title: On the expansion of "dangerous" gene repertoires by whole-genome duplications in early vertebrates.
abstract: The emergence and evolutionary expansion of gene families implicated in cancers and other severe genetic diseases is an evolutionary oddity from a natural selection perspective. Here, we show that gene families prone to deleterious mutations in the human genome have been preferentially expanded by the retention of "ohnolog" genes from two rounds of whole-genome duplication (WGD) dating back from the onset of jawed vertebrates. We further demonstrate that the retention of many ohnologs suspected to be dosage balanced is in fact indirectly mediated by their susceptibility to deleterious mutations. This enhanced retention of "dangerous" ohnologs, defined as prone to autosomal-dominant deleterious mutations, is shown to be a consequence of WGD-induced speciation and the ensuing purifying selection in post-WGD species. These findings highlight the importance of WGD-induced nonadaptive selection for the emergence of vertebrate complexity, while rationalizing, from an evolutionary perspective, the expansion of gene families frequently implicated in genetic disorders and cancers.
authors.affiliation: CNRS UMR168, UPMC, Institut Curie, Research Center, 26, rue d'Ulm, 75248 Paris, France.
authors.forename: Param Priya
authors.initials: PP
authors.lastname: Singh
authors.forename: Séverine
authors.initials: S
authors.lastname: Affeldt
authors.forename: Ilaria
authors.initials: I
authors.lastname: Cascone
authors.forename: Rasim
authors.initials: R
authors.lastname: Selimoglu
authors.forename: Jacques
authors.initials: J
authors.lastname: Camonis
authors.forename: Hervé
authors.initials: H
authors.lastname: Isambert
mesh_terms: D000818:Animals; D030541:Databases, Genetic; D004198:Disease Susceptibility; D019143:Evolution, Molecular; D018628:Gene Dosage; D020440:Gene Duplication; D016678:Genome; D015894:Genome, Human; D006801:Humans; D008957:Models, Genetic; D017384:Sequence Deletion; D014714:Vertebrates / Q000235:genetics*