Thomas Nyambo | HUBERT KAIRUKI MEMORIAL UNIVERSITY (original) (raw)

Papers by Thomas Nyambo

AIJR Abstracts, Jul 24, 2021

Diabetes, Jun 1, 2022

African ancestry populations are underrepresented in human genetic studies, which leaves a knowle... more 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. Funded by ADA Pathway award 1-19-VSN-02. Disclosure D.Hui: None. T.B.Nyambo: None. S.Chanock: None. S.A.Tishkoff: None. D.Harris: None. M.Mcquillan: None. M.Hansen: None. A.Ranciaro: None. W.Beggs: None. S.W.Mpoloka: None. D.Woldemeskel: None. A.K.K.Njamnshi: None. Funding American Diabetes Association (1-19-VSN-02) ; National Institutes of Health (R35 GM134957-01, R01AR076241, 5T32DK007314-39, 1OT3HL142479-01, 1OT3HL142478-01, 1OT3HL142481-01, 1OT3HL142480-01, 1OT3HL147154-01)

This book contains the abstracts of the papers/posters presented at the Tanzania Health Summit 20... more This book contains the abstracts of the papers/posters presented at the Tanzania Health Summit 2020 (THS-2020) Organized by the Ministry of Health Community Development, Gender, Elderly and Children (MoHCDGEC); President Office Regional Administration and Local Government (PORALG); Ministry of Health, Social Welfare, Elderly, Gender, and Children Zanzibar; Association of Private Health Facilities in Tanzania (APHFTA); National Muslim Council of Tanzania (BAKWATA); Christian Social Services Commission (CSSC); & Tindwa Medical and Health Services (TMHS) held on 25–26 November 2020. The Tanzania Health Summit is the annual largest healthcare platform in Tanzania that attracts more than 1000 participants, national and international experts, from policymakers, health researchers, public health professionals, health insurers, medical doctors, nurses, pharmacists, private health investors, supply chain experts, and the civil society. During the three-day summit, stakeholders and decision-m...

Human Molecular Genetics, 2020

Leukocyte telomere length (LTL) might be causal in cardiovascular disease and major cancers. To e... more Leukocyte telomere length (LTL) might be causal in cardiovascular disease and major cancers. To elucidate the roles of genetics and geography in LTL variability across humans, we compared LTL measured in 1295 sub-Saharan Africans (SSAs) with 559 African–Americans (AAms) and 2464 European–Americans (EAms). LTL differed significantly across SSAs (P = 0.003), with the San from Botswana (with the oldest genomic ancestry) having the longest LTL and populations from Ethiopia having the shortest LTL. SSAs had significantly longer LTL than AAms [P = 6.5(e-16)] whose LTL was significantly longer than EAms [P = 2.5(e-7)]. Genetic variation in SSAs explained 52% of LTL variance versus 27% in AAms and 34% in EAms. Adjustment for genetic variation removed the LTL differences among SSAs. LTL genetic variation among SSAs, with the longest LTL in the San, supports the hypothesis that longer LTL was ancestral in humans. Identifying factors driving LTL variation in Africa may have important ramificat...

Proceedings of the National Academy of Sciences of the United States of America, Feb 19, 2019

Anatomically modern humans arose in Africa ∼300,000 years ago, but the demographic and adaptive h... more Anatomically modern humans arose in Africa ∼300,000 years ago, but the demographic and adaptive histories of African populations are not well-characterized. Here, we have generated a genomewide dataset from 840 Africans, residing in western, eastern, southern, and northern Africa, belonging to 50 ethnicities, and speaking languages belonging to four language families. In addition to agriculturalists and pastoralists, our study includes 16 populations that practice, or until recently have practiced, a huntinggathering (HG) lifestyle. We observe that genetic structure in Africa is broadly correlated not only with geography, but to a lesser extent, with linguistic affiliation and subsistence strategy. Four East African HG (EHG) populations that are geographically distant from each other show evidence of common ancestry: the Hadza and Sandawe in Tanzania, who speak languages with clicks classified as Khoisan; the Dahalo in Kenya, whose language has remnant clicks; and the Sabue in Ethiopia, who speak an unclassified language. Additionally, we observed common ancestry between central African rainforest HGs and southern African San, the latter of whom speak languages with clicks classified as Khoisan. With the exception of the EHG, central African rainforest HGs, and San, other HG groups in Africa appear genetically similar to neighboring agriculturalist or pastoralist populations. We additionally demonstrate that infectious disease, immune response, and diet have played important roles in the adaptive landscape of African history. However, while the broad biological processes involved in recent human adaptation in Africa are often consistent across populations, the specific loci affected by selective pressures more often vary across populations. African hunter-gatherers | African diversity | population genetics | natural selection | human evolution

