Biochemistry and Molecular Biology

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1284-P: Genetic and Lifestyle Associations with Cardiometabolic Traits and Diabetes Risk Factors in Ethnically Diverse Africans
(Diabetes, 2022-06-01) Nyambo, Thomas B.
African ancestry populations are underrepresented in human genetic studies, which leaves a knowledge gap about genetic and environmental risk factors for metabolic disease which can bias healthcare treatment. To alleviate these shortcomings, we conducted a series of genome-wide association studies of cardiometabolic traits in a diverse sampling of ∼2,500 (max sample size) ethnically and geographically diverse Africans from populations practicing agriculturalist, hunter-gatherer, and pastoralist subsistence strategies. This study includes the Fulani pastoralists who have a relatively high incidence of adult-onset diabetes, despite having a low average body mass index (BMI) . All individuals in the present study are sampled from rural populations that have relatively homogeneous lifestyles and diet within a community. This unique aspect to the study cohort allows for within- and between- group comparisons to identify trait variation attributable to genetics vs. lifestyle variation. Subjects were genotyped on a new African-focused SNP array from the Human Heredity and Health in Africa (H3 Africa) consortium. Genome-wide data was imputed based on a panel of African whole-genome sequences and data from the 1000 genomes project, resulting in a total of million variants for trait association analysis. Genetic associations were tested for BMI, blood pressure, and blood biomarkers of cardiometabolic health. We checked for replication of genotype/phenotype associations by comparison to large non-African cohorts studied for the same traits. We find that most associations identified in non-African populations do not replicate in the Africans. However, we identified a number of novel loci associated with cardiometabolic traits in the African populations. This study has important implications for identifying genetic risk factors that may play a role in metabolic disease in individuals of African ancestry.
1470-P: Novel Associations of Glycometabolic Traits in Ethnically Diverse Africans
(Diabetes Journal, 2023-06-20) Nyambo, Thomas B.
Prior studies have identified genetic factors that impact an individual’s risk of developing type 2 diabetes (T2D). However, African ancestry is underrepresented in genetic studies despite the higher prevalence of T2D in African Americans compared to European or Asian Americans. To better understand risk factors for this health disparity, we used a unique dataset of T2D biomarkers (C-peptide and standing glucose) and ~5 million single nucleotide polymorphism genotypes from an ethnically diverse sampling of sub-Saharan Africans (N~1,250) to identify genetic variants associated with these traits. Because the individuals in our dataset practice traditional subsistence patterns and live in rural settings, there is less environmental heterogeneity than observed in urban settings. Between both traits, we uncovered hundreds of novel marginal associations (p<10−5) and three genome-wide significant associations (p<5×10−8), one with C-peptide (rs147703855, in DAAM1) and two with glucose (rs74085215, near KLC1; rs951516, intergenic). The minor alleles for these three associations are rare outside of Africa (<0.1%) but attain frequencies ~5-10% in at least one African ancestry group. Although none of these associations have been previously reported, the genes near the marginal C-peptide associations (<200kbp) are enriched for variants with previously reported T2D associations (GWAS catalogue), as well as chylomicron, VLDL, and triglyceride associations. The genes near our marginal glucose associations were not found to be enriched for previously reported T2D associations (p>0.05), though they were significantly enriched for body size, chylomicron, and triglyceride associations (p<0.006). We are following up this preliminary study with an expanded GWAS using a new proteomics dataset in ~500 subjects, and a metabolomics dataset in ~700 subjects. These data will be used to construct polygenic risk scores for biomarkers of T2D that are more effective in people of recent African descent.
191-LB: Impact of Subsistence and Genetics on Lipid Profiles in Ethnically Diverse Africans.
(Diabetes, 2021-06-01) Nyambo, Thomas B.
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.
African evolutionary history inferred from whole genome sequence data of 44 indigenous African populations.
(Genome Biology, 2019-04-26) Nyambo, Thomas B.
