The indigenous populations as the model by nature to understand human genomic-phenomics interactions

Abstract

Background: The advancement of genomics has progressed in lightning speed over the past two decades. Numerous large-scale genome sequencing initiatives were announced, along with the rise of the holistic precision medicine approach. However, the field of genomic medicine has now come to a bottleneck since genomic-phenomic interactions are not fully comprehended due to the complexity of the human systems biology and environmental influence, hence the emergence of human phenomics.

Results: This review attempts to provide an overview of the potential advantages of investigating the human phenomics of indigenous populations and the challenges ahead.

Conclusion: We believe that the indigenous populations serve as an ideal model to excavate our understanding of genomic-environmental-phenomics interactions.

Graphical abstract

Keywords

indigenous populations / Orang Asli / genomics / phenomics

References

[1] Venter, J. C., Adams, M. D., Myers, E. W., Li, P. W., Mural, R. J., Sutton, G. G., Smith, H. O., Yandell, M., Evans, C. A., Holt, R. A., (2001) The sequence of the human genome. Science, 291, 1304–1351

[2] Lander, E. S., Linton, L. M., Birren, B., Nusbaum, C., Zody, M. C., Baldwin, J., Devon, K., Dewar, K., Doyle, M., FitzHugh, W., (2001) Initial sequencing and analysis of the human genome. Nature, 409, 860–921

[3] International HapMap Consortium. (2003) The International HapMap Project. Nature, 426, 789–796

[4] Frazer, K. A., Ballinger, D. G., Cox, D. R., Hinds, D. A., Stuve, L. L., Gibbs, R. A., Belmont, J. W., Boudreau, A., Hardenbol, P., Leal, S. M., (2007) A second generation human haplotype map of over 3.1 million SNPs. Nature, 449, 851–861

[5] The International HapMap 3 Consortium. (2010) Integrating common and rare genetic variation in diverse human populations. Nature., 467, 52–58

[6] Wellcome Trust Case Control Consortium. (2007) Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature, 447, 661–678

[7] Fujimoto, A., Nakagawa, H., Hosono, N., Nakano, K., Abe, T., Boroevich, K. A., Nagasaki, M., Yamaguchi, R., Shibuya, T., Kubo, M., (2010) Whole-genome sequencing and comprehensive variant analysis of a Japanese individual using massively parallel sequencing. Nat. Genet., 42, 931–936

[8] Ahn, S. M., Kim, T. H., Lee, S., Kim, D., Ghang, H., Kim, D. S., Kim, B. C., Kim, S. Y., Kim, W. Y., Kim, C., (2009) The first Korean genome sequence and analysis: full genome sequencing for a socio-ethnic group. Genome Res., 19, 1622–1629

[9] Kim, J. I., Ju, Y. S., Park, H., Kim, S., Lee, S., Yi, J. H., Mudge, J., Miller, N. A., Hong, D., Bell, C. J., (2009) A highly annotated whole-genome sequence of a Korean individual. Nature, 460, 1011–1015

[10] The 1000 Genomes Project Consortium. (2010) A map of human genome variation from population-scale sequencing. Nature, 467, 1061–1073

[11] The 1000 Genomes Project Consortium. (2015) A global reference for human genetic variation. Nature, 526, 68–74

[12] The UK10K Consortium. (2015) The UK10K project identifies rare variants in health and disease. Nature, 526, 82–89

[13] Wu, D., Dou, J., Chai, X., Bellis, C., Wilm, A., Shih, C. C., Soon, W. W. J., Bertin, N., Lin, C. B., Khor, C. C., (2019) Large-scale whole-genome sequencing of three diverse Asian populations in Singapore. Cell, 179, 736–749.e15

[14] The GenomeAsia 100K Consortium. (2019) The GenomeAsia 100K Project enables genetic discoveries across Asia. Nature, 576, 106–111

[15] Cao, Y., Li, L., Xu, M., Feng, Z., Sun, X., Lu, J., Xu, Y., Du, P., Wang, T., Hu, R., (2020) The ChinaMAP analytics of deep whole genome sequences in 10,588 individuals. Cell Res., 30, 717–731

