Understanding Evolutionary Origin of Human Disease-Risk Through Ancient Human Genome

ABSTRACT: Genetic variation is the driving force of evolution. A part of the variation is deleterious to the function of the affected genes, causing a high risk of developing various types of diseases in humans. Knowing the evolutionary origin of deleterious variation in modern humans is fundamental to protecting human health. Despite rich knowledge of the roles of deleterious variation in human diseases, however, its origin remains largely elusive due largely to the lack of variation information in ancient humans. Rapid progress in extracting DNA from Carbon-14-dated ancient human fossils and coupling it with high-throughput DNA sequencing has generated massive ancient human genomic DNA sequences, which may provide an opportunity to be used as a reference to determine the evolutionary origin of deleterious variation in modern humans. We explored this possibility by using the cancer-risk deleterious variation in human DNA damage repair (DDR) genes as a model. By systematic comparison of the variation data in hundreds of DDR genes between modern humans and ancient humans, we observed that 1066 (6.2%) of the 20,272 deleterious variants in 91 DDR genes of modern humans were also present in 73 DDR genes of ancient humans dated within the past 10,000 years, peaking between 7000 and 4000 years before present. We propose that the short history of deleterious variants in ancient humans can be largely attributed to human population expansion after the agricultural revolution. Our study demonstrates that the ancient human genome data can be a powerful means to bridge the gap between evolution and medicine, allowing deep understanding of the evolutionary origin of disease risk in modern humans. Our study also highlights that cancer risk by germline deleterious variation in modern humans can be a byproduct of human evolution.