Base‐Biased Evolution of Disease‐Associated Mutations in the Human Genome

: Understanding the evolution of disease-associated mutations is fundamental to analyze pathogenetics of diseases. Mutation, recombination (by GC-biased gene conversion, gBGC), and selection have been known to shape the evolution of disease-associated mutations, but how these evolutionary forces work together is still an open question. In this study, we analyzed several human large-scale datasets (1000 Genomes, ESP6500, ExAC and ClinVar), and found that base-biased mutagenesis generates more GC→AT than AT→GC mutations, while gBGC promotes the fixation of AT→GC mutations to balance the impact of base-biased mutation on genome. Due to this effect of gBGC, purifying selection removes more deleterious AT→GC mutations than GC→AT from population, but many high-frequency (fixed and nearly fixed) deleterious AT→GC mutations are remained possibly due to high genetic load. As a special subset, disease-associated mutations follow this evolutionary rule, in which disease-associated GC→AT mutations are more enriched in rare mutations compared with AT→GC, while disease-associated AT→GC are more enriched in mutations with high frequency. Thus, we presented a base-biased evolutionary framework that explains the base-biased generation and accumulation of disease-associated mutations in human populations.