Evolutionary Origin of Germline Pathogenic Variations in Modern Humans.

MUTYH plays an essential role in preventing oxidation-caused DNA damage. Pathogenic germline variations in damage its function, causing intestinal polyposis and colorectal cancer. Determination of the evolutionary origin of the variation is essential to understanding the etiological relationship between variation and cancer development. In this study, we analyzed the origins of pathogenic germline variants in human . Using a phylogenic approach, we searched pathogenic variants in modern humans in the of 99 vertebrates across eight clades. We did not find pathogenic variants shared between modern humans and the non-human vertebrates following the evolutionary tree, ruling out the possibility of cross-species conservation as the origin of human pathogenic variants in . We then searched the variants in the of 5031 ancient humans and extinct Neanderthals and Denisovans. We identified 24 pathogenic variants in 42 ancient humans dated between 30,570 and 480 years before present (BP), and three pathogenic variants in Neanderthals dated between 65,000 and 38,310 years BP. Data from our study revealed that human pathogenic variants mostly arose in recent human history and partially originated from Neanderthals.