Medical Faculty, Department of Medical Genetics, Medical University of Sofia, Sofia 1000, Bulgaria.
Bulgarian Academy of Sciences, Sofia 1000, Bulgaria.
Genes (Basel). 2023 Mar 16;14(3):727. doi: 10.3390/genes14030727.
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 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.
大约 6 万年前，走出非洲的远古时期现代人（AMHs）与其他古人类物种，尤其是尼安德特人和丹尼索瓦人相遇。他们相互杂交，现代人类的基因组保留了这些杂交事件遗传的 DNA。最近，高质量（高覆盖度）的古人类基因组已被测序，这使得我们可以直接估算个体杂合度，结果表明这些古人类群体的遗传多样性非常低，表明其种群规模较小。在这项研究中，我们分析了十个人类古基因组全基因组数据，其中四个具有高覆盖度。我们对这些古基因组全基因组数据进行了与单基因疾病相关的致病性突变筛查，并在个体中发现了致病性突变的异常聚集，包括一个 12 万年前的尼安德特人存在与苯丙酮尿症相关的 基因的四重纯合致病性变异。这种致病性突变的聚集在当代人群中极为罕见，而在古人类中存在这种情况可能是由于临床表现不明显，再加上社区规模较小，导致更高的近亲繁殖水平。我们的研究结果表明，与罕见疾病相关的致病性变异可能是来自其他古人类物种的基因渗入的结果，因此古人类的混合可能会影响现代人的疾病风险。
