Human Genetics

, Volume 137, Issue 2, pp 161–173 | Cite as

Genomic structure of the native inhabitants of Peninsular Malaysia and North Borneo suggests complex human population history in Southeast Asia

  • Chee-Wei Yew
  • Dongsheng Lu
  • Lian Deng
  • Lai-Ping Wong
  • Rick Twee-Hee Ong
  • Yan Lu
  • Xiaoji Wang
  • Yunus Yushimah 
  • Farhang Aghakhanian
  • Mokhtar Siti Shuhada 
  • Hoque Mohammad Zahirul 
  • Christopher Lok-Yung Voo
  • Thuhairah Abdul Rahman
  • Jong Bhak
  • Maude E. Phipps
  • Shuhua Xu
  • Yik-Ying Teo
  • Subbiah Vijay Kumar
  • Boon-Peng Hoh
Original Investigation


Southeast Asia (SEA) is enriched with a complex history of peopling. Malaysia, which is located at the crossroads of SEA, has been recognized as one of the hubs for early human migration. To unravel the genomic complexity of the native inhabitants of Malaysia, we sequenced 12 samples from 3 indigenous populations from Peninsular Malaysia and 4 native populations from North Borneo to a high coverage of 28–37×. We showed that the Negritos from Peninsular Malaysia shared a common ancestor with the East Asians, but exhibited some level of gene flow from South Asia, while the North Borneo populations exhibited closer genetic affinity towards East Asians than the Malays. The analysis of time of divergence suggested that ancestors of Negrito were the earliest settlers in the Malay Peninsula, whom first separated from the Papuans ~ 50–33 thousand years ago (kya), followed by East Asian (~ 40–15 kya), while the divergence time frame between North Borneo and East Asia populations predates the Austronesian expansion period implies a possible pre-Neolithic colonization. Substantial Neanderthal ancestry was confirmed in our genomes, as was observed in other East Asians. However, no significant difference was observed, in terms of the proportion of Denisovan gene flow into these native inhabitants from Malaysia. Judging from the similar amount of introgression in the Southeast Asians and East Asians, our findings suggest that the Denisovan gene flow may have occurred before the divergence of these populations and that the shared similarities are likely an ancestral component.



This study is funded by Ministry of Science, Technology and Innovation (MOSTI) erBiotek Grant # 100-RM/BIOTEK 16/6/2 B (1/2011) and [100-RMI/GOV 16/6/2 (19/2011] awarded to HBP, VK, and MEP for supporting the experimental work. HBP received the FRGS/1/2015/ST03/UCSI/01/1 for supporting the data analysis. MEP and FA acknowledge human genomics grant from Tropical Medicine and Biology platform, Monash University Malaysia. We thank all the indigenous participants, JAKOA, and the Sabah state authorities for their full cooperation and assistance during the various field trips, the medical team from Faculty of Medicine Universiti Teknologi MARA, for their involvement during sample collection, and all staffs who assisted. L.P.W., R.T.H.O., and Y.Y.T. acknowledge support by the National Research Foundation, Prime Minister’s Office, Singapore under its Research Fellowship (NRF-RF-2010-05) and administered by the National University of Singapore. S.X. is Max–Planck Independent Research Group Leader and member of CAS Youth Innovation Promotion Association. S.X. gratefully acknowledges support by the National Natural Science Foundation of China (NSFC) Grants (91331204, 31525014, 91731303, 31771388, 31501011, and 31711530221), the Chinese Academy of Sciences (CAS) (XDB13040100 and QYZDJ-SSW-SYS009), and the Program of Shanghai Academic Research Leader (16XD1404700). JB was supported by the Industrial Strategic technology development program, 10040231, “Bioinformatics platform development for the next generation bioinformation analysis” funded by the Ministry of Knowledge Economy (MKE, Korea)” and 2014 Research Fund (1.150014.01) of UNIST (Ulsan National Institute of Science & Technology).

Compliance with ethical standards

Conflict of interest

The authors declare that there is no conflict of interest.