[16] Jeon, S., Bhak, Y., Choi, Y., Jeon, Y., Kim, S., Jang, J., Jang, J., Blazyte, A., Kim, C., Kim, Y., (2020) Korean Genome Project: 1094 Korean personal genomes with clinical information. Sci. Adv., 6, eaaz7835

[17] Houle, D., Govindaraju, D. R. and Omholt, S. (2010) Phenomics: the next challenge. Nat. Rev. Genet., 11, 855–866

[18] Cano-Gamez, E. and Trynka, G. (2020) From GWAS to function: using functional genomics to identify the mechanisms underlying complex diseases. Front. Genet., 11, 424

[19] Manolio, T. A., Collins, F. S., Cox, N. J., Goldstein, D. B., Hindorff, L. A., Hunter, D. J., McCarthy, M. I., Ramos, E. M., Cardon, L. R., Chakravarti, A., (2009) Finding the missing heritability of complex diseases. Nature, 461, 747–753

[20] Altshuler, D., Daly, M. J. and Lander, E. S. (2008) Genetic mapping in human disease. Science, 322, 881–888

[21] Bustamante, C. D., De La Vega, F. M. and Burchard, E. G. (2011) Genomics for the world. Nature, 475, 163–165

[22] Ozaki, K., Ohnishi, Y., Iida, A., Sekine, A., Yamada, R., Tsunoda, T., Sato, H., Sato, H., Hori, M., Nakamura, Y., (2002) Functional SNPs in the lymphotoxin-α gene that are associated with susceptibility to myocardial infarction. Nat. Genet., 32, 650–654

[23] Lango Allen, H., Estrada, K., Lettre, G., Berndt, S. I., Weedon, M. N., Rivadeneira, F., Willer, C. J., Jackson, A. U., Vedantam, S., Raychaudhuri, S., (2010) Hundreds of variants clustered in genomic loci and biological pathways affect human height. Nature, 467, 832–838

[24] Yang, J., Benyamin, B., McEvoy, B. P., Gordon, S., Henders, A. K., Nyholt, D. R., Madden, P. A., Heath, A. C., Martin, N. G., Montgomery, G. W., (2010) Common SNPs explain a large proportion of the heritability for human height. Nat. Genet., 42, 565–569

[25] Nikpay, M., Goel, A., Won, H.-H., Hall, L. M., Willenborg, C., Kanoni, S., Saleheen, D., Kyriakou, T., Nelson, C. P., Hopewell, J. C., (2015) A comprehensive 1,000 Genomes-based genome-wide association meta-analysis of coronary artery disease. Nat. Genet., 47, 1121–1130

[26] Doherty, A., Smith-Byrne, K., Ferreira, T., Holmes, M. V., Holmes, C., Pulit, S. L. and Lindgren, C. M. (2018) GWAS identifies 14 loci for device-measured physical activity and sleep duration. Nat. Commun., 9, 5257

[27] Band, G., Le, Q. S., Jostins, L., Pirinen, M., Kivinen, K., Jallow, M., Sisay-Joof, F., Bojang, K., Pinder, M., Sirugo, G., (2013) Imputation-based meta-analysis of severe malaria in three African populations. PLoS Genet., 9, e1003509

[28] Klarin, D., Lynch, J., Aragam, K., Chaffin, M., Assimes, T. L., Huang, J., Lee, K. M., Shao, Q., Huffman, J. E., Natarajan, P., (2019) Genome-wide association study of peripheral artery disease in the Million Veteran Program. Nat. Med., 25, 1274–1279

[29] Zhang, K., Weder, A. B., Eskin, E. and O’Connor, D. T. (2010) Genome-wide case/control studies in hypertension: only the ‘tip of the iceberg’. J. Hypertens., 28, 1115–1123

[30] Wang, Y. and Wang, J.-G. (2019) Genome-wide association studies of hypertension and several other cardiovascular diseases. Pulse (Basel), 6, 169–186

[31] Freimer, N. and Sabatti, C. (2003) The human phenome project. Nat. Genet., 34, 15–21

[32] Dominiczak, A., Delles, C. and Padmanabhan, S. (2017) Genomics and precision medicine for clinicians and scientists in hypertension. Hypertension, 69, e10–e13