Background: Africa is the origin of modern humans within the past 300 thousand years. To infer the complex demographic history of African populations and adaptation to diverse environments, we sequenced the genomes of 92 individuals from 44 indigenous African populations. Results: Genetic structure analyses indicate that among Africans, genetic ancestry is largely partitioned by geography and language, though we observe mixed ancestry in many individuals, consistent with both short- and long-range migration events followed by admixture. Phylogenetic analysis indicates that the San genetic lineage is basal to all modern human lineages. The San and Niger-Congo, Afroasiatic, and Nilo-Saharan lineages were substantially diverged by 160 kya (thousand years ago). In contrast, the San and Central African rainforest hunter-gatherer (CRHG), Hadza hunter-gatherer, and Sandawe hunter-gatherer lineages were diverged by ~ 120–100 kya. Niger-Congo, Nilo-Saharan, and Afroasiatic lineages diverged more recently by ~ 54–16 kya. Eastern and western CRHG lineages diverged by ~ 50– 31 kya, and the western CRHG lineages diverged by ~ 18–12 kya. The San and CRHG populations maintained the largest effective population size compared to other populations prior to 60 kya. Further, we observed signatures of positive selection at genes involved in muscle development, bone synthesis, reproduction, immune function, energy metabolism, and cell signaling, which may contribute to local adaptation of African populations. Conclusions: We observe high levels of genomic variation between ethnically diverse Africans which is largely correlated with geography and language. Our study indicates ancient population substructure and local adaptation of Africans. Keywords: African populations, Genomic variation, Human evolution, Local adaptation, Demographic history, Effective population size, Whole genome sequencing
AmpFlSTR® IdentifilerTM STR allele frequencies in Tanzania, Africa.
(Journal of forensic sciences, 2008-01) Nyambo, Thomas B.
Allele frequencies of the fifteen AMPLFlSTRÒ IdentifilerTM STR loci were determined for the population of Tanzania, East Africa. Two hundred and seventy-two saliva samples were gath- ered from unrelated healthy student or employee volunteers at Muhimbili University College of Health Sciences in Dar es Sal- aam, Tanzania during the summer of 2003. The tribal affiliation of each donor was recorded to ensure that representative sam- pling was achieved, and a total of 19 widely distributed adminis- trative regions of the country and 42 tribes were represented in the final genotypic data. DNA was extracted using the QIAamp spin column protocol for saliva (Qiagen, Valencia, CA) and quantitated using the QuantiblotÒ colorimetric system (Applied Biosystems, Foster City, CA). Approximately 1 ng of DNA was amplified from each sample using the IdentifilerTM system (Applied Biosystems) and subjected to capillary electrophoresis on a 310 Genetic Analyzer (Applied Biosystems). Raw data was collected, sorted, and sized using ABI Gene CollectionÒ and GenescanÒ software (Applied Biosystems), and alleles were assigned using ABI GenotyperÒ software (Applied Biosystems). Allele frequencies were calculated using GENEPOPÓ online software, v. 3.4 (1). Table 1 lists the frequencies of the alleles at each locus, indicates the total number of samples used to generate the table, and provides the database validation statistics. A Fisher Exact Test was used to test adherence to Hardy Wein- berg Equilibrium (HWE) at all loci (2,000 shufflings, GENEPOPÓ online software, v 3.4). Twelve of the 15 loci yielded p-values of >0.05, and thus failed to reject the hypothesis that the population is in HWE at these loci. The remaining three loci, D8S1178, D3S1358, and D2S1338, yielded p-values <0.05; however, a trun- cated product test for adherence of all loci yielded a p-value of 0.0654, thus validating the database for general use (2).
Ancient human genomes suggest three ancestral populations for present-day Europeans.
(Nature, 2014-09-17) Nyambo, Thomas B.
We sequenced the genomes of a ∼7,000-year-old farmer from Germany and eight ∼8,000-year-old hunter-gatherers from Luxembourg and Sweden. We analysed these and other ancient genomes1,2,3,4 with 2,345 contemporary humans to show that most present-day Europeans derive from at least three highly differentiated populations: west European hunter-gatherers, who contributed ancestry to all Europeans but not to Near Easterners; ancient north Eurasians related to Upper Palaeolithic Siberians3, who contributed to both Europeans and Near Easterners; and early European farmers, who were mainly of Near Eastern origin but also harboured west European hunter-gatherer related ancestry. We model these populations’ deep relationships and show that early European farmers had ∼44% ancestry from a ‘basal Eurasian’ population that split before the diversification of other non-African lineages.
Association between telomere length and Plasmodium falciparum malaria endemicity in sub-Saharan Africans
(2024-05-03) Nyambo, Thomas B.
Leukocyte telomere length (LTL) varies significantly across human populations, with individuals of African ancestry having longer LTL than non-Africans. However, the genetic and environmental drivers of LTL variation in Africans remain largely unknown. We report here on the relationship between LTL, genetics, and a variety of environmental and climatic factors in ethnically diverse African adults (n = 1,818) originating from Botswana, Tanzania, Ethiopia, and Cameroon. We observe significant variation in LTL among populations, finding that the San hunter-gatherers from Botswana have the longest leukocyte telomeres and that the Fulani pastoralists from Cameroon have the shortest telomeres. Genetic factors explain ∼50% of LTL variation among individuals. Moreover, we observe a significant negative association between Plasmodium falciparum malaria endemicity and LTL while adjusting for age, sex, and genetics. Within Africa, adults from populations indigenous to areas with high malaria exposure have shorter LTL than those in populations indigenous to areas with low malaria exposure. Finally, we explore to what degree the genetic architecture underlying LTL in Africa covaries with malaria exposure.
Characterization of genetic variation and natural selection at the arylamine N-acetyltransferase genes in global human populations.
(Pharmacogenomics, 2011-11-01) Nyambo, Thomas B.
Functional variability at the arylamine N-acetyltransferase genes is associated with drug response in humans and may have been adaptive in the past owing to selection pressure from diet and exposure to toxins during human evolution. Aims: We have characterized nucleotide variation at the NAT1 and NAT2 genes, and at the NATP1 pseudogene in global human populations, including many previously under-represented African populations, in order to identify potential functional variants and to understand the role that natural selection has played in shaping variation at these loci in globally diverse populations. Materials & methods: We have resequenced approximately 2800 bp for each of the NAT1 and NAT2 gene regions, as well as the pseudogene NATP1, in 197 African and 132 nonAfrican individuals. Results & conclusion: We observe a signature of balancing selection maintaining variation in the 3’-UTR of NAT1, suggesting that these variants may play a functional role that is currently undefined. In addition, we observed high levels of nonsynonymous functional variation at the NAT2 locus that differs amongst ethnically diverse populations.
Community-based survey on helminth infections in Kwilu province, the Democratic Republic of the Congo, and implications for local control strategies.
(PLoS neglected tropical diseases, 2020) Nyandele, Janepaula.
To adequately plan mass drug administration campaigns, the Democratic Republic of the Congo (DRC) needs further support for the mapping and monitoring of schistosomiasis (SCH) and soil-transmitted helminths (STH). We conducted a community-based survey in the health districts of Mosango and Yasa Bonga of the Kwilu province, DRC. A stratified two-stage cluster random sampling method was used to include participants into three different strata: Preschool-aged children (PSAC), school-aged children (SAC), and adults who were further subdivided into women of reproductive age (WRA) and other adults. In total, surveyors visited 30 villages, and 1 206 individuals participated in the study. Stool samples were collected to perform duplicate Kato-Katz smears for the detection of SCH and STH infection. Hookworm was the most prevalent infection in both districts, 34.1% (95%CI: 32.0–38.4), followed by A. lumbricoides (2.7%; 95%CI: 1.3–2.9) and T. trichiura (1.9%; 95%CI: 1.1–2.7). We did not find any SCH infection. The prevalence of each STH infection was similar across all risk groups, and the majority of the infected individuals was carrying light intensity infection. Compared to SAC, other adults were equally infected with hookworm. The prevalence of STH infection in SAC guides the MDA implementation because schoolchildren are most at risk and easily accessible program targets if school attendance is high. The current treatment strategy targets PSAC, SAC and WRA. However, this study shows that adults in general could also benefit from deworming. Therefore, community-wide preventive chemotherapy would be the most appropriate choice to control the hookworm burden rapidly.
