulec, Z. Prdm9 deficiency of rat oocytes causes synapsis among non-homologous chromosomes and aneuploidy. Mamm Genome (2022). https://doi.org/10.1007/s00335-022-09954-z

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  • DOI: https://doi.org/10.1007/s00335-022-09954-z