Abstract: Background: Arsenic in drinking water causes severe health effects. Indigenous people in the South American Andes have likely lived with arsenic-contaminated drinking water for thousands of years. Inhabitants of San Antonio de los Cobres (SAC) in the Argentinean highlands generally carry an AS3MT (the major arsenic-metabolizing gene) haplotype associated with reduced health risks due to rapid arsenic excretion and lower urinary fraction of the monomethylated metabolite.
Objectives: We hypothesized an adaptation to high-arsenic living conditions via a possible positive selection for protective AS3MT variants and compared AS3MT haplotype frequencies among different indigenous groups.
Methods: Indigenous groups we evaluated were a) inhabitants of SAC and villages near Salta in northern Argentina (n = 346), b) three Native American populations from the Human Genome Diversity Project (HGDP; n = 25), and c) five Peruvian populations (n = 97). The last two groups have presumably lower historical exposure to arsenic.
Results: We found a significantly higher frequency of the protective AS3MT haplotype in the SAC population (68.7%) compared with the HGDP (14.3%, p < 0.001, Fisher exact test) and Peruvian (50.5%, p < 0.001) populations. Genome-wide microsatellite (n = 671) analysis showed no detectable level of population structure between SAC and Peruvian populations (measure of population differentiation FST = 0.006) and low levels of structure between SAC and HGDP populations (FST < 0.055 for all pairs of populations compared).
Conclusions: Because population stratification seems unlikely to explain the differences in AS3MT haplotype frequencies, our data raise the possibility that, during a few thousand years, natural selection for tolerance to the environmental stressor arsenic may have increased the frequency of protective variants of AS3MT. Further studies are needed to investigate this hypothesis.
Abstract: BACKGROUND: The current San and Khoe populations are remnant groups of a much larger and widely dispersed population of hunter-gatherers and pastoralists, who had exclusive occupation of southern Africa before the influx of Bantu-speakers from 2 ka (ka = kilo annum [thousand years] old/ago) and sea-borne immigrants within the last 350 years. Here we use mitochondrial DNA (mtDNA) to examine the population structure of various San and Khoe groups, including seven different Khoe-San groups (Ju/'hoansi, !Xun, /Gui+//Gana, Khwe, =Khomani, Nama and Karretjie People), three different Coloured groups and seven other comparative groups. MtDNA hyper variable segments I and II (HVS I and HVS II) together with selected mtDNA coding region SNPs were used to assign 538 individuals to 18 haplogroups encompassing 245 unique haplotypes. Data were further analyzed to assess haplogroup histories and the genetic affinities of the various San, Khoe and Coloured populations. Where possible, we tentatively contextualize the genetic trends through time against key trends known from the archaeological record. RESULTS: The most striking observation from this study was the high frequencies of the oldest mtDNA haplogroups (L0d and L0k) that can be traced back in time to ~100 ka, found at high frequencies in Khoe-San and sampled Coloured groups. Furthermore, the L0d/k sub-haplogroups were differentially distributed in the different Khoe-San and Coloured groups and had different signals of expansion, which suggested different associated demographic histories. When populations were compared to each other, San groups from the northern parts of southern Africa (Ju speaking: !Xun, Ju/'hoansi and Khoe-speaking: /Gui+//Gana) grouped together and southern groups (historically Tuu speaking: =Khomani and Karretjie People and some Coloured groups) grouped together. The Khoe group (Nama) clustered with the southern Khoe-San and Coloured groups. The Khwe mtDNA profile was very different from other Khoe-San groups with high proportions of Bantu-speaking admixture but also unique distributions of other mtDNA lineages. CONCLUSIONS: On the whole, the research reported here presented new insights into the multifaceted demographic history that shaped the existing genetic landscape of the Khoe-San and Coloured populations of southern Africa.
