RESUMO
BACKGROUND: The CFTR gene (Cystic Fibrosis conductance Transmembrane Regulator) is the gene responsible for Cystic Fibrosis, the most common severe autosomal recessive disease in Europeans. It has been extensively explored in several European and European-derived populations, but poorly studied in the other major human groups. AIM: To characterize the variability of the CFTR gene in an African population. SUBJECTS AND METHODS: Using DGGE, all 27 exons (4443 bp) and 2184 bp of the flanking intronic regions of the CFTR gene were studied in a random sample of 45 Mossì from Burkina Faso (Western sub-Saharan Africa). RESULTS: Sixteen variable sites were found: 13 SNPs (one in the promoter region, four non-synonymous and five synonymous in the exons and three in the introns) and three intronic STRs. Only the promoter site ( - 94 G/T), slightly polymorphic in the present survey, was not variable in different European populations. Comparison between Western Africans, Eastern Africans, Europeans and Eastern Asians showed that alleles at two intronic STRs (T(n) and (TG)(m) in intron 8), four exonic (M470V, 2694 T/G, 4002 A/G and 4521 G/A) and one intronic (875+40 A/G) SNPs have very different frequencies among at least two major human groups. Moreover, the overall degree of non-synonymous variability in Mossì is much lower than that in Europeans. A possible interpretation of this finding is proposed. CONCLUSIONS: The CFTR gene has been since long hypothesized to have undergone selection in Europeans. The present study by comparing Africans and Europeans for the overall variability of the gene supports this hypothesis.
Assuntos
População Negra/genética , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Polimorfismo de Nucleotídeo Único , Alelos , Burkina Faso , Fibrose Cística/epidemiologia , Fibrose Cística/etnologia , Europa (Continente)/epidemiologia , Éxons/genética , Frequência do Gene , Humanos , Íntrons/genética , Mutação , Regiões Promotoras GenéticasRESUMO
An average of about 1700 CFTR (cystic fibrosis transmembrane conductance regulator) alleles from normal individuals from different European populations were extensively screened for DNA sequence variation. A total of 80 variants were observed: 61 coding SNSs (results already published), 13 noncoding SNSs, three STRs, two short deletions, and one nucleotide insertion. Eight DNA variants were classified as non-CF causing due to their high frequency of occurrence. Through this survey the CFTR has become the most exhaustively studied gene for its coding sequence variability and, though to a lesser extent, for its noncoding sequence variability as well. Interestingly, most variation was associated with the M470 allele, while the V470 allele showed an 'extended haplotype homozygosity' (EHH). These findings make us suggest a role for selection acting either on the M470V itself or through an hitchhiking mechanism involving a second site. The possible ancient origin of the V allele in an 'out of Africa' time frame is discussed.
Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística/genética , Variação Genética , Haplótipos/genética , População Branca/genética , Frequência do Gene , Humanos , Desequilíbrio de Ligação , MutaçãoAssuntos
Predisposição Genética para Doença , Hanseníase/genética , Hanseníase/imunologia , Mycobacterium leprae/imunologia , Polimorfismo Genético , Membro 3 da Subfamília B de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/genética , Abatacepte , Proteínas de Transporte de Cátions/genética , Proteína de Ligação ao Complemento C4b , Antígenos HLA/genética , Antígenos de Histocompatibilidade/genética , Humanos , Imunoconjugados/genética , Interleucina-10/genética , Hanseníase/microbiologia , Glicoproteínas de Membrana/genética , Proteínas dos Microfilamentos , Chaperonas Moleculares , Proteínas/genética , Receptores de Superfície Celular/genética , Receptores Toll-Like , Fator de Necrose Tumoral alfa/genética , Ubiquitina-Proteína Ligases/genéticaRESUMO
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.