Human Molecular Genetics, Mar 2, 2016

Leukocyte telomere length (LTL), which reflects telomere length in other somatic tissues, is a co... more Leukocyte telomere length (LTL), which reflects telomere length in other somatic tissues, is a complex genetic trait. Eleven SNPs have been shown in genome-wide association studies to be associated with LTL at a genome-wide level of significance within cohorts of European ancestry. It has been observed that LTL is longer in African Americans than in Europeans. The underlying reason for this difference is unknown. Here we show that LTL is significantly longer in sub-Saharan Africans than in both Europeans and African Americans. Based on the 11 LTL-associated alleles and genetic data in phase 3 of the 1000 Genomes Project, we show that the shifts in allele frequency within Europe and between Europe and Africa do not fit the pattern expected by neutral genetic drift. Our findings suggest that differences in LTL within Europeans and between Europeans and Africans is influenced by polygenic adaptation and that differences in LTL between Europeans and Africans might explain, in part, ethnic differences in risks for human diseases that have been linked to LTL.

Molecular Biology and Evolution, Jul 21, 2007

Little is known about the history of click-speaking populations in Africa. Prior genetic studies ... more Little is known about the history of click-speaking populations in Africa. Prior genetic studies revealed that the clickspeaking 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.

Environmental Health and Preventive Medicine, 2004

Objective: The aim of this survey was to compare the seroprevalences of Helicobacter Pylori (H. p... more Objective: The aim of this survey was to compare the seroprevalences of Helicobacter Pylori (H. pylori) and chronic atrophic gastritis (CAG) in Tanzania and the Dominican Republic, both of which are tropical countries, and thereafter compare the prevalences in Tanzania and the Dominican Republic with prevalences from our previous studies done in Japan (1991) and China (1996/97). Methods: Community-based study in which 573 inhabitants of Tanzania and 1,215 inhabitants of the Dominican Republic answered detailed questionnaires on upper digestive tract diseases, and then underwent screening for gastric cancer by serum pepsinogen and testing for antibody to H. pylori. Results: After adjusting to the 'Age-Standardized Rate' (ASR) using the world population in 1995, the seroprevalences of H. pylori infection in male and female subjects for Tanzania (m=85.3% & f=88.2%) were very high compared to those for the Dominican Republic (m=63.5% & f=62.4%) and Japan (m=62.0% & f=46.8%), and similar to those of China (m=78.0% & f=77.3%). Also, the agestandardized prevalences of CAG in males and females for Tanzania (m=0.237 & f=0.458) were higher than those of the Dominican Republic (m=0.168 & f=0.211) and China (m=0.111 & f=0.107) and compared well with those of Japan (m=0.266 & f=0.352). Conclusions: Although Tanzania and the Dominican Republic are both developing countries, Tanzania had a very high age-standardized prevalence of H. pylori and CAG compared to that of the Dominican Republic, which showed a trend similar to that of Japan.

Human Immunology, Sep 1, 2019

Aim: Nasopharyngeal carcinoma (NPC) has a distinct racial and geographic distribution caused by a... more Aim: Nasopharyngeal carcinoma (NPC) has a distinct racial and geographic distribution caused by a combination of Epstein-Barr virus (EBV) infection and environmental factors. It also had been shown a strong and consistent HLA associated. The HLA genes differ greatly among populations making it as a powerful tool for the study of population genetics and disease association. We have conducted a molecular HLA typing project to describe the HLA class I profiling in the high NPC incident aera of Southern China. The results also compared with reported data from Northern Chinese population previously. Methods: High resolution HLA typing was informative for 629 unrelated cancer free individuals. The difference between these subjects and the former reported northern Chinese population were characterized in frequencies and in the presence of alleles and haplotypes. Results: A number of 26, 52, and 21 alleles in HLA-A, B, and C loci were identified in these subjects. 21 alleles with significantly different distributions were observed in HLA-A, B, and C loci between these two groups. HLA-A*11:01 is the most common allele with extraordinary high frequencies which indicates nature selective forces may acted on the population of NPC high incident regions. Conclusions: Our study demonstrates a distinct HLA class I alleles distribution in high NPC incident region of southern Han Chinese compare with northern Han Chinese. Haplotype analyses have shown that a fewer predominant haplotype patterns in this population with higher population coverage illustrated the direction for deeply exploring by future studies. Disclosures: M.