Comparison of prevalence of chronic atrophic gastritis in Japan, China, Tanzania, and the Dominican Republic.
(Annals of epidemiology, 2005-03-30) Nyambo, Thomas B.
Purpose: To compare the prevalence of chronic atrophic gastritis (CAG) in Japan, China, Tanzania, and the Dominican Republic and to assess the usefulness of Helicobacter pylori infection and serum gastrin level as markers of CAG. Methods: The subjects were volunteers from local communities in Japan (n = 859), China (n = 1741), Tanzania (n = 573), and the Dominican Republic (n = 1215). Each individual underwent a health checkup and blood sampling for measurement of serum pepsinogen I and II, pepsinogen I /II ratio, serum gastrin, and H. pylori antibodies, and responded to a questionnaire on upper digestive tract diseases. Results: The prevalences of H. pylori infection (23.5–96.1%), CAG (5.6–60.4%), and serum gastrin (62.0–136.5 pg/ml) varied by age, sex, and country. Serum gastrin level for men differed in each country according to age. In Tanzanian men, the median gastrin level (101.0 pg/ml) was the highest in the 40 to 49 years age group (p < 0.01) while there was no significant difference among different age groups in Tanzanian women. Serum gastrin level in subjects ≥ 70 years was higher than in other age groups in both sexes in the Dominican Republic (males, 92.5, females, 136.5 pg/ml). The prevalence of H. pylori infection increased (p < 0.01) with advancing age in Japan (only for women) and the Dominican Republic but was high in all age groups of both sexes in China and Tanzania. The prevalence of CAG increased (p < 0.01) with age in both sexes in Japan, China (women only), and the Dominican Republic, but not in Tanzania. The odds ratio of CAG in H. pylori infected subjects was 5.3 times that in H. pylori-negative subjects. The odds ratio of CAG increased by 0.6%/1 pg/ml increase in serum gastrin. Conclusions: Our results indicated that H. pylori infection, serum gastrin, and advancing age are good markers of CAG and that the prevalence of CAG is the highest in Japan.
Convergent adaptation of human lactase persistence in Africa and Europe.
(Nature genetics, 2007-12-10) Nyambo, Thomas B.
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.
Diverse African genomes reveal selection on ancient modern human introgressions in Neanderthals
(Current Biology, 2023-10-13) Nyambo, Thomas B.
Comparisons of Neanderthal genomes to anatomically modern human (AMH) genomes show a history of Neanderthal-to-AMH introgression stemming from interbreeding after the migration of AMHs from Af- rica to Eurasia. All non-sub-Saharan African AMHs have genomic regions genetically similar to Neander- thals that descend from this introgression. Regions of the genome with Neanderthal similarities have also been identified in sub-Saharan African populations, but their origins have been unclear. To better understand how these regions are distributed across sub-Saharan Africa, the source of their origin, and what their distribution within the genome tells us about early AMH and Neanderthal evolution, we analyzed a dataset of high-coverage, whole-genome sequences from 180 individuals from 12 diverse sub-Saharan African populations. In sub-Saharan African populations with non-sub-Saharan African ancestry, as much as 1% of their genomes can be attributed to Neanderthal sequence introduced by recent migration, and subsequent admixture, of AMH populations originating from the Levant and North Africa. However, most Neanderthal homologous regions in sub-Saharan African populations originate from migration of AMH populations from Africa to Eurasia 250 kya, and subsequent admixture with Neanderthals, resulting in 6% AMH ancestry in Neanderthals. These results indicate that there have been multiple migration events of AMHs out of Africa and that Neanderthal and AMH gene flow has been bi-directional. Observing that genomic regions where AMHs show a depletion of Neanderthal introgression are also regions where Neanderthal genomes show a depletion of AMH introgression points to deleterious interactions between introgressed variants and background genomes in both groups—a hallmark of incipient speciation.
