Sexual dimorphism in the meiotic requirement for PRDM9: a mammalian evolutionary safeguard

Abstract

In many mammals, genomic sites for recombination are determined by histone methyltransferase PRMD9. Mice lacking PRDM9 are infertile, but instances of fertility or semi-fertility in the absence of PRDM9 have been reported in mice, canines and a human female. Such findings raise the question of how the loss of PRDM9 is circumvented to maintain reproductive fitness. We show that genetic background and sex-specific modifiers can obviate the requirement for PRDM9 in mice. Specifically, the meiotic DNA damage checkpoint protein CHK2 acts as a modifier allowing female-specific fertility in the absence of PRDM9. We also report that in the absence of PRDM9, a PRDM9-independent recombination system is compatible with female meiosis and fertility, suggesting sex-specific regulation of meiotic recombination, a finding with implications for speciation.One Sentence SummarySex-specific modulation of a meiotic DNA damage checkpoint limits the requirement for PRDM9 in mammalian fertility.

Single-cell and bulk transcriptional profiling of mouse ovaries reveals novel genes and pathways associated with DNA damage response in oocytes

“…For ovaries, it has been shown that IR-and chemotherapy-induced DNA damage causes accelerated depletion of the ovarian follicle reserve (9,10). Multiple studies have highlighted the critical role of checkpoint kinase 2 (CHEK2) in the establishment and maintenance of the ovarian follicle reserve (11)(12)(13)(14)(15). Moreover, CHEK2 loss-of-function variants in humans correlate with females having a larger ovarian follicle reserve and later onset of menopause (16,17).…”