Abstract: Continued ability to digest lactose after weaning provides a possible selective advantage to individuals who have access to milk as a food source. The lactase persistence (LP) phenotype exists at varying frequencies in different populations and SNPs that modulate the regulation of the LCT gene have been identified in many of these populations. Very strong positive selection for LP has been illustrated for a single SNP (rs4988235) in northwestern European populations, which has become a textbook example of the effect of recent selective sweeps on genetic variation and linkage disequilibrium. In this study, we employed two different methods to detect signatures of positive selection in an East African pastoralist population in the HapMap collection, the Maasai from Kenya, and compared results with other HapMap populations. We found that signatures of recent selection coinciding with the LCT gene are the strongest across the genome in the Maasai population. Furthermore, the genome-wide signal of recent positive selection on haplotypic variation and population differentiation around the LCT gene is greater in the Maasai than in the CEU population (northwestern European descent), possibly due to stronger selection pressure, but it could also be an indication of more recent selection in Maasai compared with the Central European group or more efficient selection in the Maasai due to less genetic drift for their larger effective population size. This signal of recent selection is driven by a putative East African LP haplotype that is different from the haplotype that contributes to the LP phenotype in northwestern Europe.
Abstract: When modern humans left Africa ca. 60,000 years ago (60 kya), they were already infected with Helicobacter pylori, and these bacteria have subsequently diversified in parallel with their human hosts. But how long were humans infected by H. pylori prior to the out-of-Africa event? Did this co-evolution predate the emergence of modern humans, spanning the species divide? To answer these questions, we investigated the diversity of H. pylori in Africa, where both humans and H. pylori originated. Three distinct H. pylori populations are native to Africa: hpNEAfrica in Afro-Asiatic and Nilo-Saharan speakers, hpAfrica1 in Niger-Congo speakers and hpAfrica2 in South Africa. Rather than representing a sustained co-evolution over millions of years, we find that the coalescent for all H. pylori plus its closest relative H. acinonychis dates to 88-116 kya. At that time the phylogeny split into two primary super-lineages, one of which is associated with the former hunter-gatherers in southern Africa known as the San. H. acinonychis, which infects large felines, resulted from a later host jump from the San, 43-56 kya. These dating estimates, together with striking phylogenetic and quantitative human-bacterial similarities show that H. pylori is approximately as old as are anatomically modern humans. They also suggest that H. pylori may have been acquired via a single host jump from an unknown, non-human host. We also find evidence for a second Out of Africa migration in the last 52,000 years, because hpEurope is a hybrid population between hpAsia2 and hpNEAfrica, the latter of which arose in northeast Africa 36-52 kya, after the Out of Africa migrations around 60 kya.
Abstract: The San and Khoe people currently represent remnant groups of a much larger and widely distributed population of hunter gatherers and pastoralists who had exclusive occupation of southern Africa before the arrival of Bantu-speaking groups in the past 1,200 years and sea-borne immigrants within the last 350 years. Genetic studies (mitochondrial DNA and Y-chromosome) conducted on San and Khoe groups revealed that they harbour some the most divergent lineages found in living peoples throughout the world. Recently, high-density autosomal SNP-array studies confirmed the early divergence of Khoe-San population groups from all other human populations. The present study made use of 220 autosomal SNP markers, in the format of both haplotypes and genotypes, to examine the population structure of various San and Khoe groups and their relatedness to other neighbouring groups. While analyses based on the genotypic SNP data only supported the division of the included populations into three main groups, Khoe-San, Bantu-spe kers and non- African populations, haplotype analyses revealed finer structure within Khoe-San populations. Through using only 44 short SNP haplotypes (compiled from a total of 220 SNPs), most of the Khoe-San groups could be resolved as separate groups by applying STRUCTURE analyses. Therefore, by carefully selecting a few SNPs and combining them into haplotypes, we were able to achieve the same level of population distinction as achieved previously in high-density SNP studies on the same population groups. Using haplotypes proved to be a very efficient and cost-effective way to study population structure.
Abstract: The history of click-speaking Khoe-San, and African populations in general, remains poorly understood. We genotyped ~2.3 million single-nucleotide polymorphisms in 220 southern Africans and found that the Khoe-San diverged from other populations â¥100,000 years ago, but population structure within the Khoe-San dated back to about 35,000 years ago. Genetic variation in various sub-Saharan populations did not localize the origin of modern humans to a single geographic region within Africa; instead, it indicated a history of admixture and stratification. We found evidence of adaptation targeting muscle function and immune response; potential adaptive introgression of protection from ultraviolet light; and selection predating modern human diversification, involving skeletal and neurological development. These new findings illustrate the importance of African genomic diversity in understanding human evolutionary history.
