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On the retention of gene duplicates prone to dominant deleterious mutations.
Malaguti, Giulia; Singh, Param Priya; Isambert, Hervé.
Afiliación
  • Malaguti G; Institut Curie, CNRS-UMR168, UPMC, 26 rue d'Ulm, 75005 Paris, France.
  • Singh PP; Institut Curie, CNRS-UMR168, UPMC, 26 rue d'Ulm, 75005 Paris, France.
  • Isambert H; Institut Curie, CNRS-UMR168, UPMC, 26 rue d'Ulm, 75005 Paris, France. Electronic address: herve.isambert@curie.fr.
Theor Popul Biol ; 93: 38-51, 2014 May.
Article en En | MEDLINE | ID: mdl-24530892
ABSTRACT
Recent studies have shown that gene families from different functional categories have been preferentially expanded either by small scale duplication (SSD) or by whole-genome duplication (WGD). In particular, gene families prone to dominant deleterious mutations and implicated in cancers and other genetic diseases in human have been greatly expanded through two rounds of WGD dating back from early vertebrates. Here, we strengthen this intriguing observation, showing that human oncogenes involved in different primary tumors have retained many WGD duplicates compared to other human genes. In order to rationalize this evolutionary outcome, we propose a consistent population genetics model to analyze the retention of SSD and WGD duplicates taking into account their propensity to acquire dominant deleterious mutations. We solve a deterministic haploid model including initial duplicated loci, their retention through sub-functionalization or their neutral loss-of-function or deleterious gain-of-function at one locus. Extensions to diploid genotypes are presented and population size effects are analyzed using stochastic simulations. The only difference between the SSD and WGD scenarios is the initial number of individuals with duplicated loci. While SSD duplicates need to spread through the entire population from a single individual to reach fixation, WGD duplicates are de facto fixed in the small initial post-WGD population arising through the ploidy incompatibility between post-WGD individuals and the rest of the pre-WGD population. WGD duplicates prone to dominant deleterious mutations are then shown to be indirectly selected through purifying selection in post-WGD species, whereas SSD duplicates typically require positive selection. These results highlight the long-term evolution mechanisms behind the surprising accumulation of WGD duplicates prone to dominant deleterious mutations and are shown to be consistent with cancer genome data on the prevalence of human oncogenes with WGD duplicates.
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Duplicación de Gen / Genes Dominantes / Mutación Tipo de estudio: Risk_factors_studies Límite: Humans Idioma: En Revista: Theor Popul Biol Año: 2014 Tipo del documento: Article País de afiliación: Francia

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Duplicación de Gen / Genes Dominantes / Mutación Tipo de estudio: Risk_factors_studies Límite: Humans Idioma: En Revista: Theor Popul Biol Año: 2014 Tipo del documento: Article País de afiliación: Francia