Abstract
The KhoeSan populations are the earliest known indigenous inhabitants of southern Africa. The relatively recent expansion of Bantu-speaking agropastoralists, as well as European colonial settlement along the south–west coast, dramatically changed patterns of genetic diversity in a region which had been largely isolated for thousands of years. Owing to this unique history, population structure in southern Africa reflects both the underlying KhoeSan genetic diversity as well as differential recent admixture. This population structure has a wide range of biomedical and sociocultural implications; such as changes in disease risk profiles. Here, we consolidate information from various population genetic studies that characterize admixture patterns in southern Africa with an aim to better understand differences in adverse disease phenotypes observed among groups. Our review confirms that ancestry has a direct impact on an individual’s immune response to infectious diseases. In addition, we emphasize the importance of collaborative research, especially for populations in southern Africa that have a high incidence of potentially fatal infectious diseases such as HIV and tuberculosis.
Similar content being viewed by others
References
Abel L, El-Baghdadi J, Bousfiha AA, et al (2014) Human genetics of tuberculosis: a long and winding road. Phil Trans R Soc B 369:20130428. doi:10.1098/rstb.2013.0428
Adams LA, Möller M, Nebel A, et al (2011) Polymorphisms in MC3R promoter and CTSZ 3′UTR are associated with tuberculosis susceptibility. Eur J Hum Genet 19:676–681. doi:10.1038/ejhg.2011.1
Adoga MP, Fatumo SA, Agwale SM (2014) H3Africa: a tipping point for a revolution in bioinformatics, genomics and health research in Africa. Source Code Biol Med 9:10. doi:10.1186/1751-0473-9-10
Alkhatib G, Combadiere C, Broder CC et al (1996) CC CKR5: a RANTES, MIP-1alpha, MIP-1beta receptor as a fusion cofactor for macrophage-tropic HIV-1. Science 272:1955–1958
Anoosheh S, Farnia P, Kargar M (2011) Association between TNF-alpha (-857) gene polymorphism and susceptibility to tuberculosis. Iran Red Crescent Med J 13:243–248.
Balamurugan A, Sharma SK, Mehra NK (2004) Human leukocyte antigen class I supertypes influence susceptibility and severity of tuberculosis. J Infect Dis 189:805–811. doi:10.1086/381689
Barbieri C, Vicente M, Rocha J et al (2013) Ancient substructure in early mtDNA lineages of Southern Africa. Am J Hum Genet 92:285–292. doi:10.1016/j.ajhg.2012.12.010
Barbieri C, Güldemann T, Naumann C et al (2014a) Unraveling the complex maternal history of Southern African Khoisan populations. Am J Phys Anthropol 153:435–448. doi:10.1002/ajpa.22441
Barbieri C, Vicente M, Oliveira S, et al (2014b) Migration and interaction in a contact zone: mtDNA variation among Bantu-speakers in Southern Africa. PLoS One 9:e99117. doi:10.1371/journal.pone.0099117
Barbieri C, Hübner A, Macholdt E et al (2016) Refining the Y chromosome phylogeny with southern African sequences. Hum Genet 135:541–553. doi:10.1007/s00439-016-1651-0
Batini C, Jobling MA (2011) The jigsaw puzzle of our African ancestry: unsolved, or unsolvable? Genome Biol 12:118. doi:10.1186/gb-2011-12-6-118
Behar DM, van Oven M, Rosset S et al (2012) A “Copernican” reassessment of the human mitochondrial DNA tree from its root. Am J Hum Genet 90:675–684. doi:10.1016/j.ajhg.2012.03.002
Breton G, Schlebusch CM, Lombard M, et al (2014) Lactase persistence alleles reveal partial East african ancestry of southern african Khoe pastoralists. Curr Biol 24:852–858. doi:10.1016/j.cub.2014.02.041
Brown KS, Marean CW, Herries AIR et al (2009) Fire as an engineering tool of early modern humans. Science 325:859–862. doi:10.1126/science.1175028
