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 E100 -150 genes). In the present investigation, a large random European population sample (average n g E1500) 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 (q40.005), much lower than that of the synonymous (S) substitutions, but they showed a similar rate of subpolymorphic (qo0.005) 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.

Scanning the Cystic Fibrosis Transmembrane Conductance Regulator Gene Using High-Resolution DNA Melting Analysis

“…Twenty-one apparent benign variants were identified, but only 6 had an allele frequency Ͼ0.02. The identity and frequency of variants were similar to those reported previously (30 ), although 4 novel variants were identified. Using the melting patterns of the 6 most common heterozygotes, we eliminated 45 of 47 benign variants from consideration.…”

Haplotype block structure study of the CFTR gene. Most variants are associated with the M470 allele in several European populations

“…It amounts to about 1700 haploid genomes. For a detailed list of the sample size studied for each exon see Modiano et al 1 …”

“…1 It consists of 1337 healthy, unrelated individuals (selected on the basis of the birth place of the four grandparents) from six geographical areas: Northern Italy, Verona (n ¼ 300); Central Italy, Rome (n ¼ 300); Southern France, Montpellier (n ¼ 300); Northern France, Brest (n ¼ 278); Czech Republic, Prague (n ¼ 118); and Spain, Barcelona (n ¼ 41). All individuals gave their informed consent.…”

“…However, the study of its overall random variability, wherein disease causing mutations should be framed, has started only recently. 1 For many of the several hundreds CFTR variants reported, it is not known whether they are or not CFcausing and this may produce difficulties for genetic counselling. Besides the obvious criteria to identify with certainty the CF-causing mutations (eg frameshift and termination mutations), a purely statistical approach to identify not fully penetrant CF-causing mutations has been proposed by Bombieri et al 2 It is based on the consideration that every CFTR variant with a frequency certainly higher than the cumulative frequency of the not unambiguously identified CF-causing alleles cannot be a fully penetrant CF-causing allele.…”

Clinical and Laboratory Findings of Infants with Cystic Fibrosis

“…3,4 KFTR geninde 1500'den fazla mutasyon tespit edilmiştir. 5 Solunum yolu epiteli, pankreas kanal epiteli, safra kanal epiteli, vas deferens, ter bezleri, ince ve kalın barsak epitellerinde normalde KFTR protein yer almaktadır. Hücrede endoplazmik retikulumda sentezlenerek Golgi cisimciğinde glukolize olmakta ve epitel hücresi apikal membranında yerleşerek c-AMP ile aktive olan klor kanalı görevi yapmaktadır.…”