Human Genetics, Apr 23, 2013

Malaria is one of the strongest selective pressures in recent human evolution. African population... more Malaria is one of the strongest selective pressures in recent human evolution. African populations have been and continue to be at risk for malarial infections. However, few studies have resequenced malaria susceptibility loci across geographically and genetically diverse groups in Africa. We examined nucleotide diversity at Intercellular adhesion molecule-1 (ICAM-1), a malaria susceptibility candidate locus, in a number of human populations with a specific focus on diverse African ethnic groups. We used tests of neutrality to assess whether natural selection has impacted this locus and tested whether SNP variation at ICAM-1 is correlated with malaria endemicity. We observe differing patterns of nucleotide and haplotype variation in global populations and higher levels of diversity in Africa. Although we do not observe a deviation from neutrality based on the allele frequency distribution, we do observe several alleles at ICAM-1, including the ICAM-1 Kilifi allele, that are correlated with malaria endemicity. We show that the ICAM-1 Kilifi allele, which is common in Africa and Asia, exists on distinct haplotype backgrounds and is likely to have arisen more recently in Asia. Our results suggest that correlation analyses of allele frequencies and malaria endemicity may be useful for identifying candidate functional variants that play a role in malaria resistance and susceptibility.

Pharmacogenomics Journal, Apr 16, 2013

There is established clinical evidence for differences in drug response, cure rates and survival ... more There is established clinical evidence for differences in drug response, cure rates and survival outcomes between different ethnic populations, but the causes are poorly understood. Differences in frequencies of functional genetic variants in key drug response and metabolism genes may significantly influence drug response differences in different populations. To assess this, we genotyped 1330 individuals of African (n = 372) and European (n = 958) descent for 4535 singlenucleotide polymorphisms in 350 key drug absorption, distribution, metabolism, elimination and toxicity genes. Important and remarkable differences in the distribution of genetic variants were

Pharmacogenomics, Nov 1, 2011

Functional variability at the arylamine N-acetyltransferase genes is associated with drug respons... more 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.

Genetic Epidemiology, Nov 28, 2011

Sub-Saharan Africa has been identified as the part of the world with the greatest human genetic d... more Sub-Saharan Africa has been identified as the part of the world with the greatest human genetic diversity. This high level of diversity causes difficulties for genome-wide association (GWA) studies in African populations-for example, by reducing the accuracy of genotype imputation in African populations compared to non-African populations. Here, we investigate haplotype variation and imputation in Africa, using 253 unrelated individuals from 15 Sub-Saharan African populations. We identify the populations that provide the greatest potential for serving as reference panels for imputing genotypes in the remaining groups. Considering reference panels comprising samples of recent African descent in Phase 3 of the HapMap Project, we identify mixtures of reference groups that produce the maximal imputation accuracy in each of the sampled populations. We find that optimal HapMap mixtures and maximal imputation accuracies identified in detailed tests of imputation procedures can instead be predicted by using simple summary statistics that measure relationships between the pattern of genetic variation in a target population and the patterns in potential reference panels. Our results provide an empirical basis for facilitating the selection of reference panels in GWA studies of diverse human populations, especially those of African ancestry.

Nature Genetics, Jul 1, 2012

Users may view, print, copy, download and text and data-mine the content in such documents, for t... more Users may view, print, copy, download and text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

Diabetes, Jun 20, 2023

Prior studies have identified genetic factors that impact an individual’s risk of developing type... more 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. Disclosure M.Hansen: None. D.Harris: None. A.M.Harris: None. T.B.Nyambo: None. G.Belay: None. S.Mpoloka: None. C.Burant: Research Support; Rhythm Pharmaceuticals, Inc. S.A.Tishkoff: None. Funding American Diabetes Association (1-19-VSN-02 to S.A.T.); National Institutes of Health (R35GM134922)

HLA: Immune Response Genetics, Mar 30, 2023

Diabetes, Jun 1, 2021

African Americans are at higher risk for cardiometabolic disease relative to individuals with Eur... more 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)

