Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

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

Nature Genetics volume 49, pages 1403–1407 (2017)Cite this article

Subjects

Abstract

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

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).

Similar content being viewed by others

References

  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 

Download references

Acknowledgements

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.

Author information

Author notes

  1. Niraj Rai

    Present address: Birbal Sahni Institute of Palaeosciences, Lucknow, India

  2. David Reich and Kumarasamy Thangaraj: These authors jointly directed this work.

Authors and Affiliations

  1. Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA

    Nathan Nakatsuka, Arti Tandon & David Reich

  2. Harvard-MIT Division of Health Sciences and Technology, Harvard Medical School, Boston, Massachusetts, USA

    Nathan Nakatsuka

  3. Department of Biological Sciences, Columbia University, New York, New York, USA

    Priya Moorjani

  4. Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA

    Priya Moorjani, Arti Tandon, Nick Patterson & David Reich

  5. CSIR-Centre for Cellular and Molecular Biology, Hyderabad, India

    Niraj Rai & Kumarasamy Thangaraj

  6. Anthropological Survey of India, Kolkata, India

    Biswanath Sarkar

  7. Department of Medical Genetics, Kasturba Medical College, Manipal University, Manipal, India

    Gandham SriLakshmi Bhavani & Katta Mohan Girisha

  8. Department of Applied Zoology, Mangalore University, Mangalore, India

    Mohammed S Mustak

  9. Centre for Human Genetics, Bangalore, India

    Sudha Srinivasan

  10. Amity Institute of Biotechnology, Amity University, Noida, India

    Amit Kaushik

  11. School of Life Sciences, Manipal University, Manipal, India

    Saadi Abdul Vahab & Kapaettu Satyamoorthy

  12. Fetal Care Research Foundation, Chennai, India

    Sujatha M Jagadeesh

  13. Genome Foundation, Hyderabad, India

    Lalji Singh

  14. Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts, USA

    David Reich

Authors
  1. Nathan Nakatsuka
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Priya Moorjani
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Niraj Rai
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Biswanath Sarkar
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Arti Tandon
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Nick Patterson
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Gandham SriLakshmi Bhavani
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Katta Mohan Girisha
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Mohammed S Mustak
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Sudha Srinivasan
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Amit Kaushik
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Saadi Abdul Vahab
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Sujatha M Jagadeesh
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Kapaettu Satyamoorthy
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Lalji Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. David Reich
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Kumarasamy Thangaraj
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

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.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

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)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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). https://doi.org/10.1038/ng.3917

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.3917

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing