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

Haemoglobin S (HbS; beta 6Glu -> Val) and HbC (beta 6Glu -> 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

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. Until now, however, investigations on their genetic structure have been scarce mainly identifying East Asian signatures. Results High-resolution analyses of mitochondrial-DNA (including 34 complete sequences) and Y-chromosome (67 SNPs and 12 STRs) variations carried out in 173 Tharus (two groups from Central and one from Eastern Terai), and 104 Indians (Hindus from Terai and New Delhi and tribals from Andhra Pradesh) allowed the identification of three principal components: East Asian, West Eurasian and Indian, the last including both local and inter-regional sub-components, at least for the Y chromosome. Conclusion Although remarkable quantitative and qualitative differences appear among the various population groups and also between sexes within the same group, many mitochondrial-DNA and Y-chromosome lineages are shared or derived from ancient Indian haplogroups, thus revealing a deep shared ancestry between Tharus and Indians. Interestingly, the local Y-chromosome Indian component observed in the Andhra-Pradesh tribals is present in all Tharu groups, whereas the inter-regional component strongly prevails in the two Hindu samples and other Nepalese populations. The complete sequencing of mtDNAs from unresolved haplogroups also provided informative markers that greatly improved the mtDNA phylogeny and allowed the identification of ancient relationships between Tharus and Malaysia, the Andaman Islands and Japan as well as between India and North and East Africa. Overall, this study gives a paradigmatic example of the importance of genetic isolates in revealing variants not easily detectable in the general population

Two Ethnic-Specific Polymorphisms in the Human Beta Pseudogene of Hemoglobin

Two polymorphic sites, — 107 C -\u3e T and — 100 G -\u3e 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 -\u3e• T site turned out to be polymorphic in all five European populations and the Indian population (pooled q = 0.142 ± 0.018) and in the two Asian populations (pooled q = 0.073 ± 0.025), but it was monomorphic in the two sub-Saharan populations. On the contrary, the — 100 G -\u3e C site was polymorphic in the two sub-Saharan samples (q = 0.093 ± 0.024), but the variant allele was not found in any of the European, Indian, or Asian samples. Thus this only 8-bp-long stretch of DNA is informative for estimating the extent of genetic admixture in sub-Saharan Africans

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 = 0.142 +/- 0.018) and in the two Asian populations (pooled q = 0.073 +/- 0.025), but it was monomorphic in the two sub-Saharan populations. On the contrary, the -100 G --> C site was polymorphic in the two sub-Saharan samples (q = 0.093 +/- 0.024), but the variant allele was not found in any of the European, Indian, or Asian samples. Thus this only g-bp-long stretch of DNA is informative for estimating the extent of genetic admixture in sub-Saharan Africans

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. The original population lived at a latitude of 35 degrees N, where the Sephardis still live. The Ashkenazis, however, moved to a latitude of 50 degrees N, starting about 10 centuries ago. The present study examines 3 latitude-correlated polymorphisms: PGP, PGM1, and AHSG, We found that PGP*2 and AHSG*2 alleles most likely underwent selection-driven evolution, but that PGM1*ts allele was not similarly affected, Since temperature might have been considered a reasonable selective factor, we also studied a population living at >800 m above sea level from Aosta Valley (Italy)