Supplementary material

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  1. Aghakhanian F, Yunus Y, Naidu R et al (2015) Unravelling the genetic history of Negritos and Indigenous populations of Southeast Asia. Genome Biol Evol 7:1206–1215CrossRefPubMedPubMedCentralGoogle Scholar
  2. Alexander DH, Novembre J, Lange K (2009) Fast model-based estimation of ancestry in unrelated individuals. Genome Res 19:1655–1664CrossRefPubMedPubMedCentralGoogle Scholar
  3. 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 90:675–684CrossRefPubMedPubMedCentralGoogle Scholar
  4. Bellwood P (2007) Prehistory of the Indo-Malaysian archipelago, 4th edn. ANU E Press, CanberraCrossRefGoogle Scholar
  5. Bustamante CD, Burchard EG, De la Vega FM (2011) Genomics for the world. Nature 475:163–165CrossRefPubMedPubMedCentralGoogle Scholar
  6. Conrad DF, Keebler JEM, DePristo MA et al (2011) Variation in genome-wide mutation rates within and between human families. Nat Genet 43:712–714CrossRefPubMedPubMedCentralGoogle Scholar
  7. Curnoe D, Datan I, Taçon PSC et al (2016) Deep Skull from Niah Cave and the Pleistocene Peopling of Southeast Asia. Front Ecol Evol. Google Scholar
  8. Delaneau O, Marchini J, Zagury J (2012) A linear complexity phasing method for thousands of genomes. 9:179–181Google Scholar
  9. Deng L, Hoh BP, Lu D et al (2014) The population genomic landscape of human genetic structure, admixture history and local adaptation in Peninsular Malaysia. Hum Genet 133:1169–1185CrossRefPubMedGoogle Scholar
  10. Deng L, Hoh B-P, Lu D et al (2015) Dissecting the genetic structure and admixture of four geographical Malay populations. Sci Rep 5:14375. CrossRefPubMedPubMedCentralGoogle Scholar
  11. Fan S, Hansen MEB, Lo Y, Tishkoff SA (2016) Going global by adapting local: a review of recent human adaptation. Science 354:54–59CrossRefPubMedPubMedCentralGoogle Scholar
  12. Fucharoen G, Fucharoen S, Horai S (2001) Mitochondrial DNA polymorphisms in Thailand. J Hum Genet 46:115–125CrossRefPubMedGoogle Scholar
  13. Fumagalli M, Moltke I, Grarup N et al (2015) Greenlandic Inuit show genetic signatures of diet and climate adaptation. Science 349:1343–1347CrossRefPubMedGoogle Scholar
  14. Gray RD, Drummond AJ, Greenhill SJ (2009) Language phylogenies reveal expansion pulses and pauses in Pacific settlement. Science 323(5913):479–483CrossRefPubMedGoogle Scholar
  15. Green RE, Krause J, Briggs AW et al (2010) A draft sequence of the Neandertal genome. Science 328:710–722CrossRefPubMedPubMedCentralGoogle Scholar
  16. Hanebuth T, Stattegger K, Grootes PM (2000) Rapid flooding of the Sunda Shelf: a late-Glacial Sea-level record 288:1033–1035Google Scholar
  17. Hill C, Soares P, Mormina M et al (2006) Phylogeography and ethnogenesis of aboriginal Southeast Asians. Mol Biol Evol 23:2480–2491CrossRefPubMedGoogle Scholar
  18. Hill C, Soares P, Mormina M et al (2007) A mitochondrial stratigraphy for island southeast Asia. Am J Hum Genet 80:29–43CrossRefPubMedGoogle Scholar
  19. Jinam TA, Hong L, Phipps ME et al (2012) Evolutionary history of continental Southeast Asians: “Early Train” hypothesis based on genetic analysis of mitochondrial and autosomal DNA data. Mol Biol Evol 29:3513–3527CrossRefPubMedGoogle Scholar
  20. Jinam TA, Phipps ME, Aghakhanian F et al (2017) Discerning the origins of the Negritos, First Sundaland People: deep divergence and archaic admixture. Genome Biol Evol 9:2013–2022. CrossRefPubMedPubMedCentralGoogle Scholar
  21. Kloss-brandstätter A, Binna R, Weissensteiner H et al (2011) HaploGrep : a fast and reliable algorithm for automatic classification of mitochondrial DNA haplogroups. Hum Mutat 32(1):25–32CrossRefPubMedGoogle Scholar
