title: Base-Biased Evolution of Disease-Associated Mutations in the Human Genome.
abstract: 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.
authors: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas.
authors: Cheng
authors: C
authors: Xue
authors: Center for Computational Genomics, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.
authors: Hua
authors: H
authors: Chen
authors: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas. fyu@bcm.edu.
authors: Fuli
authors: F
authors: Yu
mesh_terms: D001482:Base Composition; D030541:Databases, Genetic; D019143:Evolution, Molecular; D005785:Gene Conversion; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D006801:Humans; D008957:Models, Genetic; D009154:Mutation; D011995:Recombination, Genetic; D012641:Selection, Genetic
keywords: base-bias; disease-associated; evolution; mutation; selection