Drug resistance to sulphadoxine-pyrimethamine (SP) in Plasmodium falciparum malaria in Mlimba, Tanzania [MIM-EM-543567]
(Elsevier Science bv., 2006-10-31) Nyambo, Thomas B.;
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 first-line drug against malaria in Tanzania and other malaria-endemic countries.
Effects of natural selection and gene conversion on the evolution of human glycophorins coding for MNS blood polymorphisms in malaria-endemic African populations.
(The American Journal of Human Genetics, 2011-06-10) Nyambo, Thomas B.
Malaria has been a very strong selection pressure in recent human evolution, particularly in Africa. Of the one million deaths per year due to malaria, more than 90% are in sub-Saharan Africa, a region with high levels of genetic variation and population substructure. However, there have been few studies of nucleotide variation at genetic loci that are relevant to malaria susceptibility across geograph- ically and genetically diverse ethnic groups in Africa. Invasion of erythrocytes by Plasmodium falciparum parasites is central to the pathology of malaria. Glycophorin A (GYPA) and B (GYPB), which determine MN and Ss blood types, are two major receptors that are expressed on erythrocyte surfaces and interact with parasite ligands. We analyzed nucleotide diversity of the glycophorin gene family in 15 African populations with different levels of malaria exposure. High levels of nucleotide diversity and gene conversion were found at these genes. We observed divergent patterns of genetic variation between these duplicated genes and between different extracellular domains of GYPA. Specifically, we identified fixed adaptive changes at exons 3–4 of GYPA. By contrast, we observed an allele frequency spectrum skewed toward a significant excess of intermediate-frequency alleles at GYPA exon 2 in many populations; the degree of spec- trum distortion is correlated with malaria exposure, possibly because of the joint effects of gene conversion and balancing selection. We also identified a haplotype causing three amino acid changes in the extracellular domain of glycophorin B. This haplotype might have evolved adaptively in five populations with high exposure to malaria.
Erratum for the Research Article: “Loci associated with skin pigmentation identified in African populations”
(Science, 2020-01-17) Nyambo, Thomas B.
In the Research Article “Loci associated with skin pigmentation identified in African populations,” the authors made the inaccurate conclusion that mfsd12a targeting in zebrafish disrupts xanthophore function. This happened because of a misinterpretation of experimental observations, not from errors in data collection or reporting. In the original experiments, a loss of normal methylene blue staining occurred in 100% of mfsd12a −/− embryos at 5 days postfertilization. These mfsd12a −/− embryos were derived from matings between mosaic F0 founder fish (mfsd12a targeted mosaic F0 x mfsd12a targeted mosaic F0). The single guide RNAs for mfsd12a were extremely efficient, and no wild-type F1 offspring were obtained from the F0 inbreeding. Therefore, the clutches of 100% mfsd12a −/− embryos were compared with embryos derived from matings of wild-type fish (mfsd12a +/+ x mfsd12a +/+ ) in which loss of methylene blue staining was not observed. In each case, multiple clutches were analyzed from independent matings. Additionally, the wild-type breeders originated from the same colony of TAB5 fish that were used to generate fertilized eggs for Cas9 injections to generate the mfsd12a F0 founders. These reproducible results led the authors to conclude that mfsd12a was required for normal methylene blue staining of xanthophores. However, in subsequent work, the authors have observed a lack of methylene blue staining in clutches originating from other matings within their facility. They have confirmed that this lack of methylene blue staining segregates with a population variant linked to chromosome 12 within their TAB5 colony. This variant was likely present at a high-enough frequency in their mfsd12a-targeted F0 founder fish to affect the outcome. These recent data thus do not support their previous conclusion that mfsd12a functions in zebrafish pigmentation (presented in Fig. 7, A and B, of the original manuscript). Importantly, however, it does not alter the main conclusions of the manuscript that MFSD12 is associated with mammalian pigment variation in both human and mouse. The sections of the results referring to the zebrafish knockout have been removed entirely, along with the accompanying figure and cited references. Both the HTML and PDF versions of the text have been corrected.
