Úbeda Francisco, Russell Timothy W, Jansen Vincent A A
School of Biological Sciences, Royal Holloway University of London, Egham, Surrey, TW20 0EX, UK.
School of Biological Sciences, Royal Holloway University of London, Egham, Surrey, TW20 0EX, UK.
Theor Popul Biol. 2019 Apr;126:19-32. doi: 10.1016/j.tpb.2018.12.005. Epub 2019 Jan 17.
Recombination in mammals is not uniformly distributed along the chromosome but concentrated in small regions known as recombination hotspots. Recombination starts with the double-strand break of a chromosomal sequence and results in the transmission of the sequence that does not break (preventing recombination) more often than the sequence that breaks (allowing recombination). Thus recombination itself renders individual recombination hotspots inactive and over time should drive them to extinction in the genome. Empirical evidence shows that individual recombination hotspots die but, far from being driven to extinction, they are abundant in the genome: a contradiction referred to as the Recombination Hotspot Paradox. What saves recombination hotspots from extinction? The current answer relies in the formation of new recombination hotspots in new genomic sites driven by viability selection in favor of recombination. Here we formulate a population genetics model that incorporates the molecular mechanism initiating recombination in mammals (PRDM9-like genes), to provide an alternative solution to the paradox. We find that weak selection allows individual recombination hotspots to become inactive (die) while saving them from extinction in the genome by driving their re-activation (resurrection). Our model shows that when selection for recombination is weak, the introduction of rare variants causes recombination sites to oscillate between hot and cold phenotypes with a recombination hotspot dying only to come back. Counter-intuitively, we find that low viability selection leaves a hard selective sweep signature in the genome, with the selective sweep at the recombination hotspot being the hardest when viability selection is the lowest. Our model can help to understand the rapid evolution of PRDM9, the co-existence of two types of hotspots, the life expectancy of hotspots, and the volatility of the recombinational landscape (with hotspots rarely being shared between closely related species).
哺乳动物中的重组并非沿染色体均匀分布，而是集中在被称为重组热点的小区域。重组始于染色体序列的双链断裂，导致未断裂序列（阻止重组）的传递频率高于断裂序列（允许重组）。因此，重组本身会使单个重组热点失活，随着时间的推移，应会导致它们在基因组中灭绝。经验证据表明，单个重组热点会消失，但它们在基因组中非但没有走向灭绝，反而数量众多：这一矛盾被称为重组热点悖论。是什么使重组热点免于灭绝？目前的答案依赖于由有利于重组的生存力选择驱动的新基因组位点中新重组热点的形成。在此，我们构建了一个群体遗传学模型，该模型纳入了启动哺乳动物重组的分子机制（PRDM9样基因），以提供对这一悖论的另一种解决方案。我们发现，弱选择会使单个重组热点失活（消失），同时通过驱动它们重新激活（复活）使其免于在基因组中灭绝。我们的模型表明，当对重组的选择较弱时，稀有变异的引入会导致重组位点在热点和冷点表型之间振荡，一个重组热点消失后又会重现。与直觉相反，我们发现低生存力选择会在基因组中留下强烈的选择性清除信号，当生存力选择最低时，重组热点处的选择性清除最为强烈。我们的模型有助于理解PRDM9的快速进化、两种热点的共存、热点的寿命以及重组景观的波动性（密切相关物种之间很少共享热点）。