  22. Li H, Durbin R (2011) Inference of human population history from individual whole-genome sequences. Nature 475:493–496CrossRefPubMedPubMedCentralGoogle Scholar
  23. Lipson M, Loh P-R, Patterson N et al (2014) Reconstructing Austronesian population history in Island Southeast Asia. Nat Commun 5:4689. CrossRefPubMedPubMedCentralGoogle Scholar
  24. Liu X, Yunus Y, Lu D et al (2015) Differential positive selection of malaria resistance genes in three indigenous populations of Peninsular Malaysia. Hum Genet 134:375–392CrossRefPubMedGoogle Scholar
  25. 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
  26. Lu D, Lou H, Yuan K et al (2016) Ancestral origins and genetic history of Tibetan highlanders. Am J Hum Genet 99:580–594CrossRefPubMedPubMedCentralGoogle Scholar
  27. Macaulay V, Hill C, Achilli A et al (2005) Single, rapid coastal settlement of Asia revealed by analysis of complete mitochondrial genomes. Science 308:1034–1036CrossRefPubMedGoogle Scholar
  28. Malaspinas A-S, Westaway MC, Muller C et al (2016) A genomic history of Aboriginal Australia. Nature 538:207–214CrossRefPubMedGoogle Scholar
  29. Mallick S, Li H, Lipson M et al (2016) The Simons Genome Diversity Project: 300 genomes from 142 diverse populations. Nature 538:201–206CrossRefPubMedPubMedCentralGoogle Scholar
  30. Matsumura H, Oxenham MF (2014) Demographic transitions and migration in prehistoric East/Southeast Asia through the lens of nonmetric dental traits. Am J Phys Anthropol 155:45–65CrossRefPubMedGoogle Scholar
  31. McEvoy BP, Bradley D (2010) Irish genetics and celts. In: Cunliffe B, Koch JT (eds) Celtic from the West. Oxbow Books, OxfordGoogle Scholar
  32. 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 21:821–829CrossRefPubMedPubMedCentralGoogle Scholar
  33. McKenna A, Hanna M, Banks E et al (2010) The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res 20:1297–1303CrossRefPubMedPubMedCentralGoogle Scholar
  34. Mendez FL, Watkins JC, Hammer MF (2012) A haplotype at STAT2 introgressed from neanderthals and serves as a candidate of positive selection in Papua New Guinea. Am J Hum Genet 91:265–274CrossRefPubMedPubMedCentralGoogle Scholar
  35. Meyer M, Kircher M, Gansauge M-T et al (2012) A high-coverage genome sequence from an archaic Denisovan individual. Science 338:224–226Google Scholar
  36. Mondal M, Casals F, Xu T et al (2016) Genomic analysis of Andamanese provides insights into ancient human migration into Asia and adaptation. Nat Genet. PubMedGoogle Scholar
  37. Mörseburg A, Pagani L, Ricaut F-X et al (2016) Multi-layered population structure in Island Southeast Asians. Eur J Hum Genet. PubMedPubMedCentralGoogle Scholar
  38. Pagani L, Lawson DJ, Jagoda E et al (2016) Genomic analyses inform on migration events during the peopling of Eurasia. Nature 538:238–242CrossRefPubMedPubMedCentralGoogle Scholar
  39. Peng MS, Quang HH, Dang KP et al (2010) Tracing the Austronesian footprint in Mainland Southeast Asia: a perspective from mitochondrial DNA. Mol Biol Evol 27:2417–2430CrossRefPubMedGoogle Scholar
  40. Perdomo-Sabogal A, Kanton S, Walter MBC, Nowick K (2014) The role of gene regulatory factors in the evolutionary history of humans. Curr Opin Genet Dev 29C:60–67CrossRefGoogle Scholar
  41. Pickrell JK, Pritchard JK (2012) Inference of population splits and mixtures from genome-wide allele frequency data. PLoS Genet. Google Scholar
  42. Price AL, Patterson NJ, Plenge RM et al (2006) Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet 38:904–909CrossRefPubMedGoogle Scholar
