Re-engineering the zinc fingers of PRDM9 reverses hybrid sterility in mice

Journal article

The DNA-binding protein PRDM9 directs positioning of the double strand breaks (DSBs) initiating meiotic recombination, in mice and humans. PRDM9 is the only mammalian speciation gene yet identified and is responsible for sterility phenotypes in male hybrids of certain mouse subspecies. To investigate PRDM9 binding and its role in fertility and meiotic recombination, we humanized PRDM9’s DNA-binding domain in C57BL/6 mice. This change repositions DSB hotspots and completely restores fertility in male hybrids. We show that alteration of one Prdm9 allele impacts the behaviour of DSBs controlled by the other allele at chromosome-wide scales. These effects correlate strongly with the degree to which each PRDM9 variant binds both homologues at the DSB sites it controls. Furthermore, higher genome-wide levels of such “symmetric” PRDM9 binding associate with increasing fertility measures and comparisons of individual hotspots suggest binding symmetry plays a downstream role in the recombination process. These findings reveal that subspecies-specific degradation of PRDM9 binding sites by meiotic drive, which steadily increases asymmetric PRDM9 binding, has impacts beyond simply changing hotspot positions, and strongly support a direct involvement in hybrid infertility. Because such meiotic drive occurs across mammals, PRDM9 may play a wider, yet transient, role in early stages of speciation.

Authors: Davies, B; Hatton, E; Altemose, N; Hussin, J; Pratto, F

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Nature Research
• Journal: Nature
• Volume: 530
• Issue: 2016
• Pages: 171-176
• Publication date: 2016-02-03
• Acceptance date: 2015-12-21
• DOI: 10.1038/nature16931
• EISSN: 1476-4687
• ISSN: 0028-0836