Abstract: The Karretjie people of the South African Great Karoo are itinerants who subsist by sheep shearing. Although officially classified 'Coloured', they are aware of their Khoe and San roots. To investigate the maternal and paternal ancestries of the Karretjie people we analyzed their mitochondrial and Y-chromosome DNA variation. Their genetic ancestry was compared with a neighboring group of 'Coloured' individuals. We found that the mitochondrial DNA (mtDNA) haplogroup L0d was present in all the Karretjie people examined, suggesting a maternal contribution, exclusively from the Khoe and San, whereas the paternal ancestry in males was more heterogeneous. The Coloured sample, on the other hand, were found to have a lower frequency of L0d (64.5%), but did harbor other African (27.6%) and non-African (7.9%) mtDNA haplogroups. Similar to the Karretjie people, the Y-chromosome lineages identified in the Coloured group had heterogeneous origins. This study also enabled an assessment of mtDNA variation within L0d sub-haplogroups. All seven of the L0d sub-clades were identified in the combined sample and were used to construct an L0d network.
Abstract: BACKGROUND: There is substantial ethnic, cultural and linguistic diversity among the people living in east Africa, Sudan and the Nile Valley. The region around the Nile Valley has a long history of succession of different groups, coupled with demographic and migration events, potentially leading to genetic structure among humans in the region. RESULTS: We report the genotypes of the 15 Identifiler microsatellite markers for 498 individuals from 18 Sudanese populations representing different ethnic and linguistic groups. The combined power of exclusion (PE) was 0.9999981, and the combined match probability was 1 in 7.4 1017. The genotype data from the Sudanese populations was combined with previously published genotype data from Egypt, Somalia and the Karamoja population from Uganda. The Somali population was found to be genetically distinct from the other northeast African populations. Individuals from northern Sudan clustered together with those from Egypt, and individuals from southern Sudan clustered with those from the Karamoja population. The similarity of the Nubian and Egyptian populations suggest that migration, potentially bidirectional, occurred along the Nile river Valley, which is consistent with the historical evidence for long-term interactions between Egypt and Nubia. CONCLUSION: We show that despite the levels of population structure in Sudan, standard forensic summary statistics are robust tools for personal identification and parentage analysis in Sudan. Although some patterns of population structure can be revealed with 15 microsatellites, a much larger set of genetic markers is needed to detect fine-scale population structure in east Africa and the Nile Valley.
Abstract: BACKGROUND:
The ability of the Y chromosome to retain a record of its evolution has seen it become an essential tool of molecular anthropology. In the last few years, however, it has also found use in forensic genetics, providing information on the geographic origin of individuals. This has been aided by the development of efficient screening methods and an increased knowledge of geographic distribution. In this study, we describe the development of single base extension assays used to resolve 61 Y chromosome haplogroups, mainly within haplogroups A, B and E, found in Africa.
RESULTS:
Seven multiplex assays, which incorporated 60 Y chromosome markers, were developed. These resolved Y chromosomes to 61 terminal branches of the major African haplogroups A, B and E, while also including a few Eurasian haplogroups found occasionally in African males. Following its validation, the assays were used to screen 683 individuals from Southern Africa, including south eastern Bantu speakers (BAN), Khoe-San (KS) and South African Whites (SAW). Of the 61 haplogroups that the assays collectively resolved, 26 were found in the 683 samples. While haplogroup sharing was common between the BAN and KS, the frequencies of these haplogroups varied appreciably. Both groups showed low levels of assimilation of Eurasian haplogroups and only two individuals in the SAW clearly had Y chromosomes of African ancestry.
CONCLUSIONS:
The use of these single base extension assays in screening increased haplogroup resolution and sampling throughput, while saving time and DNA. Their use, together with the screening of short tandem repeat markers would considerably improve resolution, thus refining the geographic ancestry of individuals.
Abstract: BACKGROUND: Women who carry germline mutations in the breast-ovarian cancer susceptibility genes, BRCA1 and BRCA2, are at very high risk of developing breast and/or ovarian cancer. Both genes are tumour suppressor genes that protect all cells from deregulation, and there are reports of their involvement in other cancers that vary and seem to depend on the population investigated. It is therefore important to investigate the other associated cancers in different populations to assist with risk assessments. OBJECTIVES: To assess the cancer risk profile in BRCA-mutation-positive and negative South African breast-ovarian cancer families, mainly of Caucasian origin. DESIGN: Descriptive study in which the prevalence of all cancers in the pedigrees of BRCA1- and BRCA2-mutation-positive groups and a group of families without mutations in either gene were compared with the general population. RESULTS: As expected, female breast and ovarian cancer was significantly increased in all three groups. Furthermore, male breast cancer was significantly elevated in the BRCA2-positive and BRCA-negative groups. Stomach cancer prevalence was significantly elevated in the BRCA2-positive families compared with the general population. CONCLUSIONS: These results can be applied in estimation of cancer risks and may contribute to more comprehensive counselling of mutation-positive Caucasian breast and/or ovarian cancer families.
