Pathogenic Variants Associated with Rare Monogenic Diseases Established in Ancient Neanderthal and Denisovan Genome-Wide Data

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 similar to 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 similar to 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.

Automated summary

Based on the analysis of ancient human genome data, the study found unusual aggregation of pathogenic mutations in some ancient individuals, which is extremely rare in contemporary populations. This aggregation may be explained by small population sizes and higher levels of inbreeding in ancient human groups. These results suggest that pathogenic variants associated with rare diseases might come from introgression from other archaic human species, and archaic admixture could have influenced disease risk in modern humans.