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The promise of discovering population-specific disease-associated genes in South Asia


The more than 1.5 billion people who live in South Asia are correctly viewed not as a single large population but as many small endogamous groups. We assembled genome-wide data from over 2,800 individuals from over 260 distinct South Asian groups. We identified 81 unique groups, 14 of which had estimated census sizes of more than 1 million, that descend from founder events more extreme than those in Ashkenazi Jews and Finns, both of which have high rates of recessive disease due to founder events. We identified multiple examples of recessive diseases in South Asia that are the result of such founder events. This study highlights an underappreciated opportunity for decreasing disease burden among South Asians through discovery of and testing for recessive disease-associated genes.

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Figure 1: Data set overview.
Figure 2: Example histograms of IBD segments, illustrating the differences between groups with founder events of different magnitudes.
Figure 3: IBD scores relative to Finns (FIN).

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  1. Mastana, S.S. Unity in diversity: an overview of the genomic anthropology of India. Ann. Hum. Biol. 41, 287–299 (2014).

    Article  PubMed  Google Scholar 

  2. Bamshad, M.J. et al. Female gene flow stratifies Hindu castes. Nature 395, 651–652 (1998).

    Article  CAS  PubMed  Google Scholar 

  3. Basu, A. et al. Ethnic India: a genomic view, with special reference to peopling and structure. Genome Res. 13, 2277–2290 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Reich, D., Thangaraj, K., Patterson, N., Price, A.L. & Singh, L. Reconstructing Indian population history. Nature 461, 489–494 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Lim, E.T. et al. Distribution and medical impact of loss-of-function variants in the Finnish founder population. PLoS Genet. 10, e1004494 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  6. Arcos-Burgos, M. & Muenke, M. Genetics of population isolates. Clin. Genet. 61, 233–247 (2002).

    Article  CAS  PubMed  Google Scholar 

  7. Patterson, N. et al. Ancient admixture in human history. Genetics 192, 1065–1093 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  8. Moorjani, P. et al. Genetic evidence for recent population mixture in India. Am. J. Hum. Genet. 93, 422–438 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Metspalu, M. et al. Shared and unique components of human population structure and genome-wide signals of positive selection in South Asia. Am. J. Hum. Genet. 89, 731–744 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Behar, D.M. et al. The genome-wide structure of the Jewish people. Nature 466, 238–242 (2010).

    Article  CAS  PubMed  Google Scholar 

  11. Basu, A., Sarkar-Roy, N. & Majumder, P.P. Genomic reconstruction of the history of extant populations of India reveals five distinct ancestral components and a complex structure. Proc. Natl. Acad. Sci. USA 113, 1594–1599 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. 1000 Genomes Project Consortium et al. A global reference for human genetic variation. Nature 526, 68–74 (2015).

  13. Manoharan, I., Wieseler, S., Layer, P.G., Lockridge, O. & Boopathy, R. Naturally occurring mutation Leu307Pro of human butyrylcholinesterase in the Vysya community of India. Pharmacogenet. Genomics 16, 461–468 (2006).

    CAS  PubMed  Google Scholar 

  14. Shukla, A. et al. Homozygous p.(Glu87Lys) variant in ISCA1 is associated with a new multiple mitochondrial dysfunctions syndrome. J. Hum. Genet. 62, 723–727 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Dalal, A. et al. Analysis of the WISP3 gene in Indian families with progressive pseudorheumatoid dysplasia. Am. J. Med. Genet. A. 158A, 2820–2828 (2012).

    Article  PubMed  Google Scholar 

  16. Bhavani, G.S. et al. Novel and recurrent mutations in WISP3 and an atypical phenotype. Am. J. Med. Genet. A. 167A, 2481–2484 (2015).

    Article  PubMed  Google Scholar 

  17. Raz, A.E. Can population-based carrier screening be left to the community? J. Genet. Couns. 18, 114–118 (2009).

    Article  PubMed  Google Scholar 

  18. Rajasimha, H.K. et al. Organization for rare diseases India (ORDI): addressing the challenges and opportunities for the Indian rare diseases' community. Genet. Res. (Camb.) 96, e009 (2014).

