Human Genetics

, Volume 133, Issue 9, pp 1169–1185 | Cite as

The population genomic landscape of human genetic structure, admixture history and local adaptation in Peninsular Malaysia

  • Lian Deng
  • Boon Peng Hoh
  • Dongsheng Lu
  • Ruiqing Fu
  • Maude E. Phipps
  • Shilin Li
  • Ab Rajab Nur-Shafawati
  • Wan Isa Hatin
  • Endom Ismail
  • Siti Shuhada Mokhtar
  • Li Jin
  • Bin Alwi Zilfalil
  • Christian R. Marshall
  • Stephen W. Scherer
  • Fahd Al-Mulla
  • Shuhua XuEmail author
Original Investigation


Peninsular Malaysia is a strategic region which might have played an important role in the initial peopling and subsequent human migrations in Asia. However, the genetic diversity and history of human populations—especially indigenous populations—inhabiting this area remain poorly understood. Here, we conducted a genome-wide study using over 900,000 single nucleotide polymorphisms (SNPs) in four major Malaysian ethnic groups (MEGs; Malay, Proto-Malay, Senoi and Negrito), and made comparisons of 17 world-wide populations. Our data revealed that Peninsular Malaysia has greater genetic diversity corresponding to its role as a contact zone of both early and recent human migrations in Asia. However, each single Orang Asli (indigenous) group was less diverse with a smaller effective population size (N e) than a European or an East Asian population, indicating a substantial isolation of some duration for these groups. All four MEGs were genetically more similar to Asian populations than to other continental groups, and the divergence time between MEGs and East Asian populations (12,000—6,000 years ago) was also much shorter than that between East Asians and Europeans. Thus, Malaysian Orang Asli groups, despite their significantly different features, may share a common origin with the other Asian groups. Nevertheless, we identified traces of recent gene flow from non-Asians to MEGs. Finally, natural selection signatures were detected in a batch of genes associated with immune response, human height, skin pigmentation, hair and facial morphology and blood pressure in MEGs. Notable examples include SYN3 which is associated with human height in all Orang Asli groups, a height-related gene (PNPT1) and two blood pressure-related genes (CDH13 and PAX5) in Negritos. We conclude that a long isolation period, subsequent gene flow and local adaptations have jointly shaped the genetic architectures of MEGs, and this study provides insight into the peopling and human migration history in Southeast Asia.


Admixture Event Population Admixture Autosomal SNPs Malaysian Population Continental Group 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The authors would like to thank many of the group members for their helpful discussions and LetPub for its linguistic assistance during the preparation of this manuscript. We thank M. Seielstad for assistance in reviewing the manuscript and his comments. These studies were supported by the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB13040100), by the National Science Foundation of China (NSFC) grants (91331204 and 31171218). S.X. is Max-Planck Independent Research Group Leader and member of CAS Youth Innovation Promotion Association. S.X. also gratefully acknowledges the support of the National Program for Top-notch Young Innovative Talents of The “Ten-Thousand-Talents” Project and the support of K.C.Wong Education Foundation, Hong Kong. B.P.H., M.E.P. and the Malaysian investigators were supported by research grant Ministry of Science, Technology and Innovation (MOSTI) grant erBiotek Grant # 100-RM/BIOTEK 16/6/2 B (1/2011) and [100-RMI/GOV 16/6/2 (19/2011)]. B.A.Z also received funding from the following reserach grants: APEX Delivering Excellence 2012 (DE 2012) grant: (1002/PPSP/910343), USM short term grant: (304/PPSP/61311034) and MOSTI (ER-BIOTEK) grant: (304/PPSP/6150113/K105). S.W.S. was supported by the University of Toronto McLaughlin Centre and The Hospital for Sick Children Foundation. S.W.S. holds the GlaxoSmithKline-CIHR Chair in Genome Sciences at the University of Toronto and The Hospital for Sick Children. GSK has no influence on how research funding is allocated and spent. None of the funders had any role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Conflict of interest

The authors have declared that no competing interests exist.

