Bianca Maria Ciminelli

The lower susceptibility to Plasmodium falciparum malaria of Fulani of Burkina Faso (west Africa) is associated with low frequencies of classic malaria-resistance genes.

The gene frequencies in 1993-94 for haemoglobin S, haemoglobin C, alpha-3.7 deletional thalassaemia, G6PDA-, HLAB*5301 were estimated in Fulani, Mossi and Rimaibé ethnic groups of Burkina Faso, West Africa. The aim of the study was to verify whether the previously reported Fulani lower susceptibility to Plasmodium falciparum malaria was associated with any of these malaria-resistance genes. Similar frequencies for haemoglobin S were recorded in the 3 ethnic groups (0.024 +/- 0.008, 0.030 +/- 0.011, 0.022 +/- 0.013; in Mossi, Rimaibé and Fulani, respectively). The Mossi and Rimaibé showed higher frequencies when compared to Fulani for haemoglobin C (0.117 +/- 0.018, 0.127 +/- 0.020, 0.059 +/- 0.020), alpha-3.7 deletional thalassaemia (0.227 +/- 0.040, 0.134 +/- 0.032, 0.103 +/- 0.028), G6PDA- (0.196 +/- 0.025, 0.187 +/- 0.044, 0.069 +/- 0.025) and HLA B*5301 (0.189 +/- 0.038, 0.202 +/- 0.041, 0.061 +/- 0.024). Among Fulani the proportion of individuals not having any of these protective alleles was more than 3-fold greater than in the Mossi-Rimaibé group (56.8% vs 16.7%; P < 0.001). These findings exclude the involvement of these genetic factors of resistance to P. falciparum in the lower susceptibility to malaria of Fulani. This evidence, in association with the previously reported higher immune reactivity to malaria of Fulani, further supports the existence in this ethnic group of unknown genetic factor(s) of resistance to malaria probably involved in the regulation of humoral immune responses.

Differential structuring of human populations for homologous X and Y microsatellite loci.

The global pattern of variation at the homologous microsatellite loci DYS413 (Yq11) and DXS8174 and DXS8175 (Xp22) was analyzed by examination of 30 world populations from four continents, accounting for more than 1,100 chromosomes per locus. The data showed discordant patterns of among- and within-population gene diversity for the Y-linked and the X-linked microsatellites. For the Y-linked polymorphism, all groups of populations displayed high FST values (the correlation between random haplotypes within subpopulations, relative to haplotypes of the total population) and showed a general trend for the haplotypes to cluster in a population-specific way. This was especially true for sub-Saharan African populations. The data also indicated that a large fraction of the variation among populations was due to the accumulation of new variants associated with the radiation process. Europeans exhibited the highest level of within-population haplotype diversity, whereas sub-Saharan Africans showed the lowest. In contrast, data for the two X-linked polymorphisms were concordant in showing lower FST values, as compared with those for DYS413, but higher within-population variances, for African versus non-African populations. Whereas the results for the X-linked loci agreed with a model of greater antiquity for the African populations, those for DYS413 showed a confounding pattern that is apparently at odds with such a model. Possible factors involved in this differential structuring for homologous X and Y microsatellite polymorphisms are discussed.

Recurrent simple tandem repeat mutations during human Y-chromosome radiation in Caucasian subpopulations.

The haplotypes at four polymorphic loci of theY chromosome were determined in 245 Caucasian males from 12 subpopulations. The data show that haplotype radiation occurred among Caucasians. Haplotype radiation was accompanied by recurrent mutations at STR loci that caused partial randomization of haplotype structure. The present distribution of alleles at short tandem repeats (STRs) can be explained by a mutation pattern similar to those described for autosomal STRs. The degree of variation among groups of subpopulations was assayed by using the Analysis of Molecular Variance. The results confirm a faster divergence of the Y chromosome as compared to the rest of the genome.

Characterization of a Small Family (CAIII) of Microsatellite-Containing Sequences with X-Y Homology

Abstract. Four X-linked loci showing homology with a previously described Y-linked polymorphic locus (DYS413) were identified and characterized. By fluorescent in situ hybridization (FISH), somatic cell hybrids, and YAC screening, the X-linked members of this small family of sequences (CAIII) all map in Xp22, while the Y members map in Yq11. These loci contribute to the overall similarity of the two genomic regions. All of the CAIII loci contain an internal microsatellite of the (CA)n type. The microsatellites display extensive length polymorphism in two of the X-linked members as well as in the Y members. In addition, common sequence variants are found in the portions flanking the microsatellites in two of the X-linked members. Our results indicate that, during the evolution of this family, length variation on the Y chromosome was accumulated at a rate not slower than that on the X chromosome. Finally, these sequences represent a model system with which to analyze human populations for similar X- and Y-linked polymorphisms.

Cystic fibrosis and lactase persistence: a possible correlation.