[33] Peck, R. W. (2018) Precision medicine is not just genomics: the right dose for every patient. Annu. Rev. Pharmacol. Toxicol., 58, 105–122

[34] Hoh, B. P., Abdul Rahman, T. and Yusoff, K. (2019) Natural selection and local adaptation of blood pressure regulation and their perspectives on precision medicine in hypertension. Hereditas, 156, 1

[35] Mills, K. T., Bundy, J. D., Kelly, T. N., Reed, J. E., Kearney, P. M., Reynolds, K., Chen, J. and He, J. (2016) Global disparities of hypertension prevalence and control: A systematic analysis of population-based studies from 90 countries. Circulation, 134, 441–450

[36] Manosroi, W. and Williams, G. H. (2019) Genetics of Human Primary Hypertension: Focus on Hormonal Mechanisms. Endocr. Rev., 40, 825–856

[37] Tocci, G., Ferrucci, A., Pontremoli, R., Ferri, C., Rosei, E. A., Morganti, A., Trimarco, B., Mancia, G., Borghi, C. and Volpe, M. (2015) Blood pressure levels and control in Italy: comprehensive analysis of clinical data from 2000‒2005 and 2005‒2011 hypertension surveys. J. Hum. Hypertens., 29, 696–701

[38] Korner, P. I. (2010) The phenotypic patterns of essential hypertension are the key to identifying “high blood pressure” genes. Physiol. Res., 59, 841–857

[39] Basting, T. and Lazartigues, E. (2017) DOCA-salt hypertension: an update. Curr Hypertens Rep., 19, 1–8

[40] Coffman, T. M. (2011) Under pressure: the search for the essential mechanisms of hypertension. Nat. Med., 17, 1402–1409

[41] Kato, N. (2012) Ethnic differences in genetic predisposition to hypertension. Hypertens. Res., 35, 574–581

[42] Thompson, E. E., Kuttab-Boulos, H., Witonsky, D., Yang, L., Roe, B. A. and Di Rienzo, A. (2004) CYP3A variation and the evolution of salt-sensitivity variants. Am. J. Hum. Genet., 75, 1059–1069

[43] Nakajima, T., Wooding, S., Sakagami, T., Emi, M., Tokunaga, K., Tamiya, G., Ishigami, T., Umemura, S., Munkhbat, B., Jin, F., (2004) Natural selection and population history in the human angiotensinogen gene (AGT): 736 complete AGT sequences in chromosomes from around the world. Am. J. Hum. Genet., 74, 898–916

[44] Young, J.H., Chang, Y.P.C., Kim, J.D.O., Chretien, J.P., Klag, M.J., Levine, M.A., Ruff, C.B., Wang, N.Y., Chakravarti, A. (2005) Differential susceptibility to hypertension is due to selection during the out-of-Africa expansion. PLoS Genet., 1, e82

[45] Verma, A., Lucas, A., Verma, S. S., Zhang, Y., Josyula, N., Khan, A., Hartzel, D. N., Lavage, D. R., Leader, J., Ritchie, M. D., (2018) PheWAS and beyond: the landscape of associations with medical diagnoses and clinical measures across 38,662 individuals from geisinger. Am. J. Hum. Genet., 102, 592–608

[46] Safarova, M. S., Satterfield, B. A., Fan, X., Austin, E. E., Ye, Z., Bastarache, L., Zheng, N., Ritchie, M. D., Borthwick, K. M., Williams, M. S., (2019) A phenome-wide association study to discover pleiotropic effects of PCSK9, APOB, and LDLR. NPJ Genom. Med., 4, 3

[47] Denny, J. C., Bastarache, L., Ritchie, M. D., Carroll, R. J., Zink, R., Mosley, J. D., Field, J. R., Pulley, J. M., Ramirez, A. H., Bowton, E., (2013) Systematic comparison of phenome-wide association study of electronic medical record data and genome-wide association study data. Nat. Biotechnol., 31, 1102–1111