Supplementary material

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  1. Adams B, Dörfler P, Aguzzi A et al (1992) Pax-5 encodes the transcription factor BSAP and is expressed in B lymphocytes, the developing CNS, and adult testis. Genes Dev 6:1589–1607PubMedCrossRefGoogle Scholar
  2. Andaya LY (2002) Orang Asli and the Melayu in the history of the Malay Peninsula. J Malayan Branch R Asiat Soc 75:23–48Google Scholar
  3. Ang KC, Leow JWH, Yeap WK et al (2011) Phylogenetic relationships of the Orang Asli and Iban of Malaysia based on maternal markers. Genet Mol Res 10:640–649PubMedCrossRefGoogle Scholar
  4. Ang KC, Ngu MS, Reid KP et al (2012) Skin color variation in Orang Asli tribes of Peninsular Malaysia. PLoS One 7:e42752PubMedCentralPubMedCrossRefGoogle Scholar
  5. Anney RJL, Lasky-su J, Colm Ó et al (2008) Conduct disorder and ADHD: evaluation of conduct problems as a categorical and quantitative trait in the international multicentre ADHD genetics study. Am J Med Genet B Neuropsychiatr Genet 147B:1369–1378PubMedGoogle Scholar
  6. Armitage SJ, Jasim SA, Marks AE et al (2011) The southern route “out of Africa”: evidence for an early expansion of modern humans into Arabia. Science 331:453–456PubMedCrossRefGoogle Scholar
  7. Balaresque PL, Ballereau SJ, Jobling MA (2007) Challenges in human genetic diversity: demographic history and adaptation. Hum Mol Genet 16:R134–R139PubMedCrossRefGoogle Scholar
  8. Benjamin G (1976) Austroasiatic subgroupings and prehistory in the Malay Peninsula. In: Jenner P, Thompson LC, Starosta S (eds) Austroasiatic Studies, University of Hawaii, Honolulu, pp 37–128Google Scholar
  9. Browning BL, Browning SR (2009) A unified approach to genotype imputation and haplotype-phase inference for large data sets of trios and unrelated individuals. Am J Hum Genet 84:210–223PubMedCentralPubMedCrossRefGoogle Scholar
  10. Chakraborty R, Weiss KM (1988) Admixture as a tool for finding linked genes and detecting that difference from allelic association between loci. Proc Natl Acad Sci USA 85:9119–9123 Google Scholar
  11. Clavano-Harding AB, Ambler GR, Cowell CT et al (1999) Initial characterization of the GH-IGF axis and nutritional status of the Ati Negritos of the Philippines. Clin Endocrinol (Oxf) 51:741–747Google Scholar
  12. Dávila N, Shea BT, Omoto K et al (2002) Growth hormone binding protein, insulin-like growth factor-I and short stature in two pygmy populations from the Philippines. J Pediatr Endocrinol Metab 15:269–276PubMedCrossRefGoogle Scholar
  13. Emelyanov AV, Kovac CR, Sepulveda MA, Birshtein BK (2002) The interaction of Pax5 (BSAP) with Daxx can result in transcriptional activation in B cells. J Biol Chem 277:11156–11164PubMedCrossRefGoogle Scholar
  14. Endicott P, Gilbert MTP, Stringer C et al (2003) The genetic origins of the Andaman islanders. Am J Hum Genet 72:178–184PubMedCentralPubMedCrossRefGoogle Scholar
  15. Evanno G, Regnaut S, Goudet J (2005) Detecting the number of clusters of individuals using the software STRUCTURE: a simulation study. Mol Ecol 14:2611–2620PubMedCrossRefGoogle Scholar
  16. Fix AG (1995) Malayan paleosociology: implications for patterns of genetic variation among the Orang Asli. Am Anthropol 97:313–323CrossRefGoogle Scholar
  17. Gautier M, Vitalis R (2012) rehh: an R package to detect footprints of selection in genome-wide SNP data from haplotype structure. Bioinformatics 28:1176–1177PubMedCrossRefGoogle Scholar
  18. Gronau I, Hubisz MJ, Gulko B et al (2011) Bayesian inference of ancient human demography from individual genome sequences. Nat Genet 43:1031–1034PubMedCentralPubMedCrossRefGoogle Scholar
  19. Hatin WI, Nur-shafawati AR, Zahri M et al (2011) Population genetic structure of Peninsular Malaysia Malay sub-ethnic groups. PLoS One 6:e18312Google Scholar
  20. Hirschman C (1975) Ethnic and social stratification in Peninsular Malaysia. American Sociological Association, Washington, DCGoogle Scholar
  21. Ivanov D, Philippova M, Tkachuk V et al (2004) Cell adhesion molecule T-cadherin regulates vascular cell adhesion, phenotype and motility. Exp Cell Res 293:207–218PubMedCrossRefGoogle Scholar
  22. Jarvis JP, Scheinfeldt LB, Soi S et al (2012) Patterns of ancestry, signatures of natural selection, and genetic association with stature in Western African pygmies. PLoS Genet 8:e1002641PubMedCentralPubMedCrossRefGoogle Scholar