Tanzania Medical Journal, 1994

AIJR Abstracts, Jul 24, 2021

Diabetes, Jun 1, 2022

African ancestry populations are underrepresented in human genetic studies, which leaves a knowle... more 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. Funded by ADA Pathway award 1-19-VSN-02. Disclosure D.Hui: None. T.B.Nyambo: None. S.Chanock: None. S.A.Tishkoff: None. D.Harris: None. M.Mcquillan: None. M.Hansen: None. A.Ranciaro: None. W.Beggs: None. S.W.Mpoloka: None. D.Woldemeskel: None. A.K.K.Njamnshi: None. Funding American Diabetes Association (1-19-VSN-02) ; National Institutes of Health (R35 GM134957-01, R01AR076241, 5T32DK007314-39, 1OT3HL142479-01, 1OT3HL142478-01, 1OT3HL142481-01, 1OT3HL142480-01, 1OT3HL147154-01)

This book contains the abstracts of the papers/posters presented at the Tanzania Health Summit 20... more This book contains the abstracts of the papers/posters presented at the Tanzania Health Summit 2020 (THS-2020) Organized by the Ministry of Health Community Development, Gender, Elderly and Children (MoHCDGEC); President Office Regional Administration and Local Government (PORALG); Ministry of Health, Social Welfare, Elderly, Gender, and Children Zanzibar; Association of Private Health Facilities in Tanzania (APHFTA); National Muslim Council of Tanzania (BAKWATA); Christian Social Services Commission (CSSC); & Tindwa Medical and Health Services (TMHS) held on 25–26 November 2020. The Tanzania Health Summit is the annual largest healthcare platform in Tanzania that attracts more than 1000 participants, national and international experts, from policymakers, health researchers, public health professionals, health insurers, medical doctors, nurses, pharmacists, private health investors, supply chain experts, and the civil society. During the three-day summit, stakeholders and decision-m...

Human Molecular Genetics, 2020

Leukocyte telomere length (LTL) might be causal in cardiovascular disease and major cancers. To e... more Leukocyte telomere length (LTL) might be causal in cardiovascular disease and major cancers. To elucidate the roles of genetics and geography in LTL variability across humans, we compared LTL measured in 1295 sub-Saharan Africans (SSAs) with 559 African–Americans (AAms) and 2464 European–Americans (EAms). LTL differed significantly across SSAs (P = 0.003), with the San from Botswana (with the oldest genomic ancestry) having the longest LTL and populations from Ethiopia having the shortest LTL. SSAs had significantly longer LTL than AAms [P = 6.5(e-16)] whose LTL was significantly longer than EAms [P = 2.5(e-7)]. Genetic variation in SSAs explained 52% of LTL variance versus 27% in AAms and 34% in EAms. Adjustment for genetic variation removed the LTL differences among SSAs. LTL genetic variation among SSAs, with the longest LTL in the San, supports the hypothesis that longer LTL was ancestral in humans. Identifying factors driving LTL variation in Africa may have important ramificat...

Proceedings of the National Academy of Sciences of the United States of America, Feb 19, 2019

Anatomically modern humans arose in Africa ∼300,000 years ago, but the demographic and adaptive h... more Anatomically modern humans arose in Africa ∼300,000 years ago, but the demographic and adaptive histories of African populations are not well-characterized. Here, we have generated a genomewide dataset from 840 Africans, residing in western, eastern, southern, and northern Africa, belonging to 50 ethnicities, and speaking languages belonging to four language families. In addition to agriculturalists and pastoralists, our study includes 16 populations that practice, or until recently have practiced, a huntinggathering (HG) lifestyle. We observe that genetic structure in Africa is broadly correlated not only with geography, but to a lesser extent, with linguistic affiliation and subsistence strategy. Four East African HG (EHG) populations that are geographically distant from each other show evidence of common ancestry: the Hadza and Sandawe in Tanzania, who speak languages with clicks classified as Khoisan; the Dahalo in Kenya, whose language has remnant clicks; and the Sabue in Ethiopia, who speak an unclassified language. Additionally, we observed common ancestry between central African rainforest HGs and southern African San, the latter of whom speak languages with clicks classified as Khoisan. With the exception of the EHG, central African rainforest HGs, and San, other HG groups in Africa appear genetically similar to neighboring agriculturalist or pastoralist populations. We additionally demonstrate that infectious disease, immune response, and diet have played important roles in the adaptive landscape of African history. However, while the broad biological processes involved in recent human adaptation in Africa are often consistent across populations, the specific loci affected by selective pressures more often vary across populations. African hunter-gatherers | African diversity | population genetics | natural selection | human evolution