[48] Diogo, D., Tian, C., Franklin, C. S., Alanne-Kinnunen, M., March, M., Spencer, C. C. A., Vangjeli, C., Weale, M. E., Mattsson, H., Kilpeläinen, E., (2018) Phenome-wide association studies across large population cohorts support drug target validation. Nat. Commun., 9, 4285

[49] Zhao, X., Geng, X., Srinivasasainagendra, V., Chaudhary, N., Judd, S., Wadley, V., Gutiérrez, O. M., Wang, H., Lange, E. M., Lange, L. A., (2019) A PheWAS study of a large observational epidemiological cohort of African Americans from the REGARDS study. BMC Med. Genomics, 12, 26

[50] Pendergrass, S. A., Buyske, S., Jeff, J. M., Frase, A., Dudek, S., Bradford, Y., Ambite, J. L., Avery, C. L., Buzkova, P., Deelman, E., (2019) A phenome-wide association study (PheWAS) in the Population Architecture using Genomics and Epidemiology (PAGE) study reveals potential pleiotropy in African Americans. PLoS One, 14, e0226771

[51] Mashimo, T., Voigt, B., Kuramoto, T. and Serikawa, T. (2005) Rat Phenome Project: the untapped potential of existing rat strains. J. Appl. Physiol., 98, 371–379

[52] Bogue, M. A., Grubb, S. C., Walton, D. O., Philip, V. M., Kolishovski, G., Stearns, T., Dunn, M. H., Skelly, D. A., Kadakkuzha, B., TeHennepe, G., (2018) Mouse Phenome Database: an integrative database and analysis suite for curated empirical phenotype data from laboratory mice. Nucleic Acids Res., 46, D843–D850

[53] FitzGerald, G., Botstein, D., Califf, R., Collins, R., Peters, K., Van Bruggen, N. and Rader, D. (2018) The future of humans as model organisms. Science, 361, 552–553

[54] Yew, C. W., Lu, D., Deng, L., Wong, L. P., Ong, R. T., Lu, Y., Wang, X., Yunus, Y., Aghakhanian, F., Mokhtar, S. S., (2018) Genomic structure of the native inhabitants of Peninsular Malaysia and North Borneo suggests complex human population history in Southeast Asia. Hum. Genet., 137, 161–173

[55] Hill, C., Soares, P., Mormina, M., Macaulay, V., Meehan, W., Blackburn, J., Clarke, D., Raja, J. M., Ismail, P., Bulbeck, D., (2006) Phylogeography and ethnogenesis of aboriginal Southeast Asians. Mol. Biol. Evol., 23, 2480–2491

[56] Deng, L., Lou, H., Zhang, X., Thiruvahindrapuram, B., Lu, D., Marshall, C. R., Liu, C., Xie, B., Xu, W., Wong, L. P., (2019) Analysis of five deep-sequenced trio-genomes of the Peninsular Malaysia Orang Asli and North Borneo populations. BMC Genomics, 20, 842

[57] Endicott, K. (2016) Malaysia’s Original People: Past, Present and Future of the Orang Asli. Singapore: NUS Press

[58] Mokhsin, A., Mokhtar, S. S., Mohd Ismail, A., M Nor, F., Shaari, S. A., Nawawi, H., Yusoff, K., Abdul Rahman, T. and Hoh, B. P. (2018) Observational study of the status of coronary risk biomarkers among Negritos with metabolic syndrome in the east coast of Malaysia. BMJ Open, 8, e021580

[59] Aghakhanian, F., Wong, C., Tan, J. S. Y., Yeo, L. F., Ramadas, A., Edo, J., Hoh, B. P., Khalid, B. A. K. and Phipps, M. E. (2019) Metabolic syndrome and cardiometabolic risk factors among indigenous Malaysians. Public Health, 176, 106–113

[60] Tuan Abdul Aziz, T. A., Teh, L. K., Md Idris, M. H., Bannur, Z., Ashari, L. S., Ismail, A. I., Ahmad, A., Isa, K. M., Nor, F. M., Rahman, T. H., (2016) Increased risks of cardiovascular diseases and insulin resistance among the Orang Asli in Peninsular Malaysia. BMC Public Health, 16, 284

[61] Mills, M. C. and Rahal, C. (2019) A scientometric review of genome-wide association studies. Comm Biol., doi:10.1038/s42003-018-0261-x