Evaluation of dot-blot and phage replication techniques for detection of drug-resistant Mycobacterium tuberculosis.
(Tanzanian Medical Journal, 2005-03) Nyambo, Thomas B.
We have assessed the utility of two new methods, dot-blot and bacteriophage replication techniques, for use in a routine diagnosis laboratory in poor resource settings in the screening of drug resistant Mycobacteria tuberculosis by comparing with the conventional proportion method. A total of 145 M. tuberculosis clinical isolates were tested for resistance to rifampicin, isoniazid, streptomycin and ethambutol. The dot blot had sensitivities of 91.7%, 100%, 93.5% and 85.7 and specificities of 99.2%, 99.2%, 99.1% and 99.2 for rifampicin, streptomycin, isoniazid and ethambutol, respectively. The phage technique had sensitivities of 92% and 84.6% and specificities of 99.2% and 99.2%for rifampicin and streptomycin, respectively. Both techniques yielded results within 48 hours of receipt of the culture on solid media. The high sensitivity and specificity coupled with rapidity of results indicate that these methods are potentially useful tools for screening resistance to anti-tuberculosis drugs in our setting. However, the phage replication technique, which is simpler and technically less demanding, seems the most suitable for routine screening of drug resistant mycobacteria in resource deprived countries such as Tanzania. We are recommending further field evaluation of the phage replication method so that it can complement, and possibly replace, the conventional proportion method in drug susceptibility testing.
Evolution of Functionally Diverse Alleles Associated with PTC Bitter Taste Sensitivity in Africa
(Molecular biology and evolution, 2011-11-29) Nyambo, Thomas B.
Although human bitter taste perception is hypothesized to be a dietary adaptation, little is known about genetic signatures of selection and patterns of bitter taste perception variability in ethnically diverse populations with different diets, particularly from Africa. To better understand the genetic basis and evolutionary history of bitter taste sensitivity, we sequenced a 2,975 bp region encompassing TAS2R38, a bitter taste receptor gene, in 611 Africans from 57 populations in West Central and East Africa with diverse subsistence patterns, as well as in a comparative sample of 132 non-Africans. We also examined the association between genetic variability at this locus and threshold levels of phenylthiocarbamide (PTC) bitterness in 463 Africans from the above populations to determine how variation influences bitter taste perception. Here, we report striking patterns of variation at TAS2R38, including a significant excess of novel rare nonsynonymous polymorphisms that recently arose only in Africa, high frequencies of haplotypes in Africa associated with intermediate bitter taste sensitivity, a remarkably similar frequency of common haplotypes across genetically and culturally distinct Africans, and an ancient coalescence time of common variation in global populations. Additionally, several of the rare nonsynonymous substitutions significantly modified levels of PTC bitter taste sensitivity in diverse Africans. While ancient balancing selection likely maintained common haplotype variation across global populations, we suggest that recent selection pressures may have also resulted in the unusually high level of rare nonsynonymous variants in Africa, implying a complex model of selection at the TAS2R38 locus in African populations. Furthermore, the distribution of common haplotypes in Africa is not correlated with diet, raising the possibility that common variation may be under selection due to their role in nondietary biological processes. In addition, our data indicate that novel rare mutations contribute to the phenotypic variance of PTC sensitivity, illustrating the influence of rare variation on a common trait, as well as the relatively recent evolution of functionally diverse alleles at this locus.
Evolutionary history and adaptation from high-coverage whole-genome sequences of diverse African hunter-gatherers.
(Cell, 2012-08-03) Nyambo, Thomas B.
To reconstruct modern human evolutionary history and identify loci that have shaped hunter-gatherer adaptation, we sequenced the whole genomes of five individuals in each of three different hunter-gatherer populations at >60× coverage: Pygmies from Cameroon and Khoesan-speaking Hadza and Sandawe from Tanzania. We identify 13.4 million variants, substantially increasing the set of known human variation. We found evidence of archaic introgression in all three populations, and the distribution of time to most recent common ancestors from these regions is similar to that observed for introgressed regions in Europeans. Additionally, we identify numerous loci that harbor signatures of local adaptation, including genes involved in immunity, metabolism, olfactory and taste perception, reproduction, and wound healing. Within the Pygmy population, we identify multiple highly differentiated loci that play a role in growth and anterior pituitary function and are associated with height.
Feasibility of bioethanol production from tubers of Dioscorea sansibarensis and Pyrenacantha kaurabassana
(Bioresource Technology, 2015) Nyandele, Janepaula.
Inedible tubers from Dioscorea sansibarensis (DS) and Pyrenacantha kaurabassana (PK) were found to be suitable feedstock for bioethanol production. Important composition parameters for bioethanol production for DS and PK are dry matter (% fresh tubers) ca. 20 and 6, total carbohydrates % dry weight base (db) ca. 68 and 47 and total protein (% db) ca. 16 and 10, respectively. DS and PK were found to contain inulin and galactomannan as principal polysaccharides (% of total carbohydrate) ca. 90 and 70, respectively. Diluted acid hydrolysis yielded ca. 100% of total reducing sugars. Ethanol yield ca. 56 and 35 g/L was obtained at high efficiency through batch fermentation of acid hydrolysate (25% w/v) of DS and PK, respectively. A simple technique of recording and monitoring ethanol through CO2 generated during fermentation correlated strongly with HPLC measurement R2 = 0.99. Thus, tubers from these plants are potential feedstocks for bioethanol production with no competing uses.
The genetic and evolutionary basis of gene expression variation in East Africans.
(Genome Biology, 2023-02-24) Nyambo, Thomas B.
Background: Mapping of quantitative trait loci (QTL) associated with molecular phe‑ notypes is a powerful approach for identifying the genes and molecular mechanisms underlying human traits and diseases, though most studies have focused on individu‑ als of European descent. While important progress has been made to study a greater diversity of human populations, many groups remain unstudied, particularly among indigenous populations within Africa. To better understand the genetics of gene regulation in East Africans, we perform expression and splicing QTL mapping in whole blood from a cohort of 162 diverse Africans from Ethiopia and Tanzania. We assess replication of these QTLs in cohorts of predominantly European ancestry and identify candidate genes under selection in human populations. Results: We find the gene regulatory architecture of African and non‑African popula‑ tions is broadly shared, though there is a considerable amount of variation at individual loci across populations. Comparing our analyses to an equivalently sized cohort of European Americans, we find that QTL mapping in Africans improves the detection of expression QTLs and fine‑mapping of causal variation. Integrating our QTL scans with signatures of natural selection, we find several genes related to immunity and metabo‑ lism that are highly differentiated between Africans and non‑Africans, as well as a gene associated with pigmentation. Conclusion: Extending QTL mapping studies beyond European ancestry, particularly to diverse indigenous populations, is vital for a complete understanding of the genetic architecture of human traits and can reveal novel functional variation underlying human traits and disease.

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