Brown KS, Marean CW, Jacobs Z et al (2012) An early and enduring advanced technology originating 71,000 years ago in South Africa. Nature 491:590–593. doi:10.1038/nature11660
Bryc K, Durand EY, Macpherson JM et al (2015) The genetic ancestry of African Americans, Latinos, and European Americans across the US. Am J Hum Genet 96:37–53. doi:10.1016/j.ajhg.2014.11.010
Cann HM (2002) A human genome diversity cell line panel (letter). Science 296:261. doi:10.1126/science.296.5566.261b
Chen YS, Olckers A, Schurr TG et al (2000) mtDNA variation in the South African Kung and Khwe-and their genetic relationships to other African populations. Am J Hum Genet 66:1362–1383. doi:10.1086/302848
Chen Y-C, Hsiao C-C, Chen C-J et al (2010) Toll-like receptor 2 gene polymorphisms, pulmonary tuberculosis, and natural killer cell counts. BMC Med Genet 11:17. doi:10.1186/1471-2350-11-17
Chimusa ER, Daya M, Möller M et al (2013) Determining ancestry proportions in complex admixture scenarios in South Africa using a novel proxy ancestry selection method. PLoS One. doi:10.1371/journal.pone.0073971
Chimusa ER, Zaitlen N, Daya M et al (2014) Genome-wide association study of ancestry-specific TB risk in the South African Coloured population. Hum Mol Genet 23:796–809. doi:10.1093/hmg/ddt462
Choe H, Farzan M, Sun Y et al (1996) The beta-chemokine receptors CCR3 and CCR5 facilitate infection by primary HIV-1 isolates. Cell 85:1135–1148
Cobat A, Gallant CJ, Simkin L et al (2009) Two loci control tuberculin skin test reactivity in an area hyperendemic for tuberculosis. J Exp Med 206:2583–2591
Cobat A, Hoal EG, Gallant CJ, et al (2013) Identification of a major locus, TNF1, that controls BCG-triggered tumor necrosis factor production by leukocytes in an area hyperendemic for tuberculosis. Clin Infect Dis Off Publ Infect Dis Soc Am 57:963–970.
Cooke GS, Campbell SJ, Bennett S et al (2008) Mapping of a novel susceptibility locus suggests a role for MC3R and CTSZ in human tuberculosis. Am J Respir Crit Care Med 178:203–207. doi:10.1164/rccm.200710-1554OC
Daya M, van der Merwe L, Galal U, et al (2013) A panel of ancestry informative markers for the complex five-way admixed South African coloured population. PLoS One 8:e82224. doi:10.1371/journal.pone.0082224
Daya M, van der Merwe L, Gignoux CR et al (2014a) Using multi-way admixture mapping to elucidate TB susceptibility in the South African Coloured population. BMC Genom 15:1021. doi:10.1186/1471-2164-15-1021
Daya M, van der Merwe L, van Helden PD, et al (2014b) The role of ancestry in TB susceptibility of an admixed South African population. Tuberc Edinb Scotl 94:413–420. doi:10.1016/j.tube.2014.03.012
de Wit E, Delport W, Rugamika CE et al (2010) Genome-wide analysis of the structure of the South African Coloured Population in the Western Cape. Hum Genet 128:145–153. doi:10.1007/s00439-010-0836-1
Drögemöller B, Plummer M, Korkie L, et al (2013) Characterization of the genetic variation present in CYP3A4 in three South African populations. Front Genet 4:17. doi:10.3389/fgene.2013.00017
Feng Y, Broder CC, Kennedy PE, Berger EA (1996) HIV-1 entry cofactor: functional cDNA cloning of a seven-transmembrane, G protein-coupled receptor. Science 272:872–877
Fourie J, van Zanden JL (2013) GDP in the Dutch Cape colony: the national accounts of a slave-Based society. South Afr J Econ 81:467–490. doi:10.1111/saje.12010
Gronau I, Hubisz MJ, Gulko B et al (2011) Bayesian inference of ancient human demography from individual genome sequences. Nat Genet 43:1031–1034. doi:10.1038/ng.937
