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Convergent Evolution in European and Rroma Populations Reveals Pressure Exerted by Plague on Toll-Like Receptors

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Convergent Evolution in European and Rroma Populations Reveals Pressure Exerted by Plague on Toll-Like Receptors Convergent evolution in European and Rroma populations reveals pressure exerted by plague on Toll-like receptors Hafid Laayounia,1, Marije Oostingb,c,1, Pierre Luisia, Mihai Ioanab,d, Santos Alonsoe, Isis Ricaño-Poncef, Gosia Trynkaf,2, Alexandra Zhernakovaf, Theo S. Plantingab,c, Shih-Chin Chengb,c, Jos W. M. van der Meerb,c, Radu Poppg, Ajit Soodh, B. K. Thelmai, Cisca Wijmengaf, Leo A. B. Joostenb,c, Jaume Bertranpetita,3, and Mihai G. Neteab,c,3,4 aInstitut de Biologia Evolutiva (Consejo Superior de Investigaciones Cientificas–Universitat Pompeu Fabra), Universitat Pompeu Fabra, 08003 Barcelona, Spain; bDepartment of Medicine and cNijmegen Institute for Infection, Inflammation and Immunity, Radboud University Nijmegen Medical Centre, 6525 GA, Nijmegen, The Netherlands; dUniversity of Medicine and Pharmacy Craiova, 200349 Craiova, Romania; eDepartment of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country, Barrio Sarriena s/n, 48940 Leioa, Spain; fDepartment of Genetics, University of Groningen/University Medical Center Groningen, 9700 RB, Groningen, The Netherlands; gDepartment of Medical Genetics, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400023 Cluj-Napoca, Romania; hDepartment of Gasteroenterology, Dayanand Medical College and Hospital, Ludhiana, Punjab 141001, India; and iDepartment of Genetics, University of Delhi South Campus, New Delhi 110 021, India Edited* by Charles A. Dinarello, University of Colorado Denver, Aurora, CO, and approved January 2, 2014 (received for review September 19, 2013) Recent historical periods in Europe have been characterized by infection in modern Europeans compared with Africans (6). All severe epidemic events such as plague, smallpox, or influenza that these studies have investigated candidate genes selected on the shaped the immune system of modern populations. This study basis of biological assumptions, but comprehensive genome-wide aims to identify signals of convergent evolution of the immune approaches to identify the immune pathways under evolutionary system, based on the peculiar demographic history in which two pressure by infections are missing. In this study, we make use of the opportunity that a special populations with different genetic ancestry, Europeans and Rroma — (Gypsies), have lived in the same geographic area and have been historical demographic situation is present in Europe that is, an- cient European populations living together with Rroma in the same exposed to similar environments, including infections, during the IMMUNOLOGY geographic locations. Rroma (traditionally called Gypsies) are a last millennium. We identified several genes under evolutionary population from Northwest India that has migrated in Europe one pressure in European/Romanian and Rroma/Gipsy populations, millennium ago (7). We hypothesized that despite their different but not in a Northwest Indian population, the geographic origin of ethnic and genetic backgrounds, the strong infectious pressure the Rroma. Genes in the immune system were highly represented exerted by the major epidemics of the last millennium (of which among those under strong evolutionary pressures in Europeans, epidemics of plague are probably the most significant) has led and infections are likely to have played an important role. For to convergent evolution: specific immune genes, selected during example, Toll-like receptor 1 (TLR1)/TLR6/TLR10 gene cluster showed these European epidemics, become signatures that differ from a strong signal of adaptive selection. Their gene products are func- Yersinia pestis tional receptors for , the agent of plague, as shown Significance by overexpression studies showing induction of proinflammatory cytokines such as TNF, IL-1β, and IL-6 as one possible infection that This article gives a unique perspective on the impact of evo- may have exerted evolutionary pressures. Immunogenetic analysis lution on the immune system under pressure by infections, showed that TLR1, TLR6, and TLR10 single-nucleotide polymor- using the special demographic history of Europe in which two phisms modulate Y. pestis–induced cytokine responses. Other populations with different genetic ancestry, Europeans and infections may also have played an important role. Thus, recon- Rroma (Gypsies), have lived in the same geographic area and struction of evolutionary history of European populations has have been exposed to similar environmental hazards, including identified several immune pathways, among them TLR1/TLR6/TLR10, infections. We identified convergent evolution signals in genes as being shaped by