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Genome-wide DNA methylation landscape of four Chinese populations and epigenetic variation linked to Tibetan high-altitude adaptation

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Abstract

DNA methylation (DNAm) is one of the major epigenetic mechanisms in humans and is important in diverse cellular processes. The variation of DNAm in the human population is related to both genetic and environmental factors. However, the DNAm profiles have not been investigated in the Chinese population of diverse ethnicities. Here, we performed double-strand bisulfite sequencing (DSBS) for 32 Chinese individuals representing four major ethnic groups including Han Chinese, Tibetan, Zhuang, and Mongolian. We identified a total of 604,649 SNPs and quantified DNAm at more than 14 million CpGs in the population. We found global DNAm-based epigenetic structure is different from the genetic structure of the population, and ethnic difference only partially explains the variation of DNAm. Surprisingly, non-ethnic-specific DNAm variations showed stronger correlation with the global genetic divergence than these ethnic-specific DNAm. Differentially methylated regions (DMRs) among these ethnic groups were found around genes in diverse biological processes. Especially, these DMR-genes between Tibetan and non-Tibetans were enriched around high-altitude genes including EPAS1 and EGLN1, suggesting DNAm alteration plays an important role in high-altitude adaptation. Our results provide the first batch of epigenetic maps for Chinese populations and the first evidence of the association of epigenetic changes with Tibetans’ high-altitude adaptation.

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References

  • Alexander, D.H., Novembre, J., and Lange, K. (2009). Fast model-based estimation of ancestry in unrelated individuals. Genome Res 19, 1655–1664.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Azad, P., Stobdan, T., Zhou, D., Hartley, I., Akbari, A., Bafna, V., and Haddad, G.G. (2017). High-altitude adaptation in humans: from genomics to integrative physiology. J Mol Med 95, 1269–1282.

    Article  CAS  PubMed  Google Scholar 

  • Beall, C.M. (2007). Two routes to functional adaptation: Tibetan and Andean high-altitude natives. Proc Natl Acad Sci USA 104, 8655–8660.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bibikova, M., Le, J., Barnes, B., Saedinia-Melnyk, S., Zhou, L., Shen, R., and Gunderson, K.L. (2009). Genome-wide DNA methylation profiling using Infinium® assay. Epigenomics 1, 177–200.

    Article  CAS  PubMed  Google Scholar 

  • Bigham, A.W., and Lee, F.S. (2014). Human high-altitude adaptation: forward genetics meets the HIF pathway. Genes Dev 28, 2189–2204.

    Article  PubMed  PubMed Central  Google Scholar 

  • Bu, D., Luo, H., Huo, P., Wang, Z., Zhang, S., He, Z., Wu, Y., Zhao, L., Liu, J., Guo, J., et al. (2021). KOBAS-i: intelligent prioritization and exploratory visualization of biological functions for gene enrichment analysis. Nucleic Acids Res 49, W317–W325.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Busche, S., Shao, X., Caron, M., Kwan, T., Allum, F., Cheung, W.A., Ge, B., Westfall, S., Simon, M.M., Barrett, A., et al. (2015). Population whole-genome bisulfite sequencing across two tissues highlights the environment as the principal source of human methylome variation. Genome Biol 16, 290.

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  • Carja, O., MacIsaac, J.L., Mah, S.M., Henn, B.M., Kobor, M.S., Feldman, M.W., and Fraser, H.B. (2017). Worldwide patterns of human epigenetic variation. Nat Ecol Evol 1, 1577–1583.

    Article  PubMed  PubMed Central  Google Scholar 

  • Choudhry, H., and Harris, A.L. (2018). Advances in hypoxia-inducible factor biology. Cell Metab 27, 281–298.

