Meiotic recombination favors the spreading of deleterious mutations in human populations.
Although mutations that are detrimental to the fitness of organisms are expected to be rapidly purged from populations by natural selection, some disease-causing mutations are present at high frequencies in human populations. Several nonexclusive hypotheses have been proposed to account for this apparent paradox (high new mutation rate, genetic drift, overdominance, or recent changes in selective pressure). However, the factors ultimately responsible for the presence at high frequency of disease-causing mutations are still contentious. Here we establish the existence of an additional process that contributes to the spreading of deleterious mutations: GC-biased gene conversion (gBGC), a process associated with recombination that tends to favor the transmission of GC-alleles over AT-alleles. We show that the spectrum of amino acid-altering polymorphisms in human populations exhibits the footprints of gBGC. This pattern cannot be explained in terms of selection and is evident with all nonsynonymous mutations, including those predicted to be detrimental to protein structure and function, and those implicated in human genetic disease. We present simulations to illustrate the conditions under which gBGC can extend the persistence time of deleterious mutations in a finite population. These results indicate that gBGC meiotic drive contributes to the spreading of deleterious mutations in human populations.
Université de Lyon, Université Lyon 1, CNRS, UMR 5558, Laboratoire de Biométrie et Biologie Evolutive, Villeurbanne, France.
Anamaria
A
Necşulea
Alexandra
A
Popa
David N
DN
Cooper
Peter D
PD
Stenson
Dominique
D
Mouchiroud
Christian
C
Gautier
Laurent
L
Duret
D001482:Base Composition; D004194:Disease / Q000235:genetics; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D008540:Meiosis; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D011995:Recombination, Genetic