Traces of Neandertal and Denisovan DNA persist in the modern human gene pool, but have been systematically purged by natural selection from genes and other functionally important regions. This implies that many archaic alleles harmed the fitness of hybrid individuals, but the nature of this harm is poorly understood. Here, we show that enhancers contain less Neandertal and Denisovan variation than expected given the background selection they experience, suggesting that selection acted to purge these regions of archaic alleles that disrupted their gene regulatory functions. We infer that selection acted mainly on young archaic variation that arose in Neandertals or Denisovans shortly before their contact with humans; enhancers are not depleted of older variants found in both archaic species. Some types of enhancer appear to have tolerated introgression better than others; compared with tissue-specific enhancers, pleiotropic enhancers show stronger depletion of archaic single-nucleotide polymorphisms. To some extent, evolutionary constraint is predictive of introgression depletion, but certain tissues’ enhancers are more depleted of Neandertal and Denisovan alleles than expected given their comparative tolerance to new mutations. Foetal brain and muscle are the tissues whose enhancers show the strongest depletion of archaic alleles, but only brain enhancers show evidence of unusually stringent purifying selection. We conclude that epistatic incompatibilities between human and archaic alleles are needed to explain the degree of archaic variant depletion from foetal muscle enhancers, perhaps due to divergent selection for higher muscle mass in archaic hominins compared with humans.

尼安德特人和丹尼索瓦DNA的痕迹一直存在于现代人类基因库中，但已通过从基因和其他功能上重要的区域进行自然选择而被系统清除。这意味着许多古老的等位基因损害了杂种个体的适应能力，但是这种危害的性质却鲜为人知。在这里，我们显示增强子包含的尼安德特人和Denisovan变异比给定的背景选择所预期的要少，这表明选择起到清除这些等位基因破坏其基因调控功能的作用。我们推断，选择主要是作用于尼安德特人或丹尼索瓦人在与人类接触之前不久出现的年轻的古老变异。增强子没有耗尽在两个古老物种中发现的较旧的变体。某些类型的增强剂似乎比其他类型具有更好的耐受性。与组织特异性增强剂相比，多效性增强剂显示出古老单核苷酸多态性的更强消耗。在某种程度上，进化限制是基因渗入耗竭的预测，但是鉴于对新突变的相对耐受性，某些组织的增强子比预期的耗竭了尼安德特人和丹尼索万等位基因。胎儿的大脑和肌肉是其促进剂显示出最强的古等位基因耗竭的组织，但是只有脑部增强剂显示出净化选择异常严格的证据。我们的结论是，需要人类与古体等位基因之间的上位不相容性来解释胎儿肌肉增强剂对古体变异的耗竭程度，