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

Benjamin Davies, Edouard Hatton, Nicolas Altemose, Julie G. Hussin, Florencia Pratto, Gang Zhang, Anjali Gupta Hinch, Daniela Moralli, Daniel Biggs, Rebeca Diaz, Chris Preece, Ran Li, Emmanuelle Bitoun, Kevin Brick, Catherine M. Green, R. Daniel Camerini-Otero, Simon R. Myers () and Peter Donnelly ()
Additional contact information
Benjamin Davies: The Wellcome Trust Centre for Human Genetics, Roosevelt Drive, University of Oxford
Edouard Hatton: The Wellcome Trust Centre for Human Genetics, Roosevelt Drive, University of Oxford
Nicolas Altemose: The Wellcome Trust Centre for Human Genetics, Roosevelt Drive, University of Oxford
Julie G. Hussin: The Wellcome Trust Centre for Human Genetics, Roosevelt Drive, University of Oxford
Florencia Pratto: Genetics and Biochemistry Branch, National Institute of Diabetes, Digestive and Kidney Diseases, NIH
Gang Zhang: The Wellcome Trust Centre for Human Genetics, Roosevelt Drive, University of Oxford
Anjali Gupta Hinch: The Wellcome Trust Centre for Human Genetics, Roosevelt Drive, University of Oxford
Daniela Moralli: The Wellcome Trust Centre for Human Genetics, Roosevelt Drive, University of Oxford
Daniel Biggs: The Wellcome Trust Centre for Human Genetics, Roosevelt Drive, University of Oxford
Rebeca Diaz: The Wellcome Trust Centre for Human Genetics, Roosevelt Drive, University of Oxford
Chris Preece: The Wellcome Trust Centre for Human Genetics, Roosevelt Drive, University of Oxford
Ran Li: The Wellcome Trust Centre for Human Genetics, Roosevelt Drive, University of Oxford
Emmanuelle Bitoun: The Wellcome Trust Centre for Human Genetics, Roosevelt Drive, University of Oxford
Kevin Brick: Genetics and Biochemistry Branch, National Institute of Diabetes, Digestive and Kidney Diseases, NIH
Catherine M. Green: The Wellcome Trust Centre for Human Genetics, Roosevelt Drive, University of Oxford
R. Daniel Camerini-Otero: Genetics and Biochemistry Branch, National Institute of Diabetes, Digestive and Kidney Diseases, NIH
Simon R. Myers: The Wellcome Trust Centre for Human Genetics, Roosevelt Drive, University of Oxford
Peter Donnelly: The Wellcome Trust Centre for Human Genetics, Roosevelt Drive, University of Oxford

Nature, 2016, vol. 530, issue 7589, 171-176

Abstract: Abstract The DNA-binding protein PRDM9 directs positioning of the double-strand breaks (DSBs) that initiate 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 the DNA-binding domain of PRDM9 in C57BL/6 mice. This change repositions DSB hotspots and completely restores fertility in male hybrids. Here 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 the early stages of speciation.

Date: 2016
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DOI: 10.1038/nature16931

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