  43. Prüfer K, Racimo F, Patterson N et al (2014) The complete genome sequence of a Neanderthal from the Altai Mountains. Nature 505:43–49CrossRefPubMedGoogle Scholar
  44. Pugach I, Delfin F, Gunnarsdóttir E et al (2013) Genome-wide data substantiate Holocene gene flow from India to Australia. Proc Natl Acad Sci 110:1803–1808CrossRefPubMedPubMedCentralGoogle Scholar
  45. Qin P, Stoneking M (2015) Denisovan ancestry in East Eurasian and Native American populations. Mol Biol Evol 32:2665–2674CrossRefPubMedGoogle Scholar
  46. Racimo F (2016) Testing for ancient selection using cross-population allele frequency differentiation. Genetics 202:733–750CrossRefPubMedGoogle Scholar
  47. Reich D, Green RE, Kircher M et al (2010) Genetic history of an archaic hominin group from Denisova Cave in Siberia. Nature 468:1053–1060CrossRefPubMedPubMedCentralGoogle Scholar
  48. 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 89:516–528CrossRefPubMedPubMedCentralGoogle Scholar
  49. Reyes-Centeno H, Hubbe M, Hanihara T et al (2015) Testing modern human out-of-Africa dispersal models and implications for modern human origins. J Hum Evol 87:95–106CrossRefPubMedGoogle Scholar
  50. Salleh MZ, Teh LK, Lee LS et al (2013) Systematic pharmacogenomics analysis of a Malay whole genome: proof of concept for personalized medicine. PLoS ONE. Google Scholar
  51. Sankararaman S, Mallick S, Dannemann M et al (2014) The genomic landscape of Neanderthal ancestry in present-day humans. Nature 507:354–357CrossRefPubMedPubMedCentralGoogle Scholar
  52. Scally A, Durbin R (2012) Revising the human mutation rate: implications for understanding human evolution. Nat Rev Genet 13:745–753CrossRefPubMedGoogle Scholar
  53. Schiffels S, Durbin R (2014) Inferring human population size and separation history from multiple genome sequences. Nat Genet 46:919–925CrossRefPubMedPubMedCentralGoogle Scholar
  54. Shi H, Qi X, Zhong H et al (2013) Genetic evidence of an East Asian origin and Paleolithic northward migration of Y-chromosome haplogroup N. PLoS ONE 8:1–9. CrossRefGoogle Scholar
  55. Skoglund P, Jakobsson M (2011) Archaic human ancestry in East Asia. Proc Natl Acad Sci USA 108:18301–18306CrossRefPubMedPubMedCentralGoogle Scholar
  56. Soares PA, Trejaut JA, Loo JH, Hill C, Mormina M, Lee CL, Chen YM, Hudjashov G, Forster P, Macaulay V, Bulbeck D, Oppen-heimer S, Lin M, Richards MB (2008) Climate change and postglacial human dispersals in Southeast Asia. Mol Biol Evol 25:1209–1218CrossRefPubMedGoogle Scholar
  57. Soares PA, Trejaut JA, Rito T, Cavadas B (2016) Resolving the ancestry of Austronesian-speaking populations. Hum Genet 135:309–326CrossRefPubMedPubMedCentralGoogle Scholar
  58. Tabbada KA, Trejaut J, Loo JH et al (2010) Philippine mitochondrial DNA diversity: a populated viaduct between Taiwan and Indonesia? Mol Biol Evol 27:21–31CrossRefPubMedGoogle Scholar
  59. The 1000 Genomes Project Consortium (2010) A map of human genome variation from population scale sequencing. Nature 467:1061–1073CrossRefPubMedCentralGoogle Scholar
  60. The HUGO Pan-Asian SNP Consortium (2009) Mapping human genetic diversity in Asia. Science 326:1541–1545CrossRefGoogle Scholar
  61. Vernot B, Akey JM (2014) Resurrecting surviving Neandertal lineages from modern human genomes. Science 343:1017–1021CrossRefPubMedGoogle Scholar
  62. Vernot B, Akey JM (2015) Complex history of admixture between modern humans and Neandertals. Am J Hum Genet 975:448–453CrossRefGoogle Scholar
  63. Wall JD, Yang MA, Jay F et al (2013) Higher levels of neanderthal ancestry in East Asians than in Europeans. Genetics 194:199–209CrossRefPubMedPubMedCentralGoogle Scholar