Human Molecular Genetics, Mar 2, 2016

Leukocyte telomere length (LTL), which reflects telomere length in other somatic tissues, is a co... more Leukocyte telomere length (LTL), which reflects telomere length in other somatic tissues, is a complex genetic trait. Eleven SNPs have been shown in genome-wide association studies to be associated with LTL at a genome-wide level of significance within cohorts of European ancestry. It has been observed that LTL is longer in African Americans than in Europeans. The underlying reason for this difference is unknown. Here we show that LTL is significantly longer in sub-Saharan Africans than in both Europeans and African Americans. Based on the 11 LTL-associated alleles and genetic data in phase 3 of the 1000 Genomes Project, we show that the shifts in allele frequency within Europe and between Europe and Africa do not fit the pattern expected by neutral genetic drift. Our findings suggest that differences in LTL within Europeans and between Europeans and Africans is influenced by polygenic adaptation and that differences in LTL between Europeans and Africans might explain, in part, ethnic differences in risks for human diseases that have been linked to LTL.

Molecular Biology and Evolution, Jul 21, 2007

Little is known about the history of click-speaking populations in Africa. Prior genetic studies ... more Little is known about the history of click-speaking populations in Africa. Prior genetic studies revealed that the clickspeaking 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.

Environmental Health and Preventive Medicine, 2004

Objective: The aim of this survey was to compare the seroprevalences of Helicobacter Pylori (H. p... more Objective: The aim of this survey was to compare the seroprevalences of Helicobacter Pylori (H. pylori) and chronic atrophic gastritis (CAG) in Tanzania and the Dominican Republic, both of which are tropical countries, and thereafter compare the prevalences in Tanzania and the Dominican Republic with prevalences from our previous studies done in Japan (1991) and China (1996/97). Methods: Community-based study in which 573 inhabitants of Tanzania and 1,215 inhabitants of the Dominican Republic answered detailed questionnaires on upper digestive tract diseases, and then underwent screening for gastric cancer by serum pepsinogen and testing for antibody to H. pylori. Results: After adjusting to the 'Age-Standardized Rate' (ASR) using the world population in 1995, the seroprevalences of H. pylori infection in male and female subjects for Tanzania (m=85.3% & f=88.2%) were very high compared to those for the Dominican Republic (m=63.5% & f=62.4%) and Japan (m=62.0% & f=46.8%), and similar to those of China (m=78.0% & f=77.3%). Also, the agestandardized prevalences of CAG in males and females for Tanzania (m=0.237 & f=0.458) were higher than those of the Dominican Republic (m=0.168 & f=0.211) and China (m=0.111 & f=0.107) and compared well with those of Japan (m=0.266 & f=0.352). Conclusions: Although Tanzania and the Dominican Republic are both developing countries, Tanzania had a very high age-standardized prevalence of H. pylori and CAG compared to that of the Dominican Republic, which showed a trend similar to that of Japan.

Human Immunology, Sep 1, 2019

Aim: Nasopharyngeal carcinoma (NPC) has a distinct racial and geographic distribution caused by a... more Aim: Nasopharyngeal carcinoma (NPC) has a distinct racial and geographic distribution caused by a combination of Epstein-Barr virus (EBV) infection and environmental factors. It also had been shown a strong and consistent HLA associated. The HLA genes differ greatly among populations making it as a powerful tool for the study of population genetics and disease association. We have conducted a molecular HLA typing project to describe the HLA class I profiling in the high NPC incident aera of Southern China. The results also compared with reported data from Northern Chinese population previously. Methods: High resolution HLA typing was informative for 629 unrelated cancer free individuals. The difference between these subjects and the former reported northern Chinese population were characterized in frequencies and in the presence of alleles and haplotypes. Results: A number of 26, 52, and 21 alleles in HLA-A, B, and C loci were identified in these subjects. 21 alleles with significantly different distributions were observed in HLA-A, B, and C loci between these two groups. HLA-A*11:01 is the most common allele with extraordinary high frequencies which indicates nature selective forces may acted on the population of NPC high incident regions. Conclusions: Our study demonstrates a distinct HLA class I alleles distribution in high NPC incident region of southern Han Chinese compare with northern Han Chinese. Haplotype analyses have shown that a fewer predominant haplotype patterns in this population with higher population coverage illustrated the direction for deeply exploring by future studies. Disclosures: M.