[62] Garrison, N. A., Hudson, M., Ballantyne, L. L., Garba, I., Martinez, A., Taualii, M., Arbour, L., Caron, N. R. and Rainie, S. C. (2019) Genomic research through an indigenous lens: understanding the expectations. Annu. Rev. Genomics Hum. Genet., 20, 495–517

[63] Jinam, T. A., Phipps, M. E., Aghakhanian, F., Majumder, P. P., Datar, F., Stoneking, M., Sawai, H., Nishida, N., Tokunaga, K., Kawamura, S., (2017) Discerning the origins of the negritos, first sundaland people: deep divergence and archaic admixture. Genome Biol. Evol., 9, 2013–2022

[64] Scholes, C., Siddle, K., Ducourneau, A., Crivellaro, F., Järve, M., Rootsi, S., Bellatti, M., Tabbada, K., Mormina, M., Reidla, M., (2011) Genetic diversity and evidence for population admixture in Batak Negritos from Palawan. Am. J. Phys. Anthropol., 146, 62–72

[65] Kusuma, P., Brucato, N., Cox, M. P., Letellier, T., Manan, A., Nuraini, C., Grangé P., Sudoyo, H. and Ricaut, F. X. (2017) The last sea nomads of the Indonesian archipelago: genomic origins and dispersal. Eur. J. Hum. Genet., 25, 1004–1010

[66] Deng, L., Hoh, B. P., Lu, D., Fu, R., Phipps, M. E., Li, S., Nur-Shafawati, A. R., Hatin, W. I., Ismail, E., Mokhtar, S. S., (2014) The population genomic landscape of human genetic structure, admixture history and local adaptation in Peninsular Malaysia. Hum. Genet., 133, 1169–1185

[67] Aghakhanian, F., Yunus, Y., Naidu, R., Jinam, T., Manica, A., Hoh, B. P. and Phipps, M. E. (2015) Unravelling the genetic history of Negritos and indigenous populations of Southeast Asia. Genome Biol. Evol., 7, 1206–1215

[68] McEvoy, B. P., Lind, J. M., Wang, E. T., Moyzis, R. K., Visscher, P. M., van Holst Pellekaan, S. M. and Wilton, A. N. (2010) Whole-genome genetic diversity in a sample of Australians with deep Aboriginal ancestry. Am. J. Hum. Genet., 87, 297–305

[69] Tokunaga, K., Ohashi, J., Bannai, M. and Juji, T. (2001) Genetic link between Asians and native Americans: evidence from HLA genes and haplotypes. Hum. Immunol., 62, 1001–1008

[70] Zhou, S., Xie, P., Quoibion, A., Ambalavanan, A., Dionne-Laporte, A., Spiegelman, D., Bourassa, C. V., Xiong, L., Dion, P. A. and Rouleau, G. A. (2019) Genetic architecture and adaptations of Nunavik Inuit. Proc. Natl. Acad. Sci. USA, 116, 16012–16017

[71] Fumagalli, M., Moltke, I., Grarup, N., Racimo, F., Bjerregaard, P., Jørgensen, M. E., Korneliussen, T. S., Gerbault, P., Skotte, L., Linneberg, A., (2015) Greenlandic Inuit show genetic signatures of diet and climate adaptation. Science, 349, 1343–1347

[72] Liu, X., Yunus, Y., Lu, D., Aghakhanian, F., Saw, W. Y., Deng, L., Ali, M., Wang, X., Nor, F. M., Rahman, T. A., (2015) Differential positive selection of malaria resistance genes in three indigenous populations of Peninsular Malaysia. Hum. Genet., 134, 375–392

[73] Ilardo, M. A., Moltke, I., Korneliussen, T. S., Cheng, J., Stern, A. J., Racimo, F., de Barros Damgaard, P., Sikora, M., Seguin-Orlando, A., Rasmussen, S., (2018) Physiological and genetic adaptations to diving in sea nomads. Cell, 173, 569–580.e15

[74] Kapoor, A. K. and Kaur, J. (2012) Natural selection in a population group of Andaman and Nicobar Islands. J. Nat. Sci. Biol. Med., 3, 71–77

