title: A large-scale study of the random variability of a coding sequence: a study on the CFTR gene.
abstract: Coding single nucleotide substitutions (cSNSs) have been studied on hundreds of genes using small samples (n(g) approximately 100-150 genes). In the present investigation, a large random European population sample (average n(g) approximately 1500) was studied for a single gene, the CFTR (Cystic Fibrosis Transmembrane conductance Regulator). The nonsynonymous (NS) substitutions exhibited, in accordance with previous reports, a mean probability of being polymorphic (q > 0.005), much lower than that of the synonymous (S) substitutions, but they showed a similar rate of subpolymorphic (q < 0.005) variability. This indicates that, in autosomal genes that may have harmful recessive alleles (nonduplicated genes with important functions), genetic drift overwhelms selection in the subpolymorphic range of variability, making disadvantageous alleles behave as neutral. These results imply that the majority of the subpolymorphic nonsynonymous alleles of these genes are selectively negative or even pathogenic.
authors.affiliation: Department of Biology, University of Tor Vergata - Rome, Via della Ricerca, Scientifica, 001333 Roma, Italy. modiano@uniroma2.it
authors.forename: Guido
authors.initials: G
authors.lastname: Modiano
authors.forename: Cristina
authors.initials: C
authors.lastname: Bombieri
authors.forename: Bianca Maria
authors.initials: BM
authors.lastname: Ciminelli
authors.forename: Francesca
authors.initials: F
authors.lastname: Belpinati
authors.forename: Silvia
authors.initials: S
authors.lastname: Giorgi
authors.forename: Marie des
authors.initials: Md
authors.lastname: Georges
authors.forename: Virginie
authors.initials: V
authors.lastname: Scotet
authors.forename: Fiorenza
authors.initials: F
authors.lastname: Pompei
authors.forename: Cinzia
authors.initials: C
authors.lastname: Ciccacci
authors.forename: Caroline
authors.initials: C
authors.lastname: Guittard
authors.forename: Marie Pierre
authors.initials: MP
authors.lastname: Audrézet
authors.forename: Angela
authors.initials: A
authors.lastname: Begnini
authors.forename: Michael
authors.initials: M
authors.lastname: Toepfer
authors.forename: Milan
authors.initials: M
authors.lastname: Macek
authors.forename: Claude
authors.initials: C
authors.lastname: Ferec
authors.forename: Mireille
authors.initials: M
authors.lastname: Claustres
authors.forename: Pier Franco
authors.initials: PF
authors.lastname: Pignatti
mesh_terms: D000483:Alleles; D003550:Cystic Fibrosis / Q000235:genetics; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D005260:Female; D005808:Genes, Recessive / Q000235:genetics; D005820:Genetic Testing; D006801:Humans; D008297:Male; D008957:Models, Genetic; D016366:Open Reading Frames / Q000235:genetics*; D017354:Point Mutation / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*
chemical_list: C505032:CFTR protein, human; D019005:Cystic Fibrosis Transmembrane Conductance Regulator