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

Abstract

In many mammals, genomic sites for recombination are determined by the histone methyltransferase PRMD9. Some mouse strains lacking PRDM9 are infertile, but instances of fertility or semifertility 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 fertility. 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.

Differential effects of two catalytic mutations on full-length PRDM9 and its isolated PR/SET domain reveal a case of pseudo-modularity

“…The latter two were generated by introducing a point mutation (Glu360Pro) via CRISPR-Cas9 gene editing, onto the C57BL/6J genetic background, as previously described (B hattacharyya et al . 2019; P owers et al . 2020).…”

“…For B6 and Prdm9 EP/EP spermatocytes, ChIP-seq data our lab previously reported (B aker et al . 2014; P owers et al . 2020) was used.…”

“…In mice, we recently reported sexual dimorphism in the requirement for PRDM9 for successful meiosis (P owers et al . 2020).…”

“…We also reported two catalytic mutations— Prdm9 EP and Prdm9 EK —that straddle the threshold for female fertility in B6 mice (B hattacharyya et al . 2019; P owers et al . 2020).…”

“…2019). In contrast, homozygous female Prdm9 EP mice are able to produce variable numbers of grossly healthy, normal offspring via natural matings (P owers et al . 2020).…”