Evolutionary Origin of Human Germline Pathogenic Variants.

(Partner and localizer of BRCA2) is crucial for repairing DNA double-stranded breaks (DSBs) through homologous recombination (HR). Germline pathogenic variation in disrupts DNA damage repair and increases the risk of Fanconi Anemia, breast cancer, and ovarian cancer. Determination of the evolutionary origin of human variants will promote a deeper understanding of the biological basis of germline variation and its roles in human diseases. We tested the evolution origin for 1444 human germline variants, including 484 pathogenic and 960 benign variants. We performed a phylogenic analysis by tracing the variants in 100 vertebrates. However, we found no evidence to show that cross-species conservation was the origin of germline pathogenic variants, but it is indeed a rich source for germline benign variants. We performed a paleoanthropological analysis by tracing the variants in over 5000 ancient humans. We identified 50 pathogenic in 71 ancient humans dated from 32,895 to 689 before the present, of which 90.1% were dated within the recent 10,000 years. benign variants were also highly shared with ancient humans. Data from our study reveal that human pathogenic variants mostly arose in recent human history.