Human Genetics, Apr 23, 2013

Malaria is one of the strongest selective pressures in recent human evolution. African population... more Malaria is one of the strongest selective pressures in recent human evolution. African populations have been and continue to be at risk for malarial infections. However, few studies have resequenced malaria susceptibility loci across geographically and genetically diverse groups in Africa. We examined nucleotide diversity at Intercellular adhesion molecule-1 (ICAM-1), a malaria susceptibility candidate locus, in a number of human populations with a specific focus on diverse African ethnic groups. We used tests of neutrality to assess whether natural selection has impacted this locus and tested whether SNP variation at ICAM-1 is correlated with malaria endemicity. We observe differing patterns of nucleotide and haplotype variation in global populations and higher levels of diversity in Africa. Although we do not observe a deviation from neutrality based on the allele frequency distribution, we do observe several alleles at ICAM-1, including the ICAM-1 Kilifi allele, that are correlated with malaria endemicity. We show that the ICAM-1 Kilifi allele, which is common in Africa and Asia, exists on distinct haplotype backgrounds and is likely to have arisen more recently in Asia. Our results suggest that correlation analyses of allele frequencies and malaria endemicity may be useful for identifying candidate functional variants that play a role in malaria resistance and susceptibility.

Pharmacogenomics Journal, Apr 16, 2013

There is established clinical evidence for differences in drug response, cure rates and survival ... more There is established clinical evidence for differences in drug response, cure rates and survival outcomes between different ethnic populations, but the causes are poorly understood. Differences in frequencies of functional genetic variants in key drug response and metabolism genes may significantly influence drug response differences in different populations. To assess this, we genotyped 1330 individuals of African (n = 372) and European (n = 958) descent for 4535 singlenucleotide polymorphisms in 350 key drug absorption, distribution, metabolism, elimination and toxicity genes. Important and remarkable differences in the distribution of genetic variants were

Pharmacogenomics, Nov 1, 2011

Functional variability at the arylamine N-acetyltransferase genes is associated with drug respons... more 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.

Genetic Epidemiology, Nov 28, 2011

Sub-Saharan Africa has been identified as the part of the world with the greatest human genetic d... more Sub-Saharan Africa has been identified as the part of the world with the greatest human genetic diversity. This high level of diversity causes difficulties for genome-wide association (GWA) studies in African populations-for example, by reducing the accuracy of genotype imputation in African populations compared to non-African populations. Here, we investigate haplotype variation and imputation in Africa, using 253 unrelated individuals from 15 Sub-Saharan African populations. We identify the populations that provide the greatest potential for serving as reference panels for imputing genotypes in the remaining groups. Considering reference panels comprising samples of recent African descent in Phase 3 of the HapMap Project, we identify mixtures of reference groups that produce the maximal imputation accuracy in each of the sampled populations. We find that optimal HapMap mixtures and maximal imputation accuracies identified in detailed tests of imputation procedures can instead be predicted by using simple summary statistics that measure relationships between the pattern of genetic variation in a target population and the patterns in potential reference panels. Our results provide an empirical basis for facilitating the selection of reference panels in GWA studies of diverse human populations, especially those of African ancestry.

Nature Genetics, Jul 1, 2012

Users may view, print, copy, download and text and data-mine the content in such documents, for t... more Users may view, print, copy, download and text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

Diabetes, Jun 20, 2023

Prior studies have identified genetic factors that impact an individual’s risk of developing type... more 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. Disclosure M.Hansen: None. D.Harris: None. A.M.Harris: None. T.B.Nyambo: None. G.Belay: None. S.Mpoloka: None. C.Burant: Research Support; Rhythm Pharmaceuticals, Inc. S.A.Tishkoff: None. Funding American Diabetes Association (1-19-VSN-02 to S.A.T.); National Institutes of Health (R35GM134922)

HLA: Immune Response Genetics, Mar 30, 2023

Diabetes, Jun 1, 2021

African Americans are at higher risk for cardiometabolic disease relative to individuals with Eur... more 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)

Tanzania Medical Journal, 1994