Abstract: African mitochondrial DNA (mtDNA) haplogroups are divided into seven macro-haplogroups (L0'1'2'3'4'5'6), while the rest of the world's lineages are classified as subgroups of macro-haplogroups M, N and R. The most common approach to characterizing mtDNA variation is the sequencing of hypervariable segments I and II of the non-coding control region of the molecule. Given the higher mutation rate within the control region compared with the coding regions of the molecule, recurrent mutations in the former can sometimes hide possible phylogenetic structure. The incorporation of haplogroup-defining coding region mutations has helped in overcoming this limitation. By judiciously selecting 14 coding region SNPs and incorporating them into a multiplex minisequencing assay we were able to resolve mtDNA sequences from some sub-Saharan African populations into ten macro-haplogroups (L0-L6, M, N and R). We tested the efficacy of the panel by screening 699 individuals, consisting mostly of Khoe-San, Bantu speakers and individuals with mixed ancestries (Coloreds) and found no inconsistencies compared with hypervariable segment sequencing results. The panel provided a fast and efficient means of classifying mtDNA into the ten mitochondrial macro-haplogroups and provided a reliable screening to distinguish African from non-African-derived mtDNA lineages.
Abstract: Background and Objectives: This study reports the genotype frequencies of HPA 1-5 and -15 in blood donors from the four main population groups in South Africa (SA). Statistical comparisons are made between the frequency in each group and other populations.
Materials and Methods: 150 regular blood donors from each population group (White, Bantu-speaking, Cape Coloured, Indian) were tested after obtaining informed consent. These 600 typed donors form the preliminary group and account for 2.15% of the countryâs blood donor database. A PCR-SSP method with a "hot start" Taq technique, for high-throughput use in routine laboratory procedure for HPA 1-5 and -15 was utilized. Statistical comparison of gene frequencies between each group and other populations was made using the Chi Squared test.
Results: The South African White blood donor population shows HPA gene frequencies statistically similar to that of Europeans, whereas the SA Bantu-speaking donors share similarities with other sub-Saharan African populations. The Cape Coloured group of donors appears to be part of a unique population that shares very little HPA gene similarity with other populations. The frequency of HPA 1 in the SA Indian population is similar to that of the Indians in Western India.
Conclusion: An initial database of HPA typed blood platelet donors has been established as a result of this study. This will facilitate effective HPA matched platelet transfusions where clinically indicated. The SA population is culturally diverse and show genetic similarities in HPA gene frequencies that demonstrate ancestral connections with other, geographically distant, populations.
Abstract: Genomics and Health in the Developing World provides detailed and comprehensive coverage of population structures, human genomics, and genome variation--with particular emphasis on medical and health issues--in the emerging economies and countries of the developing world. With sections dedicated to fundamtals of genetics and genomics, epidemiology of human disease, biomarkers, comparative genomics, developments in translational genomic medicine, current and future health strategies related to genetic disease, and pertinent legislative and social factors, this volume highlights the importance of utilizing genetics/genomics knowledge to promote and achieve optimal health in the developing world. Grouped by geographic region, the chapters in this volume address:
- Inherited disorders in the developing world, including a thorough look at genetic disorders in minority groups of every continent
- The progress of diagnostic laboratory genetic testing, prenatal screening, and genetic counseling worldwide
- Rising ethical and legal concerns of medical genetics in the developing world
- Social, cultural, and religious issues related to genetic diseases across continents
Both timely and vastly informative, this book is a unique and comprehensive resource for genetists, clinicians, and public health professionals interested in the social, ethical, economic, and legal matters associated with medical genetics in the developing world.
