Histone methyltransferase PRDM9 is not essential for meiosis in male mice

Abstract

A hallmark of meiosis is the rearrangement of parental alleles to ensure genetic diversity in the gametes. These chromosome rearrangements are mediated by the repair of programmed DNA double-strand breaks (DSBs) as genetic crossovers between parental homologs. In mice, humans, and many other mammals, meiotic DSBs occur primarily at hotspots, determined by sequence-specific binding of the PRDM9 protein. Without PRDM9, meiotic DSBs occur near gene promoters and other functional sites. Studies in a limited number of mouse strains showed that functional PRDM9 is required to complete meiosis, but despite its apparent importance, Prdm9 has been repeatedly lost across many animal lineages. Both the reason for mouse sterility in the absence of PRDM9 and the mechanism by which Prdm9 can be lost remain unclear. Here, we explore whether mice can tolerate the loss of Prdm9. By generating Prdm9 functional knockouts in an array of genetic backgrounds, we observe a wide range of fertility phenotypes and ultimately demonstrate that PRDM9 is not required for completion of male meiosis. Although DSBs still form at a common subset of functional sites in all mice lacking PRDM9, meiotic outcomes differ substantially. We speculate that DSBs at functional sites are difficult to repair as a crossover and that by increasing the efficiency of crossover formation at these sites, genetic modifiers of recombination rates can allow for meiotic progression. This model implies that species with a sufficiently high recombination rate may lose Prdm9 yet remain fertile.

HELLS and PRDM9 form a Pioneer Complex to Open Chromatin at Meiotic Recombination Hotspots

“…Combined, our observations strongly support the hypothesis that the primary role of Notably, however, the severity of the infertility phenotype caused by loss of PRDM9 depends on the genetic background (Mihola et al, 2019), suggesting other components in action. Finally, through creation of aberrant sites of open chromatin, the pioneer function of the HELLS-PRDM9 complex could provide a molecular mechanism by which particular alleles are associated with genomic instability in certain cancers (Houle et al, 2018).…”

ZCWPW1 is recruited to recombination hotspots by PRDM9, and is essential for meiotic double strand break repair

“…Only eight of these varied in any of the 167 species with a potential ZCWPW1 KO mice for Prdm9 were described previously (Hayashi et al, 2005;Mihola et al, 2019) and obtained from the RIKEN BioResource Research Center in Japan (strain name B6.129P2-Prdm9<tm1Ymat>, strain number RBRC05145). Mice were genotyped at the Prdm9 locus using the following primers, and standard…”

Dual Histone Methyl Reader ZCWPW1 Facilitates Repair of Meiotic Double Strand Breaks

“…Furthermore, Prdm9 KO mice crossed into other strain backgrounds partially restores fertility in male mice (Mihola et al, 2019). Nonetheless, the evolution of PRDM9 in vertebrates replaced a pre-existing hotspot selection system based on the presence of single H3K4me3 marks at promoters with a new selection system based on the presence of dual H3K4me3/H3K36me3 marks at PRDM9 binding sites that facilitated more rapid DSB repair and synapsis.…”