  23. Jin W, Wang S, Wang H et al (2012) Exploring population admixture dynamics via empirical and simulated genome-wide distribution of ancestral chromosomal segments. Am J Hum Genet 91:1–14CrossRefGoogle Scholar
  24. Koboldt DC, Steinberg KM, Larson DE et al (2013) The next-generation sequencing revolution and its impact on genomics. Cell 155:27–38PubMedCrossRefGoogle Scholar
  25. Korn JM, Kuruvilla FG, McCarroll SA et al (2008) Integrated genotype calling and association analysis of SNPs, common copy number polymorphisms and rare CNVs. Nat Genet 40:1253–1260PubMedCentralPubMedCrossRefGoogle Scholar
  26. Lachance J, Vernot B, Elbers CC et al (2012) Evolutionary history and adaptation from high-coverage whole-genome sequences of diverse African hunter-gatherers. Cell 150:457–469Google Scholar
  27. Li JZ, Absher DM, Tang H et al (2008) Worldwide human relationships inferred from genome-wide patterns of variation. Science 319:1100–1104PubMedCrossRefGoogle Scholar
  28. Lim LS, Ang KC, Mahani MC et al (2010) Mitochondrial DNA polymorphism and phylogenetic relationships of Proto Malays in Peninsular Malaysia. J Biol Sci 10:71–83CrossRefGoogle Scholar
  29. Llaurado JG (1983) Cellular sodium transport and hypertension: a new hypothesis. West J Med 139:715–716PubMedCentralPubMedGoogle Scholar
  30. Loh P-R, Lipson M, Patterson N et al (2013) Inferring admixture histories of human populations using linkage disequilibrium. Genetics 193:1233–1254PubMedCentralPubMedCrossRefGoogle Scholar
  31. Lou H, Li S, Yang Y et al (2011) A map of copy number variations in Chinese populations. PLoS One 6:e27341PubMedCentralPubMedCrossRefGoogle Scholar
  32. Lu D, Xu S (2013) Principal component analysis reveals the 1000 Genomes Project does not sufficiently cover the human genetic diversity in Asia. Front Genet 4:1–9CrossRefGoogle Scholar
  33. Magalhães TR, Casey JP, Conroy J et al (2012) HGDP and HapMap analysis by Ancestry Mapper reveals local and global population relationships. PLoS One 7:e49438PubMedCentralPubMedCrossRefGoogle Scholar
  34. Mcevoy BP, Powell JE, Goddard ME, Visscher PM (2011) Human population dispersal “‘Out of Africa’” estimated from linkage disequilibrium and allele frequencies of SNPs. Genome Res 21:821–829PubMedCentralPubMedCrossRefGoogle Scholar
  35. Mendizabal I, Marigorta UM, Lao O, Comas D (2012) Adaptive evolution of loci covarying with the human African Pygmy phenotype. Hum Genet 131:1305–1317PubMedCentralPubMedCrossRefGoogle Scholar
  36. Migliano AB, Vinicius L, Mirazo M (2007) Life history trade-offs explain the evolution of human pygmies. Proc Natl Acad Sci USA 104:20216–20219PubMedCentralPubMedCrossRefGoogle Scholar
  37. Nei M (1987) Molecular evolutionary genetics. Columbia University, New YorkGoogle Scholar
  38. Ngamphiw C, Assawamakin A, Xu S et al (2011) PanSNPdb: the Pan-Asian SNP genotyping database. PLoS One 6:e21451PubMedCentralPubMedCrossRefGoogle Scholar
  39. Olivier M (2003) A haplotype map of the human genome. Physiol Genomics 13:3–9PubMedGoogle Scholar
  40. Perry GH, Dominy NJ (2009) Evolution of the human pygmy phenotype. Trends Ecol Evol 24:218–225PubMedCrossRefGoogle Scholar
  41. Pickrell JK, Pritchard JK (2012) Inference of population splits and mixtures from genome-wide allele frequency data. PLoS Genet 8:e1002967PubMedCentralPubMedCrossRefGoogle Scholar
  42. Price AL, Patterson NJ, Plenge RM et al (2006) Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet 38:904–909PubMedCrossRefGoogle Scholar
  43. Purcell S, Neale B, Todd-Brown K et al (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81:559–575PubMedCentralPubMedCrossRefGoogle Scholar
  44. Qian W, Deng L, Lu D, Xu S (2013) Genome-wide landscapes of human local adaptation in Asia. PLoS One 8:e54224PubMedCentralPubMedCrossRefGoogle Scholar
  45. Reich D, Thangaraj K, Patterson N et al (2009) Reconstructing Indian population history. Nature 461:489–494PubMedCentralPubMedCrossRefGoogle Scholar
  46. Reich D, Patterson N, Kircher M et al (2011) Denisova admixture and the first modern human dispersals into Southeast Asia and Oceania. Am J Hum Genet 89:516–528PubMedCentralPubMedCrossRefGoogle Scholar