C ystic fibrosis (CF) is the most common lethal genetic disease in Europeans and is transmitted as an autosomal recessive disorder caused by loss of function of the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene. Since long it has been supposed that its quite high frequency (1/ 2500 implying an allele frequency equal to 0.02) is due to a Europe-restricted selective advantage of the heterozygous CF/þ individuals. Nevertheless, this hypothesis has never been directly demonstrated nor the hypothetical selective factor identified. Here, we provide compelling evidence that the CF/þ advantage hypothesis is right. As to the identification of the selective factor, as the CFTR protein is a Cl channel (and hence involved in water excretion), diarrhea appears a reasonable candidate for such a role. Cholera has, in fact, been suggested, but its area of diffusion had not been limited to Europe. Considering that initially all humans were lactose intolerant in the post-weaning life and Europeans became cattle breeders and adopted a dairy-milk diet, we propose that the hypothetical Europe-restricted CF/þ advantage consisted of a resistance to lactose-caused diarrhea in populations that adopted such a habit while they were still lactose intolerant. This initial emergency segregational load adaptation would have been followed by a not costly one consisting of the present European quasi-fixed post-weaning lactase persistence (due to the dominant P allele of the lactase, LCT, gene), resulting in lactose tolerance. This hypothesis is supported by the positive correlation between the proportion, among the CF alleles, of the F508del allele and the P allele – recently identified with the T allele 14 Kb upstream to the LCT gene – frequency and provides a possible explanation for the well-known north–south cline of the F508del allele frequency. Both adaptations would be examples of genetic responses to a culture-rooted adverse factor. CF is the most common (1/2500 newborns) severe autosomal recessive disease in Europe. The global frequency of the CFcausing alleles of the CFTR gene, estimated as the square root of the prevalence of the disease, turned out to be about 0.02 in Europe, 0.01 in Africa and 0.002 in FarEastern Asia. The high CF allele frequency in Europe could only be accounted for by a ‘Europerestricted’ high mutation rate or by a ‘Europe-restricted’ heterozygous CF/þ advantage. The most plausible explanation seems to be the latter, mainly because a ‘Europe-restricted’ high mutation rate was judged extremely unlikely, although it was never directly disproved. In addition, the biological basis of the hypothetical ‘Europe-restricted’ CF/þ heterozygous advantage is far from being identified because of the lack of a convincing candidate adverse factor: bacteria-driven diarrheas – proposed on the basis of the functional properties of the CFTR protein – do not seem to have had ‘Europe-restricted’ histories, a fundamental prerequisite for a good candidate. In this paper, first we definitively reject the ‘Europe-restricted’ high mutation rate (mþ-CF) hypothesis; then we propose a ‘Europe-restricted’ biological factor that could account for the CF/þ heterozygous advantage.

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 (ng≈100–150 genes). In the present investigation, a large random European population sample (average ng≈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.

Biodemoraphy and genetics of the Berba of Benin

Genetic structure of the Berba of Benin was studied on the basis of biodemographic data and ABO, RH, MNS, KEL, JK, FY, ACP1, ADA, AK1, CA2, ESD, GLO1, G6PD, PGD, PGM1 (subtypes and thermostability), PGM2, PGP, SODA, HB alpha, HB beta, HB delta, BF, C3, and HP gene frequencies. Comparisons were carried out with other populations of Benin and of sub-Saharan Africa. Correspondence analysis revealed genetic differentiation among the three main groups of populations who inhabit sub-Saharan Africa: Bushmen-Hottentots, Pygmies, and Negroes. The genetic differentiation of the Negroes in relation to their linguistic affiliation and geographic localization was evident. The first group included the populations belonging to the Bantoid subfamily of the Nigritic linguistic stock living in southern Africa; in the second subcluster the populations of central-eastern Africa were localized, and the third subcluster included the populations living in the West.

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 (Tn 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.

Alcohol use disorder and GABAB receptor gene polymorphisms in an Italian sample: haplotype frequencies, linkage disequilibrium and association studies

Abstract Background: Alcohol use disorder (AUD) is a complex trait with genetic and environmental influences. Several gene variants have been associated with the risk for AUD, including genes encoding the sub-units of the γ-aminobutyric acid (GABA) receptors. Aim: This study evaluated whether specific single nucleotide polymorphisms (SNPs) in genes encoding GABAB receptor sub-units can be considered as candidates for the risk of AUD. Subjects and methods: Seventy-four AUD subjects and 128 Italian controls were genotyped for 10 SNPs in genes encoding GABA-B1 and GABA-B2 sub-units (GABBR1 and GABBR2). Allele, genotype, and haplotype frequencies were tested for the association with the AUD trait. Results: A significant difference between AUD individuals and controls was observed at genotype level for rs2900512 of GABBR2 gene. The homozygous T/T genotype was not found in the controls, whereas it was over-represented in the AUD individuals. Under the recessive model (T/T vs C/T + C/C) this result was statistically significant, as well as the Odds Ratio for the association with the AUD trait. Conclusions: The results provide preliminary data on the association between GABAB receptor gene variation and risk of AUD. To confirm this finding, studies with larger samples and additional characterisation of the phenotypic AUD trait are required.