    Article  CAS  PubMed  Google Scholar 

  • Cretu Stancu, M., van Roosmalen, M.J., Renkens, I., Nieboer, M.M., Middelkamp, S., de Ligt, J., Pregno, G., Giachino, D., Mandrile, G., Espejo Valle-Inclan, J., et al. (2017). Mapping and phasing of structural variation in patient genomes using nanopore sequencing. Nat Commun 8, 1326.

    Article  PubMed  PubMed Central  Google Scholar 

  • Dahlback, A., Gelsor, N., Stamnes, J.J., and Gjessing, Y. (2007). UV measurements in the 3000–5000 m altitude region in Tibet. J Geophys Res 112, D09308.

    Google Scholar 

  • Deaton, A.M., and Bird, A. (2011). CpG islands and the regulation of transcription. Genes Dev 25, 1010–1022.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fagny, M., Patin, E., MacIsaac, J.L., Rotival, M., Flutre, T., Jones, M.J., Siddle, K.J., Quach, H., Harmant, C., McEwen, L.M., et al. (2015). The epigenomic landscape of African rainforest hunter-gatherers and farmers. Nat Commun 6, 10047.

    Article  CAS  PubMed  Google Scholar 

  • Foox, J., Nordlund, J., Lalancette, C., Gong, T., Lacey, M., Lent, S., Langhorst, B.W., Ponnaluri, V.K.C., Williams, L., Padmanabhan, K.R., et al. (2021). The SEQC2 epigenomics quality control (EpiQC) study. Genome Biol 22, 332.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fraser, H.B., Lam, L.L., Neumann, S.M., and Kobor, M.S. (2012). Population-specificity of human DNA methylation. Genome Biol 13, R8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Galanter, J.M., Gignoux, C.R., Oh, S.S., Torgerson, D., Pino-Yanes, M., Thakur, N., Eng, C., Hu, D., Huntsman, S., Farber, H.J., et al. (2017). Differential methylation between ethnic sub-groups reflects the effect of genetic ancestry and environmental exposures. eLife 6, e20532.

    Article  PubMed  PubMed Central  Google Scholar 

  • Gao, X.D., Wang, X.X., and Zhu, B.Q. (2016). Distribution and change of the ethnic minority population in China: a “Hu Line” perspective. Popul Res 40, 3–17.

    Google Scholar 

  • Hernando-Herraez, I., Garcia-Perez, R., Sharp, A.J., and Marques-Bonet, T. (2015). DNA Methylation: Insights into Human Evolution. PLoS Genet, 11, e1005661.

    Article  PubMed  PubMed Central  Google Scholar 

  • Heyn, H., Moran, S., Hernando-Herraez, I., Sayols, S., Gomez, A., Sandoval, J., Monk, D., Hata, K., Marques-Bonet, T., Wang, L., et al. (2013). DNA methylation contributes to natural human variation. Genome Res 23, 1363–1372.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Husquin, L.T., Rotival, M., Fagny, M., Quach, H., Zidane, N., McEwen, L. M., MacIsaac, J.L., Kobor, M.S., Aschard, H., Patin, E., et al. (2018). Exploring the genetic basis of human population differences in DNA methylation and their causal impact on immune gene regulation. Genome Biol 19, 222.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jones, P.A., and Takai, D. (2001). The role of DNA methylation in mammalian epigenetics. Science 293, 1068–1070.

    Article  CAS  PubMed  Google Scholar 

  • Julian, C.G. (2017). Epigenomics and human adaptation to high altitude. J Appl Physiol 123, 1362–1370.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Julian, C.G. (2019). An aptitude for altitude: are epigenomic processes involved? Front Physiol 10, 1397.

    Article  PubMed  PubMed Central  Google Scholar 

  • Kader, F., and Ghai, M. (2017). DNA methylation-based variation between human populations. Mol Genet Genomics 292, 5–35.