Abstract: The San and Khoe people currently represent remnant groups of a much larger and widely distributed population of hunter gatherers and cattle herders, respectively, who had exclusive occupation of southern Africa before the arrival of Bantu-speaking groups in the past 1,200 years and sea-borne immigrants within the last 350 years. This project made use of mitochondrial DNA (mtDNA), Y-chromosome DNA and autosomal DNA markers to examine the population structure of various San and Khoe groups and to reconstruct their prehistory. The groups included in the study consists of six different Khoe-San groups (â¡Khomani, Nama, Khwe, !Xun, /Gui + //Gana + Kgalagari and Ju\âhoansi), four different Coloured groups and five other population groups that were included in the comparative analysis.
For the mtDNA study a minisequencing technique was successfully developed which allowed the assignment of mtDNA lineages into the 10 global mtDNA macro-haplogroups. Haplogroups were further resolved using control region sequence data obtained from both hypervariable regions (HVR I and HVR II). Using this approach 538 individuals (both males and females) were screened and their mtDNA types were resolved into 18 haplogroups encompassing 245 unique haplotypes. In addition, 353 males were examined for Y-chromosome DNA variation using 46 bi-allelic Y-chromosome markers and 12 Y-STR markers. The Y-chromosomes in the sample were assigned into 29 haplogroups (using bi-allelic variation) following the nomenclature initially recommended by the Y-chromosome Consortium and resolved into 268 unique haplotypes (Y-STR variation). To assess the level of autosomal variation, 220 genome wide autosomal SNPs were typed in 352 individuals. These SNPs were combined in different datasets and analysed using two different approaches allowing for genotype and haplotype analyses. Data from these three marker systems were analysed using different analytical methods (distance based phylogenetic analysis, network analysis, dating of lineages, principal components analysis, phylogeographic analysis, AMOVA analysis, population structure analysis, and population genetic summary statistics) to asses the ancestral associations and the genetic affinities of the various San, Khoe and Coloured populations.
The most striking observation from this study was the high frequencies of the oldest mtDNA haplogroups (L0d and L0k) and Y-chromosome haplogroups (haplogroups A and B) found in Khoe-San and Coloured groups. The sub-haplogroups were, however, differentially distributed in the different Khoe-San and Coloured groups which suggested different demographic histories.
The current distribution of Khoe-San groups comprises a wide geographic region extending from southern Angola in the north to the Cape Province (South Africa) in the south. Linguistically Khoe-San groups are also divided into northern Khoisan-speaking groups (Ju division) and southern Khoisan-speaking groups (Tuu division) with an additional linguistic group (Khoe) associated with some Khoe-speaking San groups in Botswana and the Khoe herders of South Africa and Namibia (such as the Nama). For all three genetic marker systems, northern groups (Ju speaking - !Xun, Ju\âhoansi and Khoe-speaking San - /Gui + //Gana) grouped into one cluster and southern groups (historically Tuu speaking - â¡Khomani and Coloured groups) grouped into a second cluster with the Khoe group (Nama) clustering with the southern Khoe-San and Coloured groups.
The Khwe genetic profile was very different from the other Khoe-San groups. Although high proportions of Bantu-speaking admixture were identified in the Khwe group, they also contained a unique distribution of other mtDNA and Y-chromosome lineages. A previously published theory suggested that, based on the presence of a specific E-M35 Y-chromosome haplotype, the Khwe might be descendants of an east African pastoralist group that introduced the pastoralist culture to a region located in the present day northern Botswana. This pattern also mirrors what archaeologists have found with respect to the introduction of pastoralism to southern Africa. The theory was further supported and elaborated on in the present thesis. Considering the frequency and distribution of E-M35, the highest frequency (46%) was found in the Khwe with a present-day distribution in northern Botswana and southern Angola while a decrease in frequency is observed towards the south with low frequencies (<10%) in the Karoo Coloured groups. Conversely, none of the mtDNA (female) L0k and L0d lineages observed in the Khwe group were observed in the southern Khoe-San and Coloured groups. From these observations a theory was proposed that after introduction into the region of northern Botswana, the southwards spread of pastoralism was not a clear-cut demic or cultural diffusion. Rather some male individuals integrated with the southern tribes and took with them the pastoralist practice and likely also their Khoe-language.
Altogether this thesis presented new insights into the multifaceted demographic history that shaped the existing genetic landscape of the Khoe-San and Coloured populations of southern Africa.
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