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Keywords:

Alleles, transmembrane conductance regulator, Base Sequence, cystic-fibrosis patients, Comparative Study, dna marker, pancreatic insufficiency, Cystic Fibrosis, Cystic Fibrosis Transmembrane Conductance Regulator, mutations, Gene Deletion, identification, sequence, Genes, association, Haplotypes, Humans, families, deletion, Linkage Disequilibrium, Membrane Proteins, Molecular Sequence Data, Mutation, Polymorphism, Genetic, Research Support, Non-U.S. Gov't, Selection (Genetics), Science & Technology, Life Sciences & Biomedicine, Biochemistry & Molecular Biology, Genetics & Heredity, TRANSMEMBRANE CONDUCTANCE REGULATOR, CYSTIC-FIBROSIS PATIENTS, DNA MARKER, PANCREATIC INSUFFICIENCY, MUTATIONS, IDENTIFICATION, SEQUENCE, ASSOCIATION, FAMILIES, DELETION, Selection, Genetic, 06 Biological Sciences, 11 Medical and Health Sciences, 3105 Genetics

Abstract:

Ten polymorphic loci, located in a 1 Mb interval across the cystic fibrosis locus, were analyzed on normal and mutant CFTR genes. A different distribution of haplotype backgrounds among normal and mutant CFTR genes was observed. With exception of the D7S8 locus, the three most common mutations, Delta F508, G542X and N1303K, were found on an identical haplotype background. In agreement with the observed linkage equilibrium between the Q1463Q and D7S8 loci, both alleles at the D7S8 locus were found on Delta F508 CFTR genes. However, the G542X and N1303K mutations, which have been estimated to be at least 35000 years old, were found to be associated with a single allele at the D7S8 locus. Absence of recombination between the D7S8 and Q1463Q loci was also observed on normal CFTR genes with this haplotype background. At the Tn locus in intron 8, allele 9 known to result in very efficient splicing was associated with the most frequent mutations. At the M470V locus, located in a conserved region of the first nucleotide binding fold, the amino acid methionine was found to be associated with the frequent mutations, in particular with mutations located in one of the two nucleotide binding folds which are generally known as severe mutations with regard to exocrine pancreatic function. On mutant CFTR genes, this locus was in complete association with the centromeric D9 locus, in the absence of a complete association with the intervening loci. This is of particular interest, firstly since genotypes at the D9 locus, as well as other polymorphic loci in this centromeric region of the CFTR gene, have previously been shown to correlate with CF phenotypes. Secondly, a particular haplotype background at these centromerically located polymorphic loci has been hypothesized to confer a selective advantage for CFTR mutations present on this haplotype background. These data are important for a more complete understanding of the genetics, of the phenotypes and of the evolution of mutant CFTR alleles.