title: Conservation of CFTR codon frequency through primates suggests synonymous mutations could have a functional effect.
abstract: Cystic fibrosis is an inherited chronic disease that affects the lungs and digestive system, with a prevalence of about 1:3000 people. Cystic fibrosis is caused by mutations in CFTR gene, which lead to a defective function of the chloride channel, the cystic fibrosis transmembrane conductance regulator (CFTR). Up-to-date, more than 1900 mutations have been reported in CFTR. However for an important proportion of them, their functional effects and the relation to disease are still not understood. Many of these mutations are silent (or synonymous), namely they do not alter the encoded amino acid. These synonymous mutations have been considered as neutral to protein function. However, more recent evidence in bacterial and human proteins has put this concept under revision. With the aim of understanding possible functional effects of synonymous mutations in CFTR, we analyzed human and primates CFTR codon usage and divergence patterns. We report the presence of regions enriched in rare and frequent codons. This spatial pattern of codon preferences is conserved in primates, but this cannot be explained by sequence conservation alone. In sum, the results presented herein suggest a functional implication of these regions of the gene that may be maintained by purifying selection acting to preserve a particular codon usage pattern along the sequence. Overall these results support the idea that several synonymous mutations in CFTR may have functional importance, and could be involved in the disease.
authors.affiliation: Sección Bioquímica-Biología Molecular, Facultad de Ciencias, Universidad de la República, Iguá 4225, 11400 Montevideo, Uruguay.
authors.forename: Lucilla
authors.initials: L
authors.lastname: Pizzo
authors.affiliation: Dpto. de Desarrollo Biotecnológico, Instituto de Higiene, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay; Dpto. de Genómica, Instituto de Investigaciones Biológicas Clemente Estable, IIBCE, Montevideo, Uruguay; Dpto. de Bioquímica y Genómica Microbianas, Instituto de Investigaciones Biológicas Clemente Estable, IIBCE, Montevideo, Uruguay.
authors.forename: Andrés
authors.initials: A
authors.lastname: Iriarte
authors.affiliation: Sección Biomatemática, Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay.
authors.forename: Fernando
authors.initials: F
authors.lastname: Alvarez-Valin
authors.affiliation: Sección Bioquímica-Biología Molecular, Facultad de Ciencias, Universidad de la República, Iguá 4225, 11400 Montevideo, Uruguay. Electronic address: marin@fcien.edu.uy.
authors.forename: Mónica
authors.initials: M
authors.lastname: Marín
mesh_terms: D000818:Animals; D003062:Codon; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D019143:Evolution, Molecular; D006801:Humans; D008957:Models, Genetic; D009154:Mutation; D011323:Primates / Q000235:genetics*
chemical_list: C505032:CFTR protein, human; D003062:Codon; D019005:Cystic Fibrosis Transmembrane Conductance Regulator
keywords: CFTR; Codon frequency conservation; Cystic fibrosis; Synonymous mutations