Gurdasani D, Carstensen T, Tekola-Ayele F et al (2015) The African genome variation project shapes medical genetics in Africa. Nature 517:327–332. doi:10.1038/nature13997
Haber M, Mezzavilla M, Xue Y, Tyler-Smith C (2016) Ancient DNA and the rewriting of human history: be sparing with Occam’s razor. Genome Biol. doi:10.1186/s13059-015-0866-z
Hammer MF, Karafet TM, Redd AJ et al (2001) Hierarchical patterns of global human Y-chromosome diversity. Mol Biol Evol 18:1189–1203
Henn BM, Gignoux C, Lin AA, et al (2008) Y-chromosomal evidence of a pastoralist migration through Tanzania to southern Africa. Proc Natl Acad Sci 105:10693–10698. doi:10.1073/pnas.0801184105
Henn BM, Gignoux CR, Jobin M et al (2011) Hunter-gatherer genomic diversity suggests a southern African origin for modern humans. Proc Natl Acad Sci USA 108:5154–5162. doi:10.1073/pnas.1017511108
Henn BM, Cavalli-Sforza LL, Feldman MW (2012) The great human expansion. Proc Natl Acad Sci USA 109:17758–17764. doi:10.1073/pnas.1212380109
Kenyon C, Buyze J, Colebunders R (2013) HIV prevalence by race co-varies closely with concurrency and number of sex partners in South Africa. PLoS One 8:e64080. doi:10.1371/journal.pone.0064080
Kettaneh A, Seng L, Tiev KP et al (2006) Human leukocyte antigens and susceptibility to tuberculosis: a meta-analysis of case–control studies. Int J Tuberc Lung Dis 10:717–725
Kidd JM, Sharpton TJ, Bobo D et al (2014) Exome capture from saliva produces high quality genomic and metagenomic data. BMC Genom 15:262. doi:10.1186/1471-2164-15-262
Knight A, Underhill PA, Mortensen HM et al (2003) African Y chromosome and mtDNA divergence provides insight into the history of click languages. Curr Biol 13:464–473. doi:10.1016/S0960-9822(03)00130-1
Kostyu DD, Hannick LI, Traweek JL et al (1997) HLA class I polymorphism: structure and function and still questions. Hum Immunol 57:1–18
Lane A b., Soodyall H, Arndt S et al (2002) Genetic substructure in South African Bantu-speakers: Evidence from autosomal DNA and Y-chromosome studies. Am J Phys Anthropol 119:175–185. doi:10.1002/ajpa.10097
Lombard Z, Brune AE, Hoal EG et al (2006) HLA class II disease associations in southern Africa. Tissue Antigens 67:97–110. doi:10.1111/j.1399-0039.2006.00530.x
Mabunda N, Alvarado-Arnez LE, Vubil A et al (2015) Gene polymorphisms in patients with pulmonary tuberculosis from Mozambique. Mol Biol Rep 42:71–76. doi:10.1007/s11033-014-3741-1
Macholdt E, Lede V, Barbieri C, et al (2014) Tracing pastoralist migrations to southern Africa with lactase persistence alleles. Curr Biol CB 24:875–879. doi:10.1016/j.cub.2014.03.027
Macholdt E, Slatkin M, Pakendorf B, Stoneking M (2015) New insights into the history of the C-14010 lactase persistence variant in Eastern and Southern Africa. Am J Phys Anthropol 156:661–664. doi:10.1002/ajpa.22675
Mallick S, Li H, Lipson M et al (2016) The Simons genome diversity project: 300 genomes from 142 diverse populations. Nature 538:201–206. doi:10.1038/nature18964
Manry J, Laval G, Patin E et al (2011) Evolutionary genetics evidence of an essential, nonredundant role of the IFN-γ pathway in protective immunity. Hum Mutat 32:633–642. doi:10.1002/humu.21484
Marean CW (2010) Pinnacle point cave 13B (Western Cape Province, South Africa) in context: the Cape Floral kingdom, shellfish, and modern human origins. J Hum Evol 59:425–443. doi:10.1016/j.jhevol.2010.07.011
Marks SJ, Montinaro F, Levy H, et al (2014) Static and moving frontiers: the genetic landscape of Southern African Bantu-speaking populations. Mol Biol Evol: msu263. doi:10.1093/molbev/msu263
Möller M, Nebel A, van Helden PD et al (2010) Analysis of eight genes modulating interferon gamma and human genetic susceptibility to tuberculosis: a case-control association study. BMC Infect Dis 10:154. doi:10.1186/1471-2334-10-154
