Recombination often concentrates in small regions called recombination hotspots where recombination is much higher than the genome’s average. In many vertebrates, including humans, gene PRDM9 specifies which DNA motifs will be the target for breaks that initiate recombination, ultimately determining the location of recombination hotspots. Because the sequence that breaks (allowing recombination) is converted into the sequence that does not break (preventing recombination), the latter sequence is over-transmitted to future generations and recombination hotspots are self-destructive. Given their self-destructive nature, recombination hotspots should eventually become extinct in genomes where they are found. While empirical evidence shows that individual hotspots do become inactive over time (die), hotspots are abundant in many vertebrates: a contradiction called the Recombination Hotspot Paradox. What saves recombination hotspots from their foretold extinction? Here we formulate a co-evolutionary model of the interaction among sequence-specific gene conversion, fertility selection, and recurrent mutation. We find that allelic frequencies oscillate leading to stable limit cycles. From a biological perspective this means that when fertility selection is weaker than gene conversion, it cannot stop individual hotspots from dying but can save them from extinction by driving their re-activation (resuscitation). In our model, mutation balances death and resuscitation of hotspots, thus maintaining their number over evolutionary time. Interestingly, we find that multiple alleles result in oscillations that are chaotic and multiple targets in oscillations that are asynchronous between targets thus helping to maintain the average genomic recombination probability constant. Furthermore, we find that the level of expression of PRDM9 should control for the fraction of targets that are hotspots and the overall temperature of the genome. Therefore, our co-evolutionary model improves our understanding of how hotspots may be replaced, thus contributing to solve the Recombination Hotspot Paradox. From a more applied perspective our work provides testable predictions regarding the relation between mutation probability and fertility selection with life expectancy of hotspots.

重组通常集中在称为重组热点的小区域，其中重组率远高于基因组的平均水平。在包括人类在内的许多脊椎动物中，基因 PRDM9 指定哪些 DNA 基序将成为启动重组的断裂目标，最终确定重组热点的位置。因为断裂（允许重组）的序列被转换为不断裂（防止重组）的序列，后者的序列被过度传递给后代，并且重组热点是自毁性的。鉴于其自我毁灭的性质，重组热点最终应该在发现它们的基因组中消失。虽然经验证据表明，随着时间的推移，个体热点确实会变得不活跃（死亡），但许多脊椎动物的热点却很丰富：这一矛盾被称为重组热点悖论。是什么使重组热点免遭预言中的灭绝？在这里，我们制定了序列特异性基因转换、育性选择和经常突变之间相互作用的共同进化模型。我们发现等位基因频率振荡导致稳定的极限环。从生物学角度来看，这意味着当生育力选择弱于基因转换时，它不能阻止个体热点死亡，但可以通过驱动它们的重新激活（复苏）来拯救它们免于灭绝。在我们的模型中，突变平衡了热点的死亡和复苏，从而在进化过程中保持热点的数量。有趣的是，我们发现多个等位基因导致混乱的振荡，并且多个目标的振荡在目标之间是异步的，从而有助于维持平均基因组重组概率恒定。此外，我们发现 PRDM9 的表达水平应该控制热点靶标的比例和基因组的整体温度。因此，我们的共同进化模型提高了我们对热点如何被替换的理解，从而有助于解决重组热点悖论。从更应用的角度来看，我们的工作提供了关于突变概率和生育选择与热点预期寿命之间关系的可测试预测。