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* Corresponding author 1 LBBE - Laboratoire de Biométrie et Biologie Evolutive 2 Centre intégratif de génomique 3 Institute of Medical Genetics, College of Medicine 4 Institute of Medical Genetics, College of Medicine Cardiff

Abstract : 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 non-exclusive 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 which 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 non-synonymous 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.

Keywords : Life Sciences





Author: Anamaria Necsulea - Laurent Duret - Alexandra Popa - David N. Cooper - Peter Stentson - Dominique Mouchiroud - Christian Gautier

Source: https://hal.archives-ouvertes.fr/



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