  64. Wan Juhari W, Md Tamrin N, Mat Daud M et al (2014) A whole genome analyses of genetic variants in two Kelantan Malay individuals. Hugo J 8:4CrossRefPubMedPubMedCentralGoogle Scholar
  65. Wang S, Lachance J, Tishkoff SA et al (2013) Apparent variation in Neanderthal admixture among African populations is consistent with gene flow from non-African populations. Genome Biol Evol 5:2075–2081CrossRefPubMedPubMedCentralGoogle Scholar
  66. 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 92:52–66CrossRefPubMedPubMedCentralGoogle Scholar
  67. Wong L-P, Lai JK-H, Saw W-Y et al (2014) Insights into the genetic structure and diversity of 38 South Asian Indians from deep whole-genome sequencing. PLoS Genet 10:e1004377. CrossRefPubMedPubMedCentralGoogle Scholar
  68. Zhang X, Qi X, Yang Z et al (2013) Analysis of mitochondrial genome diversity identifies new and ancient maternal lineages in Cambodian aborigines. Nat Commun 4:1–11. Google Scholar
  69. Zhang X, Liao S, Qi X et al (2015) Y-chromosome diversity suggests southern origin and Paleolithic backwave migration of Austro- Asiatic speakers from eastern Asia to the Indian subcontinent. Nature. Google Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Chee-Wei Yew
    • 1
  • Dongsheng Lu
    • 2
  • Lian Deng
    • 2
  • Lai-Ping Wong
    • 3
  • Rick Twee-Hee Ong
    • 3
  • Yan Lu
    • 2
  • Xiaoji Wang
    • 2
  • Yunus Yushimah 
    • 4
  • Farhang Aghakhanian
    • 5
    • 6
  • Mokhtar Siti Shuhada 
    • 4
  • Hoque Mohammad Zahirul 
    • 7
  • Christopher Lok-Yung Voo
    • 1
  • Thuhairah Abdul Rahman
    • 8
  • Jong Bhak
    • 9
    • 10
    • 11
  • Maude E. Phipps
    • 5
  • Shuhua Xu
    • 2
    • 12
    • 13
  • Yik-Ying Teo
    • 3
    • 14
    • 15
    • 16
    • 17
  • Subbiah Vijay Kumar
    • 1
  • Boon-Peng Hoh
    • 18
  1. 1.Biotechnology Research InstituteUniversiti Malaysia SabahKota KinabaluMalaysia
  2. 2.Max Planck Independent Research Group on Population Genomics, Chinese Academy of Sciences and Max Planck Society Partner Institute for Computational Biology, Shanghai Institutes for Biological SciencesChinese Academy of Sciences ShanghaiShanghaiChina
  3. 3.Saw Swee Hock School of Public HealthNational University of SingaporeSingaporeSingapore
  4. 4.Faculty of Medicine, Institute of Medical Molecular BiotechnologyUniversiti Teknologi MARASg BulohMalaysia
  5. 5.Jeffrey Cheah School of Medicine and Health SciencesMonash University MalaysiaSunwayMalaysia
  6. 6.Tropical Medicine and Biology Platform, Monash University MalaysiaSunwayMalaysia
  7. 7.Faculty of Medicine and Health SciencesUniversiti Malaysia SabahKota KinabaluMalaysia
  8. 8.Clinical Pathology Diagnostic Centre Research Laboratory, Faculty of MedicineUniversiti Teknologi MARASg BulohMalaysia
  9. 9.Personal Genomics InstituteGenome Research FoundationSuwonRepublic of Korea
  10. 10.GeromicsUlsanRepublic of Korea
  11. 11.Biomedical Engineering Department, The Genomics InstituteUNISTUlsanRepublic of Korea
  12. 12.School of Life Science and TechnologyShanghaiTech UniversityShanghaiChina
  13. 13.Collaborative Innovation Center of Genetics and DevelopmentShanghaiChina
  14. 14.NUS Graduate School for Integrative Science and EngineeringNational University of SingaporeSingaporeSingapore
  15. 15.Life Sciences Institute, National University of SingaporeSingaporeSingapore
  16. 16.Department of Statistics and Applied ProbabilityNational University of SingaporeSingaporeSingapore
  17. 17.Genome Institute of SingaporeAgency for Science, Technology and ResearchSingaporeSingapore
  18. 18.Faculty of Medicine and Health SciencesUCSI UniversityKuala LumpurMalaysia

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