    Article  Google Scholar 

  19. Sudmant, P.H. et al. Global diversity, population stratification, and selection of human copy-number variation. Science 349, aab3761 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  20. Mallick, S. et al. The Simons Genome Diversity Project: 300 genomes from 142 diverse populations. Nature 538, 201–206 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Sudmant, P.H. et al. An integrated map of structural variation in 2,504 human genomes. Nature 526, 75–81 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Patterson, N., Price, A.L. & Reich, D. Population structure and eigenanalysis. PLoS Genet. 2, e190 (2006).

    PubMed  PubMed Central  Google Scholar 

  23. Chang, C.C. et al. Second-generation PLINK: rising to the challenge of larger and richer datasets. Gigascience 4, 7 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  24. Gusev, A. et al. Whole population, genome-wide mapping of hidden relatedness. Genome Res. 19, 318–326 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Hoaglin, D.C. & Iglewicz, B. How to Detect and Handle Outliers (ASQC Quality Press, 1993).

  26. Palamara, P.F. ARGON: fast, whole-genome simulation of the discrete time Wright-fisher process. Bioinformatics 32, 3032–3034 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Browning, S.R. & Browning, B.L. Rapid and accurate haplotype phasing and missing-data inference for whole-genome association studies by use of localized haplotype clustering. Am. J. Hum. Genet. 81, 1084–1097 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Durand, E.Y., Eriksson, N. & McLean, C.Y. Reducing pervasive false-positive identical-by-descent segments detected by large-scale pedigree analysis. Mol. Biol. Evol. 31, 2212–2222 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Browning, B.L. & Browning, S.R. Improving the accuracy and efficiency of identity-by-descent detection in population data. Genetics 194, 459–471 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  30. Bidchol, A.M. et al. GALNS mutations in Indian patients with mucopolysaccharidosis IVA. Am. J. Med. Genet. A. 164A, 2793–2801 (2014).

    Article  PubMed  Google Scholar 

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We are thankful to the many Indian, Pakistani, Bangladeshi, Sri Lankan, and Nepalese individuals who contributed the DNA samples analyzed here, including the patients with PPD and MPS IVA. We are grateful to A. Basu and P. P. Majumder (National Institute of Biomedical Genomics, Kalyani, India) for early sharing of data. Funding was provided by an NIGMS (GM007753) fellowship to N.N.; a Translational Seed Fund grant from the Dean's Office of Harvard Medical School, and grant HG006399 to D.R.; a Council of Scientific and Industrial Research, Government of India grant to K.T.; support from TIFAC-CORE to S.A.V. and K.S.; and NIGMS grant 115006 to P.M. The study of MPS IVA patients was funded by grants from the Department of Biotechnology, Government of India (BT/PR4224/MED/97/60/2011 to S.S. and S.M.J.) and the Department of Science and Technology, Government of India (SR/WOS-A/LS-83/2011 to S.S.). Funding for the mutation analysis of Indian patients with PPD was provided by the Indian Council of Medical Research (BMS 54/2/2013) to K.M.G. D.R. is supported as an Investigator of the Howard Hughes Medical Institute.

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Authors and Affiliations



N.N., P.M., D.R., and K.T. conceived the study. N.N., P.M., N.R., B.S., A.T., N.P., and D.R. performed analysis. G.S.B., K.M.G., M.S.M., S.S., A.K., S.A.V., S.M.J., K.S., L.S., and K.T. collected data. N.N., D.R., and K.T. wrote the manuscript with the help of all coauthors.

Corresponding authors

Correspondence to David Reich or Kumarasamy Thangaraj.

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The authors declare no competing financial interests.

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Supplementary Text and Figures

Supplementary Figures 1–6, Supplementary Tables 1–4 and 6, and Supplementary Note. (PDF 8052 kb)

Supplementary Table 5

IBD, FST, and group-specific drift analyses. (XLSX 114 kb)

Life Sciences Reporting Summary (PDF 134 kb)

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Nakatsuka, N., Moorjani, P., Rai, N. et al. The promise of discovering population-specific disease-associated genes in South Asia. Nat Genet 49, 1403–1407 (2017).

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