[75] Roberts-Thomson, R. A. and Roberts-Thomson, P. J. (1999) Rheumatic disease and the Australian aborigine. Ann. Rheum. Dis., 58, 266–270

[76] Leung, L. (2016) Diabetes mellitus and the Aboriginal diabetic initiative in Canada: An update review. J. Family Med. Prim. Care, 5, 259–265

[77] Wong, E. C. L. and Kapoor, A. (2017) Epidemiology of prostate and kidney cancer in the Aboriginal population of Canada: A systematic review. Can. Urol. Assoc. J., 11, E222–E232

[78] Thomas, V., Sng, K. H. and Yap, P. L. (1980) Seroepidemiology of Malaria in Orang Asli (Aborgines) Children in Kelantan, Malaysia. Geneva, available from:

[79] Baer, A. S. (1999) Health, disease, and survival : a biomedical and genetic analysis of the Orang Asli of Malaysia. 1st ed. Subang Jaya: Center for Orang Asli Concerns

[80] Kaur, G. (2009) Prevalence of clinical malaria among an Orang Asli community in Malaysia. Southeast Asian J Trop Med Public Health, 40, 665–673

[81] Muslim, A., Mohd Sofian, S., Shaari, S. A., Hoh, B. P. and Lim, Y. A. L. (2019) Prevalence, intensity and associated risk factors of soil transmitted helminth infections: A comparison between Negritos (indigenous) in inland jungle and those in resettlement at town peripheries. PLoS Negl. Trop. Dis., 13, e0007331

[82] Sahlan, N., Fadzilah, M. N., Muslim, A., Shaari, S. A., Abdul Rahman, T. and Hoh, B. P. (2019) Hepatitis B virus infection: Epidemiology and seroprevalence rate amongst Negrito tribe in Malaysia. Med. J. Malaysia, 74, 320–325

[83] Ishida, T., Yamamoto, K. and Omoto, K. (1988) A seroepidemiological survey of HTLV-1 in the Philippines. Int. J. Epidemiol., 17, 625–628

[84] Phipps, M. E., Chan, K. K. L., Naidu, R., Mohamad, N. W., Hoh, B.-P., Quek, K.-F., Ahmad, B., Harnida, S. M., Zain, A. Z. and Kadir, K. A. (2015) Cardio-metabolic health risks in indigenous populations of Southeast Asia and the influence of urbanization. BMC Public Health, 15, 47

[85] Rønn, P. F., Lucas, M., Laouan Sidi, E. A., Tvermosegaard, M., Andersen, G. S., Lauritzen, T., Toft, U., Carstensen, B., Christensen, D. L. and Jørgensen, M. E. (2017) The obesity-associated risk of cardiovascular disease and all-cause mortality is not lower in Inuit compared to Europeans: A cohort study of Greenlandic Inuit, Nunavik Inuit and Danes. Atherosclerosis, 265, 207–214

[86] Appel, E. V. R., Moltke, I., Jørgensen, M. E., Bjerregaard, P., Linneberg, A., Pedersen, O., Albrechtsen, A., Hansen, T. and Grarup, N. (2018) Genetic determinants of glycated hemoglobin levels in the Greenlandic Inuit population. Eur. J. Hum. Genet., 26, 868–875

[87] Lu, D. and Xu, S. (2013) Principal component analysis reveals the 1000 Genomes Project does not sufficiently cover the human genetic diversity in Asia. Front. Genet., 4, 127

[88] Wang, L., Olson, J. E., Bielinski, S. J., St Sauver, J. L., Fu, S., He, H., Cicek, M. S., Hathcock, M. A., Cerhan, J. R. and Liu, H. (2020) Impact of diverse data sources on computational phenotyping. Front. Genet., 11, 556

[89] Caron, N. R., Chongo, M., Hudson, M., Arbour, L., Wasserman, W. W., Robertson, S., Correard, S. and Wilcox, P. (2020) Indigenous Genomic Databases: pragmatic considerations and cultural contexts. Front. Public Health, 8, 111

RIGHTS & PERMISSIONS

The Author(s) 2021. Published by Higher Education Press