convergent evolution in two human popula- from different human populations. Reconstruction of evolu- tions with different origins under the same infectious environment. tionary history of European populations has identified Toll-like receptor 1 (TLR1)/TLR6/TLR10 as a pattern recognition pathway immunity | pattern recognition receptors | pandemics | migration shaped by convergent evolution by infections, among which plague is a likely cause, influencing the survival of these pop- y recognition and elimination of pathogenic microorganisms ulations during the infection. Bduring infection, the immune system has allowed mankind to survive. Genetic variation in the immune system is a major factor Author contributions: H.L., J.W.M.v.d.M., A.S., B.K.T., C.W., L.A.B.J., J.B., and M.G.N. de- influencing susceptibility to infections. Subsequently, genes of signed research; H.L., M.O., P.L., M.I., S.A., I.R.-P., G.T., A.Z., T.S.P., S.-C.C., R.P., A.S., and the immune system are under constant evolutionary pressure (1), L.A.B.J. performed research; M.O., P.L., M.I., S.A., I.R.-P., G.T., A.Z., T.S.P., S.-C.C., and R.P. contributed new reagents/analytic tools; H.L., M.O., P.L., M.I., S.A., I.R.-P., G.T., A.Z., T.S.P., and this pressure can change based on local conditions and mi- S.-C.C., R.P., and M.G.N. analyzed data; and H.L., M.O., M.I., S.A., J.W.M.v.d.M., A.S., B.K.T., gration routes of human populations (2). C.W., L.A.B.J., J.B., and M.G.N. wrote the paper. In time, changes induced in the immune system by infectious The authors declare no conflict of interest. pressures can shape not only the host defense and susceptibility *This Direct Submission article had a prearranged editor. to infections but also susceptibility to autoimmune or inflammatory 1H.L. and M.O. contributed equally to this work. diseases of modern human populations (2), with balancing se- 2Present address: Division of Genetics, Department of Medicine, Brigham and Women’s lection proposed as a main force shaping the innate immunity Hospital, Harvard Medical School, Boston, MA 02115; and Program in Medical and Pop- reaction (3). It has been suggested that a predominantly proin- ulation Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, flammatory profile in the immune system, induced by infections, Cambridge, MA 02142. predisposes modern human populations to autoimmune diseases 3J.B. and M.G.N. share senior authorship. (4, 5), whereas selection of certain genetic variants during epi- 4To whom correspondence should be addressed. E-mail: [email protected]. CCR5 demics [e.g., selection of C-C chemokine receptor type 5 ( ) This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. variants presumably by plague] reduces susceptibility to HIV 1073/pnas.1317723111/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1317723111 PNAS Early Edition | 1of6 Downloaded by guest on September 27, 2021 those found in the Northwest Indian populations from whom the (PCA) implemented in eigensoft program (9) and plotted using Rroma have derived (7). These signatures would enable us to multidimensional scaling (Fig. 1B). Individuals showing admix- detect recent adaptations and could lead to the understanding of ture ancestry or false allocation were excluded from further susceptibility to infections (and other immune-mediated diseases) analysis. A plot of the first versus the second eigenvectors (Fig. in modern European populations. 1B) shows a clear differentiation of the Rroma cluster of indi- viduals from the Romanian and the Indian populations. How- Results ever, Rroma are very close to Indians across eigenvector 1, in Populations. The population of Romania is comprised mainly of agreement with their evolutionary history. This indicates these Indo-European populations, among which Romanian speakers population labels have a genetic basis and are not merely so- represent 88% of the population, whereas 3.2% of inhabitants cial constructs. are of Rroma ethnic background (www.recensamantromania.ro). After ethical approval by the Ethics Committee of the University Evolutionary Analysis Identifies Innate Immune Pathways and TLR1/ of Craiova, Romania, informed consent was obtained for all TLR6/TLR10 Among Genes Under Common Selection Pressure in volunteers and DNA samples were collected from individuals Europeans/Romanians and Rroma. To identify signals of positive of European/Romanian or Rroma ethnic background. A popu- selection shared between Europeans and Rroma but not present lation of individuals of Northwestern Indian descent, represent- in the Indian population, we looked for shared signals of im- ing the geographic origin of the Rroma group (Fig. 1A), was also portant genetic differentiation between these two populations with the Indian population, accompanied by the absence of recruited. genetic differentiation between them. Two tests were used: (i) We assayed
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