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The 17q21.31 inversion polymorphism exists either as direct (H1) or inverted (H2) haplotypes with differential predispositions to disease and selection. We investigated its genetic diversity in 2,700 individuals, with an emphasis on African populations. We characterize eight structural haplotypes due to complex rearrangements that vary in size from 1.08-1.49 Mb and provide evidence for a 30-kb H1-H2 double recombination event. We show that recurrent partial duplications of the KANSL1 gene have occurred on both the H1 and H2 haplotypes and have risen to high frequency in European populations. We identify a likely ancestral H2 haplotype (H2?) lacking these duplications that is enriched among African hunter-gatherer groups yet essentially absent from West African populations. Whereas H1 and H2 segmental duplications arose independently and before human migration out of Africa, they have reached high frequencies recently among Europeans, either because of extraordinary genetic drift or selective sweeps. [ABSTRACT FROM AUTHOR]

Little is known about the history of click-speaking populations in Africa. Prior genetic studies revealed that the click-speaking Hadza of eastern Africa are as distantly related to click speakers of southern Africa as are most other African populations. The Sandawe, who currently live within 150 km of the Hadza, are the only other population in eastern Africa whose language has been classified as part of the Khoisan language family. Linguists disagree on whether there is any detectable relationship between the Hadza and Sandawe click languages. We characterized both mtDNA and Y chromosome variation of the Sandawe, Hadza, and neighboring Tanzanian populations. New genetic data show that the Sandawe and southern African click speakers share rare mtDNA and Y chromosome haplogroups; however, common ancestry of the 2 populations dates back >35,000 years. These data also indicate that common ancestry of the Hadza and Sandawe populations dates back >15,000 years. These findings suggest that at the time of the spread of agriculture and pastoralism, the click-speaking populations were already isolated from one another and are consistent with relatively deep linguistic divergence among the respective click languages. [ABSTRACT FROM PUBLISHER]

A SNP in the gene encoding lactase (LCT) (C/T-13910) is associated with the ability to digest milk as adults (lactase persistence) in Europeans, but the genetic basis of lactase persistence in Africans was previously unknown. We conducted a genotype-phenotype association study in 470 Tanzanians, Kenyans and Sudanese and identified three SNPs (G/C-14010, T/G-13915 and C/G-13907) that are associated with lactase persistence and that have derived alleles that significantly enhance transcription from the LCT promoter in vitro. These SNPs originated on different haplotype backgrounds from the European C/T-13910 SNP and from each other. Genotyping across a 3-Mb region demonstrated haplotype homozygosity extending >2.0 Mb on chromosomes carrying C-14010, consistent with a selective sweep over the past ∼7,000 years. These data provide a marked example of convergent evolution due to strong selective pressure resulting from shared cultural traits—animal domestication and adult milk consumption. [ABSTRACT FROM AUTHOR]

Background: Sulphadoxine-pyrimethamine (SP) has been and is currently used for treatment of uncomplicated Plasmodium falciparum malaria in many African countries. Nevertheless, the response of parasites to SP treatment has shown significant variation between individuals. Methods: The genes for dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) were used as markers, to investigate parasite resistance to SP in 141 children aged less than 5 years. Parasite DNA was extracted by Chelex method from blood samples collected and preserved on filter papers. Subsequently, polymerase chain reaction (PCR) and restriction fragment length polymorphism (PCR-RFLP) were applied to detect the SP resistance-associated point mutations on dhfr and dhps. Commonly reported point mutations at codons 51, 59, 108 and 164 in the dhfr and codons 437, 540 and 581 in the dhps domains were examined. Results: Children infected with parasites harbouring a range of single to quintuple dhfr/dhps mutations were erratically cured with SP. However, the quintuple dhfr/dhps mutant genotypes were mostly associated with treatment failures. High proportion of SP resistance-associated point mutations was detected in this study but the adequate clinical response (89.4%) observed clinically at day 14 of follow up reflects the role of semi-immunity protection and parasite clearance in the population. Conclusion: In monitoring drug resistance to SP, concurrent studies on possible confounding factors pertaining to development of resistance in falciparum malaria should be considered. The SP resistance potential detected in this study, cautions on its useful therapeutic life as an interim firstline drug against malaria in Tanzania and other malaria-endemic countries. [ABSTRACT FROM AUTHOR]

African Americans are at higher risk for cardiometabolic disease relative to individuals with European ancestry. Yet, populations with African ancestry are greatly under-represented in human genomics studies. To alleviate this bias and better distinguish the roles of genetics and environment on cardiometabolic traits, we conducted targeted metabolomics to measure levels of >700 lipids in 718 Africans and integrated with genomic data from >7M single nucleotide polymorphisms genotyped in the same individuals. These individuals are from 14 ethnic groups from diverse regions of Africa (Botswana, Cameroon, Ethiopia, Tanzania) and with diverse subsistence patterns (agriculturalists, pastoralists, hunter-gatherers). In contrast to US populations, most individuals were sampled from rural areas with relatively homogenous diets and, thus, we could better quantify lipids typically found at low levels in US individuals. Furthermore, several groups have similar genetic ancestry but distinct diets, and vice versa, enabling us to distinguish the role of genetic ancestry and environment on lipid variation. We identified 305 independent genetic variants associated with 103 lipid species, >50 of which have not previously been reported in similar studies of European/US populations (e.g. at ROCK2, ARHGEF28, DHODH, ALDH1A2). We observe correlations between subsistence and lipid profiles but show that genetic ancestry also plays an important role in variation within and between populations. For example, Eastern African pastoralists with a diet rich in milk and blood have relatively high levels of di-and tri-glycerides, but within each lipid class, levels are influenced by genotype. The Fulani pastoralists from Cameroon, with a high incidence of hypertension and diabetes but low BMI, also have relatively high levels of triglycerides, suggesting diet is predominantly influencing lipid levels and that genetic factors unrelated to lipid metabolism are influencing risk for disease in that population. Disclosure: R. Ma: None. H. Li: Consultant; Self; Eli Lilly and Company. C. Burant: None. S. A. Tishkoff: None. M. Hansen: None. A. Ranciaro: None. S. R. Thompson: None. W. Beggs: None. S. W. Mpoloka: None. G. G. Mokone: None. T. B. Nyambo: None. G. Michailidis: None. Funding: American Diabetes Association (1-19-VSN-02 to S.A.T.); National Institutes of Health (GM134957-01) [ABSTRACT FROM AUTHOR]

POPULATION: Identifiler—Employees and students of Muhimibili University College of Health Sciences in Dar es Salaam representing 19 widely distributed administrative districts and 42 tribes within the country. [ABSTRACT FROM AUTHOR]