Montinaro F, Busby GBJ, Gonzalez-Santos M et al (2017) Complex ancient genetic structure and cultural transitions in Southern African populations. Genetics 205:303–316. doi:10.1534/genetics.116.189209
Naidoo T, Schlebusch CM, Makkan H, et al (2010) Development of a single base extension method to resolve Y chromosome haplogroups in sub-Saharan African populations. Investig Genet 1:6. doi:10.1186/2041-2223-1-6
Patterson N, Petersen DC, van der Ross RE et al (2010) Genetic structure of a unique admixed population: implications for medical research. Hum Mol Genet 19:411–419. doi:10.1093/hmg/ddp505
Petersen DC, Libiger O, Tindall EA et al (2013) Complex patterns of genomic admixture within southern Africa. PLoS Genet 9:e1003309. doi:10.1371/journal.pgen.1003309
Pickrell JK, Patterson N, Barbieri C et al (2012) The genetic prehistory of southern Africa. Nat Commun 3:1143. doi:10.1038/ncomms2140
Pickrell JK, Patterson N, Loh P-R, et al (2014) Ancient west Eurasian ancestry in southern and eastern Africa. Proc Natl Acad Sci 111:2632–2637. doi:10.1073/pnas.1313787111
Picton ACP, Shalekoff S, Paximadis M, Tiemessen CT (2012) Marked differences in CCR5 expression and activation levels in two South African populations. Immunology 136:397–407. doi:10.1111/j.1365-2567.2012.03592.x
Pleurdeau D, Imalwa E, Détroit F et al (2012) “Of Sheep and Men”: earliest direct evidence of Caprine domestication in Southern Africa at Leopard Cave (Erongo, Namibia). PLoS One 7:e40340. doi:10.1371/journal.pone.0040340
Poznik GD, Henn BM, Yee M-C et al (2013) Sequencing Y chromosomes resolves discrepancy in time to common ancestor of males versus females. Science 341:562–565. doi:10.1126/science.1237619
Quintana-Murci L, Harmant C, Quach H et al (2010) Strong maternal Khoisan contribution to the South African coloured population: a case of gender-biased admixture. Am J Hum Genet 86:611–620. doi:10.1016/j.ajhg.2010.02.014
Ramsay M (2015) Growing genomic research on the African continent: the H3Africa Consortium. South Afr Med J Suid-Afr Tydskr Vir Geneeskd 105:1016–1017.
Ranciaro A, Campbell MC, Hirbo JB et al (2014) Genetic origins of lactase persistence and the spread of pastoralism in Africa. Am J Hum Genet 94:496–510. doi:10.1016/j.ajhg.2014.02.009
Rito T, Richards MB, Fernandes V, et al (2013) The first modern human dispersals across Africa. PLoS One 8:e80031. doi:10.1371/journal.pone.0080031
Rossouw M, Nel HJ, Cooke GS et al (2003) Association between tuberculosis and a polymorphic NFkappaB binding site in the interferon gamma gene. Lancet 361:1871–1872. doi:10.1016/S0140-6736(03)13491-5
Salie M (2014) The role of the major histocompatibility complex and the leukocyte receptor complex genes in susceptibility to tuberculosis in a South African population. University of Stellenbosch, Stellenbosch
Salie M, van der Merwe L, Möller M et al (2014) Associations between human leukocyte antigen class I variants and the Mycobacterium tuberculosis subtypes causing disease. J Infect Dis 209:216–223. doi:10.1093/infdis/jit443
Samson M, Libert F, Doranz BJ et al (1996) Resistance to HIV-1 infection in caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene. Nature 382:722–725. doi:10.1038/382722a0
Scheinfeldt LB, Soi S, Tishkoff SA (2010) In the light of evolution. National Academy of Sciences, Washington, DC
Schlebusch CM, Soodyall H (2012) Extensive population structure in San, Khoe, and mixed ancestry populations from southern Africa revealed by 44 short 5-SNP haplotypes. Hum Biol 84:695–724
Schlebusch CM, Naidoo T, Soodyall H (2009) SNaPshot minisequencing to resolve mitochondrial macro-haplogroups found in Africa. Electrophoresis 30:3657–3664. doi:10.1002/elps.200900197
