Journal Article

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

Hatton, Edouard, Preece, Chris, Donnelly, Peter, Pratto, Florencia, Green, Catherine M., Li, Ran, Altemose, Nicolas, Davies, Benjamin, Zhang, Gang, Diaz, Rebeca, Moralli, Daniela, Brick, Kevin, Hussin, Julie G., Camerini-Otero, R. Daniel, Myers, Simon R., Hinch, Anjali Gupta, Biggs, Daniel, Bitoun, Emmanuelle

2016

Overview

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. PRDM9 is a DNA-binding protein that controls the position of double-strand breaks in meiosis, and the gene that encodes it is responsible for hybrid infertility between closely related mouse species; this hybrid infertility is eliminated by introducing the zinc-finger domain sequence from the human version of the PRDM9 gene, a change which alters both the position of double-strand breaks and the symmetry of PRDM9 binding and suggests that PRDM9 may have a more general but transient role in the early stages of speciation. Mechanism of action of Prdm9 'speciation gene' PRDM9 is a DNA-binding protein that controls the position of double-strand breaks in meiosis, and the Prdm9 gene that encodes it is the only known example of a mammalian speciation gene, being responsible for hybrid infertility between closely related mouse species. These authors show that hybrid infertility in mice can be eliminated by introducing the zinc-finger domain sequence from the human version of the gene, thereby altering the position of double-strand breaks. PRDM9 may therefore have a general but transient role in the early stages of speciation.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/208/182 / 631/208/191 / Alleles / Animals / Binding Sites / Chromosome Pairing - genetics / Chromosomes / Chromosomes, Mammalian - genetics / Chromosomes, Mammalian - metabolism / Deoxyribonucleic acid / DNA / DNA Breaks, Double-Stranded / Female / Fertility / Genetic aspects / Genetic engineering / Genetic Speciation / Genomes / Health aspects / Histone-Lysine N-Methyltransferase - chemistry / Histone-Lysine N-Methyltransferase - genetics / Histone-Lysine N-Methyltransferase - metabolism / Humanities and Social Sciences / Humans / Hybridization, Genetic - genetics / Hybrids / Infertility / Infertility - genetics / Male / Mammals / Meiosis - genetics / Mice / Mice, Inbred C57BL / multidisciplinary / Observations / Protein Binding / Protein Engineering / Protein Structure, Tertiary - genetics / Protein-protein interactions / Recombination, Genetic - genetics / Rodents / Science / Speciation / Symmetry / Zinc / Zinc finger proteins / Zinc Fingers - genetics