PDF(Pubmed)
Abstract：
Ancient anatomically modern humans (AMHs) encountered other archaic human species, most notably Neanderthals and Denisovans, when they left Africa and spread across Europe and Asia ~60,000 years ago. They interbred with them, and modern human genomes retain DNA inherited from these interbreeding events. High quality (high coverage) ancient human genomes have recently been sequenced allowing for a direct estimation of individual heterozygosity, which has shown that genetic diversity in these archaic human groups was very low, indicating low population sizes. In this study, we analyze ten ancient human genome-wide data, including four sequenced with high-coverage. We screened these ancient genome-wide data for pathogenic mutations associated with monogenic diseases, and established unusual aggregation of pathogenic mutations in individual subjects, including quadruple homozygous cases of pathogenic variants in the PAH gene associated with the condition phenylketonuria in a ~120,000 years old Neanderthal. Such aggregation of pathogenic mutations is extremely rare in contemporary populations, and their existence in ancient humans could be explained by less significant clinical manifestations coupled with small community sizes, leading to higher inbreeding levels. Our results suggest that pathogenic variants associated with rare diseases might be the result of introgression from other archaic human species, and archaic admixture thus could have influenced disease risk in modern humans.
摘要：
古代解剖学现代人类（AMHs）遇到了其他古老的人类物种，尤其是尼安德特人和丹尼索瓦人,当他们离开非洲并在大约6万年前传播到欧洲和亚洲时。他们与他们杂交，现代人类基因组保留了从这些杂交事件中遗传的DNA。最近对高质量（高覆盖率）的古代人类基因组进行了测序，可以直接估计个体的杂合性。这表明这些古人类群体的遗传多样性非常低，表明人口规模低。在这项研究中,我们分析了十种古代人类全基因组数据，包括四个高覆盖率的测序。我们筛选了这些古老的全基因组数据，寻找与单基因疾病相关的致病突变，并在个体受试者中建立了异常的致病性突变聚集，包括〜120,000岁的尼安德特人中与苯丙酮尿症相关的PAH基因致病性变异的四例纯合子病例。这种致病性突变的聚集在当代人群中极为罕见，它们在古代人类中的存在可以用不那么重要的临床表现加上小社区来解释，导致更高的近亲繁殖水平。我们的结果表明，与罕见疾病相关的致病变异可能是其他古人类物种渗入的结果，和古老的混合物因此可能会影响现代人的疾病风险。