Schlebusch CM, Skoglund P, Sjödin P et al (2012) Genomic variation in seven Khoe-San groups reveals adaptation and complex African history. Science 338:374–379. doi:10.1126/science.1227721
Schurz H, Daya M, Möller M, et al (2015) TLR1, 2, 4, 6 and 9 variants associated with tuberculosis susceptibility: a systematic review and meta-analysis. PLoS One 10:e0139711. doi:10.1371/journal.pone.0139711
Smith A (2014) The origins of Herding in Southern Africa: debating the “Neolithic” model. LAP LAMBERT Academic Publishing, Saarbrücken
Sobota RS, Stein CM, Kodaman N et al (2016) A Locus at 5q33.3 confers resistance to tuberculosis in highly susceptible individuals. Am J Hum Genet 98:514–524. doi:10.1016/j.ajhg.2016.01.015
Sun Q, Zhang Q, Xiao H, Bai C (2015) Toll-like receptor polymorphisms and tuberculosis susceptibility: a comprehensive meta-analysis. J Huazhong Univ Sci Technol Med Sci Hua Zhong Ke Ji Xue Xue Bao Yi Xue Ying Wen Ban Huazhong Keji Daxue Xuebao Yixue Yingdewen Ban 35:157–168. doi:10.1007/s11596-015-1405-6
Sveinbjornsson G, Gudbjartsson DF, Halldorsson BV et al (2016) HLA class II sequence variants influence tuberculosis risk in populations of European ancestry. Nat Genet 48:318–322. doi:10.1038/ng.3498
Tian C, Zhang Y, Zhang J et al (2011) The +874T/A polymorphism in the interferon-γ gene and tuberculosis risk: an update by meta-analysis. Hum Immunol 72:1137–1142. doi:10.1016/j.humimm.2011.07.310
Tishkoff SA, Gonder MK, Henn BM et al (2007a) History of click-speaking populations of Africa inferred from mtDNA and Y chromosome genetic variation. Mol Biol Evol 24:2180–2195. doi:10.1093/molbev/msm155
Tishkoff SA, Reed FA, Ranciaro A et al (2007b) Convergent adaptation of human lactase persistence in Africa and Europe. Nat Genet 39:31–40. doi:10.1038/ng1946
Tishkoff SA, Reed FA, Friedlaender FR et al (2009) The genetic structure and history of Africans and African Americans. Science 324:1035–1044. doi:10.1126/science.1172257
Uren C, Kim M, Martin AR et al (2016) Fine-scale human population structure in Southern Africa reflects ecogeographic boundaries. Genetics. doi:10.1534/genetics.116.187369
Veeramah KR, Wegmann D, Woerner A et al (2012) An early divergence of KhoeSan ancestors from those of other modern humans is supported by an ABC-based analysis of autosomal resequencing data. Mol Biol Evol 29:617–630. doi:10.1093/molbev/msr212
Walker EA (1928) A history of Southern Africa. Longmans, Green, Harlow
WHO (2016) Global tuberculosis report 2016. http://www.who.int/tb/publications/global_report/en/. Accessed 20 Dec 2016
Yi Y-X, Han J-B, Zhao L et al (2015) Tumor necrosis factor alpha gene polymorphism contributes to pulmonary tuberculosis susceptibility: evidence from a meta-analysis. Int J Clin Exp Med 8:20690–20700
Acknowledgements
Authors thank the National Research Foundation of South Africa for funding.
Author contributions
BMH and MM conceived the review topic. CU wrote the manuscript with review from MM, PvH, BMH, and EGH.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
Authors declare that no conflict of interest exists.
Ethical approval
This article does not contain any studies, performed by the authors, involving human or animal participants.
Additional information
Communicated by S. Hohmann.
Rights and permissions
About this article
Cite this article
Uren, C., Möller, M., van Helden, P.D. et al. Population structure and infectious disease risk in southern Africa. Mol Genet Genomics 292, 499–509 (2017). https://doi.org/10.1007/s00438-017-1296-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00438-017-1296-2