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.

Population size determines the type of nucleotide variations in humans

“…Since gBGC does not affect the changes between A↔T (weak bond) and between G↔C (strong bond) previous studies have used the rate of these changes as a normalizing factor to assess the magnitude of gBGC on GC↔AT changes (Lachance and Tishkoff 2014; Glemin, et.al 2015;Xue and Chen 2016). Following this, we normalized AT→GC with A↔T changes and GC→AT with G↔C changes respectively and developed a normalized ratio, β'…”

“…These observations suggest that due to the effects of genetic drift, small populations (typically located away from Africa) have a higher fraction of high frequency (and homozygous) deleterious mutations than large populations. On the other hand, a gBGC mediated skews in the frequencies of deleterious AT→GC (relative to GC→AT) polymorphisms were also reported (Lachance and Tishkoff 2014;Xue, et al 2016). However, it is unclear whether the extent of such skews is influenced by the effective population sizes of various global populations.…”

Are Molecular Alterations Linked to Genetic Instability Worth to Be Included as Biomarkers for Directing or Excluding Melanoma Patients to Immunotherapy?

“…The accumulation and fixation of mutations into the genome, both in the transcribed or regulatory sequences and in those apparently inactive, is one of the most important ways through which evolution is carried out ( 12 ). Excluding mutations having deleterious effects with functional consequences, the great majority of sequence variants often display an undefined role (neither harmful nor beneficial) in disease pathogenesis ( 13 ).…”

The role of recombination dynamics in shaping signatures of direct and indirect selection across the Ficedula flycatcher genome

“…In some systems, there is evidence that the evolution of suppressed recombination can promote local adaptation and speciation (4)(5)(6)(7)(8), for instance when inversions capture multiple loci with beneficial variation. In addition to breaking up linkage among sites, recombination is associated with the process of GC-biased gene conversion (gBGC), which leads to the preferential fixation of G:C over A:T alleles and can interfere with fitness (9,10). Thus, recombination can have a multi-faceted impact on fitness.…”