Davies Benjamin, Hatton Edouard, Altemose Nicolas, Hussin Julie G, Pratto Florencia, Zhang Gang, Hinch Anjali Gupta, Moralli Daniela, Biggs Daniel, Diaz Rebeca, Preece Chris, Li Ran, Bitoun Emmanuelle, Brick Kevin, Green Catherine M, Camerini-Otero R Daniel, Myers Simon R, Donnelly Peter
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.
Nature. 2016 Feb 11;530(7589):171-176. doi: 10.1038/nature16931. Epub 2016 Feb 3.
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.
DNA结合蛋白PRDM9指导双链断裂（DSB）的定位，这些双链断裂启动了小鼠和人类的减数分裂重组。Prdm9是目前已鉴定出的唯一哺乳动物物种形成基因，它导致了某些小鼠亚种雄性杂种的不育表型。为了研究PRDM9的结合及其在生育力和减数分裂重组中的作用，我们对C57BL/6小鼠中PRDM9的DNA结合结构域进行了人源化改造。这一改变重新定位了DSB热点，并完全恢复了雄性杂种的生育力。在此我们表明，一个Prdm9等位基因的改变会在全染色体范围内影响由另一个等位基因控制的DSB的行为。这些效应与每个PRDM9变体在其控制的DSB位点上结合两个同源染色体的程度密切相关。此外，全基因组范围内更高水平的这种“对称”PRDM9结合与生育力指标的增加相关，对单个热点的比较表明结合对称性在重组过程中起下游作用。这些发现揭示，减数分裂驱动导致PRDM9结合位点的亚种特异性降解，这会稳步增加不对称的PRDM9结合，其影响不仅仅是简单地改变热点位置，有力地支持了其直接参与杂种不育的观点。由于这种减数分裂驱动在整个哺乳动物中都存在，PRDM9可能在物种形成的早期阶段发挥更广泛但短暂的作用。
