Anthropological features of the CFTR gene: Its variability in an African population.

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.

Haemoglobin S and haemoglobin C: 'quick but costly' versus 'slow but gratis' genetic adaptations to Plasmodium falciparum malaria.

Haemoglobin S (HbS; beta6Glu-->Val) and HbC (beta6Glu-->Lys) strongly protect against clinical Plasmodium falciparum malaria. HbS, which is lethal in homozygosity, has a multi-foci origin and a widespread geographic distribution in sub-Saharan Africa and Asia whereas HbC, which has no obvious CC segregational load, occurs only in a small area of central West-Africa. To address this apparent paradox, we adopted two partially independent haplotypic approaches in the Mossi population of Burkina Faso where both the local S (S(Benin)) and the C alleles are common (0.05 and 0.13). Here we show that: both C and S(Benin) are monophyletic; C has accumulated a 4-fold higher recombinational and DNA slippage haplotypic variability than the S(Benin) allele (P = 0.003) implying higher antiquity; for a long initial lag period, the C alleles did apparently remain very few. These results, consistent with epidemiological evidences, imply that the C allele has been accumulated mainly through a recessive rather than a semidominant mechanism of selection. This evidence explains the apparent paradox of the uni-epicentric geographic distribution of HbC, representing a 'slow but gratis' genetic adaptation to malaria through a transient polymorphism, compared to the polycentric 'quick but costly' adaptation through balanced polymorphism of HbS.

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

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.

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.

Confirmation of the potential usefulness of two human beta globin pseudogene markers to estimate gene flows to and from sub-Saharan Africans.

Two polymorphic sites, -107 and -100 with respect to the "cap" site of the human beta globin pseudogene, recently discovered in our laboratory, turned out to have an ethnically complementary distribution. The first site is polymorphic in Europeans, North Africans, Indians (Hindu), and Oriental Asians, and monomorphic in sub-Saharan Africans. Conversely, the second site is polymorphic in sub-Saharan African populations and monomorphic in the aforementioned populations. Here we report the gene frequencies of these two polymorphic sites in nine additional populations (Egyptians, Spaniards, Japanese, Chinese, Filipinos, Vietnamese, Africans from Togo and from Benin, and Pygmies), confirming their ethnospecificity and, through the analysis of these two markers in Oromo and Amhara of Ethiopia (two mixed populations), their usefulness in genetic admixture studies. Moreover, we studied another marker polymorphic in sub-Saharan African populations only, a TaqI restriction fragment length polymorphism located in the same region as the present markers, demonstrating the absence of linkage disequilibrium between it and the -100 site, so that we can exclude that the information they provide is redundant.