  47. Sabeti PC, Varilly P, Fry B et al (2007) Genome-wide detection and characterization of positive selection in human populations. Nature 449:913–918PubMedCentralPubMedCrossRefGoogle Scholar
  48. Saw SH (1988) The population of Peninsular Malaysia. Singapore University, Singapore Google Scholar
  49. Shriver MD, Kennedy GC, Parra EJ et al (2004) The genomic distribution of population substructure in four populations using 8, 525 autosomal SNPs. Hum Genomics 1:274–286PubMedCentralPubMedCrossRefGoogle Scholar
  50. Sonuga-barke EJS, Lasky-su J, Neale BM, et al (2008) Does parental expressed emotion moderate genetic effects in ADHD ? An exploration using a genome wide association scan. Am J Med Genet B Neuropsychiatr Genet 147B:1359–1368Google Scholar
  51. Sulem P, Gudbjartsson DF, Stacey SN et al (2007) Genetic determinants of hair, eye and skin pigmentation in Europeans. Nat Genet 39:1443–1452PubMedCrossRefGoogle Scholar
  52. Tamura K, Peterson D, Peterson N et al (2011) MEGA5: molecular evolutionary genetics analysis using maximum likelihood, evolutionary distance, and maximum parsimony methods. Mol Biol Evol 28:2731–2739PubMedCentralPubMedCrossRefGoogle Scholar
  53. Thangaraj K, Singh L, Reddy AG et al (2003) Genetic affinities of the Andaman islanders, a vanishing human population. Curr Biol 13:86–93PubMedCrossRefGoogle Scholar
  54. Thangaraj K, Chaubey G, Kivisild T et al (2005) Reconstructing the origin of Andaman Islanders. Science 308:996PubMedCrossRefGoogle Scholar
  55. The 1000 Genomes Project Consortium (2011) A map of human genome variation from population scale sequencing. Nature 467:1061–1073Google Scholar
  56. The DASH-Sodium Collaborative Research Group (2001) Effects on blood pressure of reduced dietary sodium and the dietary approaches to stop hypertension (DASH) diet. N Engl J Med 344:3–10CrossRefGoogle Scholar
  57. The HUGO Pan-Asian SNP Consortium (2009) Mapping human genetic diversity in Asia. Science 326:1541–1545CrossRefGoogle Scholar
  58. The International HapMap Consortium (2005) A haplotype map of the human genome. Nature 437:1299–1320PubMedCentralCrossRefGoogle Scholar
  59. The International HapMap Consortium (2007) A second generation human haplotype map of over 3.1 million SNPs. Nature 449:851–861PubMedCentralCrossRefGoogle Scholar
  60. Weir BS, Hill WG (2002) Estimating F-statistics. Annu Rev Genet 36:721–750PubMedCrossRefGoogle Scholar
  61. Wong L-P, Ong RT-H, Poh W-T et al (2013) Deep whole-genome sequencing of 100 southeast Asian Malays. Am J Hum Genet 92:52–66PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Lian Deng
    • 1
  • Boon Peng Hoh
    • 2
  • Dongsheng Lu
    • 1
  • Ruiqing Fu
    • 1
  • Maude E. Phipps
    • 3
  • Shilin Li
    • 4
  • Ab Rajab Nur-Shafawati
    • 5
  • Wan Isa Hatin
    • 5
  • Endom Ismail
    • 6
  • Siti Shuhada Mokhtar
    • 2
  • Li Jin
    • 4
  • Bin Alwi Zilfalil
    • 7
  • Christian R. Marshall
    • 8
  • Stephen W. Scherer
    • 8
    • 9
  • Fahd Al-Mulla
    • 10
  • Shuhua Xu
    • 1
    Email author
  1. 1.Max Planck Independent Research Group on Population Genomics, Chinese Academy of Sciences and Max Planck Society (CAS-MPG) Partner Institute for Computational Biology (PICB), Shanghai Institutes for Biological SciencesChinese Academy of SciencesShanghaiChina
  2. 2.Faculty of Medicine, Institute of Medical Molecular Biotechnology, Jalan HospitalUniversiti Teknologi MARASungai BulohMalaysia
  3. 3.Jeffrey Cheah School of Medicine and Health SciencesMonash University MalaysiaSelangorMalaysia
  4. 4.Ministry of Education (MOE) Key Laboratory of Contemporary Anthropology, School of Life Sciences and Institutes of Biomedical SciencesFudan UniversityShanghaiChina
  5. 5.Human Genome Center, School of Medical SciencesUniversiti Sains MalaysiaKelantanMalaysia
  6. 6.Faculty of Science and Technology, School of Biosciences and BiotechnologyUniversiti Kebangsaan MalaysiaBangiMalaysia
  7. 7.Department of Pediatrics, School of Medical SciencesUniversiti Sains MalaysiaKelantanMalaysia
  8. 8.The Centre for Applied GenomicsThe Hospital for Sick ChildrenTorontoCanada
  9. 9.McLaughlin Centre and Department of Molecular GeneticsUniversity of TorontoTorontoCanada
  10. 10.Department of Pathology, Faculty of MedicineKuwait UniversitySafatKuwait

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