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.

Mitochondrial and Y-chromosome diversity of the Tharus (Nepal): a reservoir of genetic variation.

Background: Central Asia and the Indian subcontinent represent an area considered as a source and a reservoir for human genetic diversity, with many markers taking root here, most of which are the ancestral state of eastern and western haplogroups, while others are local. Between these two regions, Terai (Nepal) is a pivotal passageway allowing, in different times, multiple population interactions, although because of its highly malarial environment, it was scarcely inhabited until a few decades ago, when malaria was eradicated. One of the oldest and the largest indigenous people of Terai is represented by the malaria resistant Tharus, whose gene pool could still retain traces of ancient complex interactions.

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.

Highly preferential association of NonF508del CF mutations with the M470 allele.

Background: On the basis of previous findings on random individuals, we hypothesized a preferential association of CF causing mutations with the M allele of the M470V polymorphic site of the CFTR gene.

Methods: We have determined the M/V-CF mutation haplotype in a series of 201 North East Italian and 73 Czech CF patients who were not F508del homozygotes, as F508del was already known to be fully associated with the M allele.

Results: Out of 358 not F508del CF genes, 84 carried the V allele and 274 the less common M allele.

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.

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.

Factors regulating Hb F synthesis in thalassemic diseases.

BACKGROUND: The thalassemic syndromes originate from mutations of the globin genes that cause, besides the characteristic clinical picture, also an increased Hb F amount. It is not yet clear if there are more factors, besides the beta globin genotype, determining the Hb F production. We have tried to find out if there are relations between total Hb and Hb F, between erythropoietin (Epo) and Hb F, between Hb F and point mutations of the gamma gene promoters.

Haemoglobin C protects against clinical Plasmodium falciparum malaria.

Haemoglobin C (HbC; beta6Glu --> Lys) is common in malarious areas of West Africa, especially in Burkina Faso. Conclusive evidence exists on the protective role against severe malaria of haemoglobin S (HbS; beta6Glu --> Val) heterozygosity, whereas conflicting results for the HbC trait have been reported and no epidemiological data exist on the possible role of the HbCC genotype. In vitro studies suggested that HbCC erythrocytes fail to support the growth of P.

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.

HLA class I in three West African ethnic groups: genetic distances from sub-Saharan and Caucasoid populations.

Fulani of Burkina Faso (West Africa) are a particularly interesting ethnic group because of their lower susceptibility to Plasmodium falciparum malaria as compared to sympatric populations, Mossi and Rimaibé. Moreover, the occurrence of a Caucasoid component in their genetic make-up has been suggested on the basis of their physical traits and cultural traditions even though this view was not supported by genetic studies. A total of 149 unrelated subjects (53 Mossi, 47 Rimaibé and 49 Fulani) have been typed for 97 HLA class I alleles with the amplification refractory mutation system/polymerase chain reaction (ARMS/PCR) technique.

Latitude-correlated genetic polymorphisms: selection or gene flow?

Latitude-correlated polymorphisms can be due to either selection-driven evolution or gene flow. To discriminate between them, we propose an approach that studies subpopulations springing from a single population that have lived for generations at different latitudes and have had a low genetic admixture. These requirements are fulfilled to a large extent by Ashkenazi and Sephardi Jews.

Serum levels of erythropoietin and soluble transferrin receptor in the course of pregnancy in non beta thalassemic and beta thalassemic women.

Background And Objectives: In non-thalassaemic women serum erythropoietin (Epo) level increases during pregnancy, whereas that of soluble transferrin receptor (STFR) drops slightly in the first two trimesters to attain the original values in the third trimester. In this study the time-course of these two parameters was explored in b-thalassemic and non-b-thalassemic women, both pregnant and not.

Design And Methods: Two hundred and fifty-seven women were studied: 64 non-b-thalassemic, non-pregnant women made up the reference group, 89 were non-b-thalassemic pregnant women, and 104 were b-thalassemic pregnant or non-pregnant women.

A new approach for identifying non-pathogenic mutations. An analysis of the cystic fibrosis transmembrane regulator gene in normal individuals.

Given q as the global frequency of the alleles causing a disease, any allele with a frequency higher than q minus the cumulative frequency of the previously known disease-causing mutations (threshold) cannot be the cause of that disease. This principle was applied to the analysis of cystic fibrosis transmembrane conductance regulator (CFTR) mutations in order to decide whether they are the cause of cystic fibrosis. A total of 191 DNA samples from random individuals from Italy, France, and Spain were investigated by DGGE (denaturing gradient gel electrophoresis) analysis of all the coding and proximal non-coding regions of the gene.

Two ethnic-specific polymorphisms in the human beta pseudogene of hemoglobin.

Two polymorphic sites, -107 C-->T and -100 G-->C with respect to the cap site of the human beta pseudogene of the hemoglobin gene, are described. They have been studied in five European, one Indian, two Asian, and two sub-Saharan African populations. The -107 C-->T site turned out to be polymorphic in all five European populations and the Indian population (pooled q = 0.

Detection of alpha-globin gene disorders by a simple PCR methodology.

Background: alpha thalassemias are very common in all thalassemic areas; however, complete knowledge of the phenotypic, genotypic and epidemiological features of these thalassemias has not yet been achieved for a number of reasons: the frequent absence of a thalassemic hematologic picture, the lack of a specific characteristic comparable to the Hb A2 increase for beta thalassemias, and the almost complete homology between the two alpha genes.

Methods And Results: A new set of PCR techniques, each based on primer(s) specific for a particular type of alpha globin gene disorder, has been devised in our laboratory. The procedures are simple, and non-radioactive.

mtDNA provides the first known marker distinguishing proto-Indians from the other Caucasoids; it probably predates the diversification between Indians and Orientals.

The concomitant presence of the two sites Ddel at 10,394 and Alul at 10,397 has been considered an East-Asian marker of ancient origin (it was also observed in Australians, Melanesians and Native Americans). Unexpectedly, it was found in more than 50% of Indians (133 Hindus and 30 Tribals) who had shown Caucasoid characteristics not only at nuclear DNA but also at mtDNA level. It can therefore no longer be considered an exclusively East-Asian mtDNA feature.

Allele and haplotype frequency distribution of the EcoRI, RsaI, and MspI COL1A2 RFLPs among various human populations.

The EcoRI, RsaI, and MspI RFLPs (restriction fragment length polymorphisms) of the COL1A2 gene, one of the two genes that encode for the polypeptides of type I collagen, have been studied in four West African and two Asian populations to evaluate their potential effectiveness as anthropological markers. All three RFLPs were in Hardy-Weinberg equilibrium. The comparisons between present data on two of the major human groups and those on Europeans and Amerindians show a considerable heterogeneity for each of the three RFLPs under study.

Genetic heterogeneity among the Hindus and their relationships with the other "Caucasoid" populations: new data on Punjab-Haryana and Rajasthan Indian states.

The genetic structure of Rajasthan Hindus and Punjab-Haryana Hindus and Sikhs has been studied for ABO, RH, APOC2, C6, C7, F13A, F13B, HP, ORM1, ACP1, ADA, AK1, ESD, GLO1, PGD, PGM1 subtyping, and PGP. This is the first genetic survey on Hindus of Rajasthan. Furthermore, many of these markers have never been studied on Hindus before (APOC2, C6, C7, F13A, F13B, ORM1, PGP).

Are the SSTR alleles stable enough to be considered monophyletic and hence reliable anthropogenetic markers? Linkage disequilibrium study on the (ACT)n COL1A2 SSTR.

An extremely low production rate of a polymorphic allele (formally called the mutation rate)--a prerequisite for using the allele as a marker (particularly for anthropogenetic purposes where the alleles must be assumed to be monophyletic)--cannot be taken for granted for alleles of highly polymorphic VNTRs, but a low production rate can be used to identify alleles produced by a single nucleotide substitution. This property was indirectly tested for the (ACT)n COL1A2 (of type I collagen) microsatellite SSTR (degree of heterozygosity H = 0.72) by searching for linkage disequilibria between the SSTR's four common alleles (n = 6, 8, 9, or 10) and three RFLPs of the same gene.

COL1A2 gene (alpha 2 gene of type I collagen) at the haplotype level as a new valuable anthropogenetic marker: a study on Sardinians.

Sardinians, a population with many distinct anthropogenetic features, has been studied for the COLIA1 and COLIA2 genes at the DNA level for two purposes: to look for new RFLPs (restriction fragment length polymorphisms) and to study the distribution of three known COLIA2 RFLPs (EcoRI, RsaI, MspI) at both the allele and the haplotype levels. None of the eleven enzyme-probe systems examined led to the discovery of a new polymorphism. The following frequency q was found for the less common allele of the three RFLPs: EcoRI, q(+) = 0.

COII/tRNA(Lys) intergenic 9-bp deletion and other mtDNA markers clearly reveal that the Tharus (southern Nepal) have Oriental affinities.

We searched for the East Asian mtDNA 9-bp deletion in the intergenic COII/tRNA(Lys) region in a sample of 107 Tharus (50 from central Terai and 57 from eastern Terai), a population whose anthropological origin has yet to be completely clarified. The deletion, detected by electrophoresis of the PCR-amplified nt 7392-8628 mtDNA fragment after digestion with HaeIII, was found in about 8% of both Tharu groups but was found in none of the 76 Hindus who were examined as a non-Oriental neighboring control population. A complete triplication of the 9-bp unit, the second case so far reported, was also observed in one eastern Tharu.