A large-scale study of the random variability of a coding sequence: a study on the CFTR gene.
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.
Modiano
Guido
G
Department of Biology, University of Tor Vergata - Rome, Via della Ricerca, Scientifica, 001333 Roma, Italy. modiano@uniroma2.it
Bombieri
Cristina
C
Ciminelli
Bianca Maria
BM
Belpinati
Francesca
F
Giorgi
Silvia
S
Georges
Marie des
Md
Scotet
Virginie
V
Pompei
Fiorenza
F
Ciccacci
Cinzia
C
Guittard
Caroline
C
Audrézet
Marie Pierre
MP
Begnini
Angela
A
Toepfer
Michael
M
Macek
Milan
M
Ferec
Claude
C
Claustres
Mireille
M
Pignatti
Pier Franco
PF
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*
C505032:CFTR protein, human; D019005:Cystic Fibrosis Transmembrane Conductance Regulator