title: Re-engineering the zinc fingers of PRDM9 reverses hybrid sterility in mice.
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.
authors: The Wellcome Trust Centre for Human Genetics, Roosevelt Drive, University of Oxford, Oxford OX3 7BN, UK.
authors: Benjamin
authors: B
authors: Davies
authors: The Wellcome Trust Centre for Human Genetics, Roosevelt Drive, University of Oxford, Oxford OX3 7BN, UK.
authors: Edouard
authors: E
authors: Hatton
authors: The Wellcome Trust Centre for Human Genetics, Roosevelt Drive, University of Oxford, Oxford OX3 7BN, UK.|Department of Statistics, 24-29 St Giles, Oxford OX1 3LB, UK.
authors: Nicolas
authors: N
authors: Altemose
authors: The Wellcome Trust Centre for Human Genetics, Roosevelt Drive, University of Oxford, Oxford OX3 7BN, UK.
authors: Julie G
authors: JG
authors: Hussin
authors: Genetics and Biochemistry Branch, National Institute of Diabetes, Digestive and Kidney Diseases, NIH, Bethesda, Maryland 20892, USA.
authors: Florencia
authors: F
authors: Pratto
authors: The Wellcome Trust Centre for Human Genetics, Roosevelt Drive, University of Oxford, Oxford OX3 7BN, UK.
authors: Gang
authors: G
authors: Zhang
authors: The Wellcome Trust Centre for Human Genetics, Roosevelt Drive, University of Oxford, Oxford OX3 7BN, UK.
authors: Anjali Gupta
authors: AG
authors: Hinch
authors: The Wellcome Trust Centre for Human Genetics, Roosevelt Drive, University of Oxford, Oxford OX3 7BN, UK.
authors: Daniela
authors: D
authors: Moralli
authors: The Wellcome Trust Centre for Human Genetics, Roosevelt Drive, University of Oxford, Oxford OX3 7BN, UK.
authors: Daniel
authors: D
authors: Biggs
authors: The Wellcome Trust Centre for Human Genetics, Roosevelt Drive, University of Oxford, Oxford OX3 7BN, UK.
authors: Rebeca
authors: R
authors: Diaz
authors: The Wellcome Trust Centre for Human Genetics, Roosevelt Drive, University of Oxford, Oxford OX3 7BN, UK.
authors: Chris
authors: C
authors: Preece
authors: The Wellcome Trust Centre for Human Genetics, Roosevelt Drive, University of Oxford, Oxford OX3 7BN, UK.|Department of Statistics, 24-29 St Giles, Oxford OX1 3LB, UK.
authors: Ran
authors: R
authors: Li
authors: The Wellcome Trust Centre for Human Genetics, Roosevelt Drive, University of Oxford, Oxford OX3 7BN, UK.
authors: Emmanuelle
authors: E
authors: Bitoun
authors: Genetics and Biochemistry Branch, National Institute of Diabetes, Digestive and Kidney Diseases, NIH, Bethesda, Maryland 20892, USA.
authors: Kevin
authors: K
authors: Brick
authors: The Wellcome Trust Centre for Human Genetics, Roosevelt Drive, University of Oxford, Oxford OX3 7BN, UK.
authors: Catherine M
authors: CM
authors: Green
authors: Genetics and Biochemistry Branch, National Institute of Diabetes, Digestive and Kidney Diseases, NIH, Bethesda, Maryland 20892, USA.
authors: R Daniel
authors: RD
authors: Camerini-Otero
authors: The Wellcome Trust Centre for Human Genetics, Roosevelt Drive, University of Oxford, Oxford OX3 7BN, UK.|Department of Statistics, 24-29 St Giles, Oxford OX1 3LB, UK.
authors: Simon R
authors: SR
authors: Myers
authors: The Wellcome Trust Centre for Human Genetics, Roosevelt Drive, University of Oxford, Oxford OX3 7BN, UK.|Department of Statistics, 24-29 St Giles, Oxford OX1 3LB, UK.
authors: Peter
authors: P
authors: Donnelly
mesh_terms: D000483:Alleles; D000818:Animals; D001665:Binding Sites; D023902:Chromosome Pairing / Q000235:genetics; D033481:Chromosomes, Mammalian / Q000235:genetics / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D005260:Female; D049810:Genetic Speciation; D011495:Histone-Lysine N-Methyltransferase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006824:Hybridization, Genetic / Q000235:genetics*; D007246:Infertility / Q000235:genetics*; D008297:Male; D008540:Meiosis / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D011485:Protein Binding; D015202:Protein Engineering; D017434:Protein Structure, Tertiary / Q000235:genetics; D011995:Recombination, Genetic / Q000235:genetics; D016335:Zinc Fingers / Q000235:genetics*
chemical_list: D011495:Histone-Lysine N-Methyltransferase; C544431:PRDM9 protein, human