    Article  CAS  PubMed  Google Scholar 

  • Leek, J.T., Johnson, W.E., Parker, H.S., Jaffe, A.E., and Storey, J.D. (2012). The sva package for removing batch effects and other unwanted variation in high-throughput experiments. Bioinformatics 28, 882–883.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Leseva, M.N., Grand, R.J., Klett, H., Boerries, M., Busch, H., Binder, A. M., and Michels, K.B. (2018). Differences in DNA methylation and functional expression in lactase persistent and non-persistent individuals. Sci Rep 8, 5649.

    Article  PubMed  PubMed Central  Google Scholar 

  • Liang, J., Zhang, K., Yang, J., Li, X., Li, Q., Wang, Y., Cai, W., Teng, H., and Sun, Z. (2021). A new approach to decode DNA methylome and genomic variants simultaneously from double strand bisulfite sequencing. Brief Bioinfom 22, bbab201.

    Article  Google Scholar 

  • Liu, Q., Fang, L., Yu, G., Wang, D., Xiao, C.L., and Wang, K. (2019). Detection of DNA base modifications by deep recurrent neural network on Oxford Nanopore sequencing data. Nat Commun 10, 2449.

    Article  PubMed  PubMed Central  Google Scholar 

  • Liu, S., Huang, S., Chen, F., Zhao, L., Yuan, Y., Francis, S.S., Fang, L., Li, Z., Lin, L., Liu, R., et al. (2018). Genomic analyses from non-invasive prenatal testing reveal genetic associations, patterns of viral infections, and Chinese population history. Cell 175, 347–359.e14.

    Article  CAS  PubMed  Google Scholar 

  • Liu, Y., Siegmund, K.D., Laird, P.W., and Berman, B.P. (2012). Bis-SNP: combined DNA methylation and SNP calling for Bisulfite-seq data. Genome Biol 13, R61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lorenzo, F.R., Huff, C., Myllymäki, M., Olenchock, B., Swierczek, S., Tashi, T., Gordeuk, V., Wuren, T., Ri-Li, G., McClain, D.A., et al. (2014). A genetic mechanism for Tibetan high-altitude adaptation. Nat Genet 46, 951–956.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lu, D., Lou, H., Yuan, K., Wang, X., Wang, Y., Zhang, C., Lu, Y., Yang, X., Deng, L., Zhou, Y., et al. (2016). Ancestral origins and genetic history of Tibetan highlanders. Am J Hum Genet 99, 580–594.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Moran, S., Arribas, C., and Esteller, M. (2016). Validation of a DNA methylation microarray for 850,000 CpG sites of the human genome enriched in enhancer sequences. Epigenomics 8, 389–399.

    Article  CAS  PubMed  Google Scholar 

  • Pan, Z., Hu, Y., Huang, Z., Han, N., Li, Y., Zhuang, X., Yin, J., Peng, H., Gao, Q., Zhang, W., et al. (2022). Alterations in gut microbiota and metabolites associated with altitude-induced cardiac hypertrophy in rats during hypobaric hypoxia challenge. Sci China Life Sci 65, 2093–2113.

    Article  CAS  PubMed  Google Scholar 

  • Pan, Z., and Xu, S. (2020). Population genomics of East Asian ethnic groups. Hereditas 157, 49.

    Article  PubMed  PubMed Central  Google Scholar 

  • Peng, Y., Cui, C., He, Y., Ouzhuluobu, Y., Zhang, H., Yang, D., Zhang, Q., Bianbazhuoma, Q., Yang, L., He, Y., et al. (2017). Down-regulation of EPAS1 transcription and genetic adaptation of Tibetans to high-altitude hypoxia. Mol Biol Evol 34, 818–830.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Peng, Y., Yang, Z., Zhang, H., Cui, C., Qi, X., Luo, X., Tao, X., Wu, T., Ouzhuluobu, T., Basang, T., et al. (2010). Genetic variations in Tibetan populations and high-altitude adaptation at the Himalayas. Mol Biol Evol 28, 1075–1081.

    Article  PubMed  Google Scholar 

  • Purcell, S., Neale, B., Todd-Brown, K., Thomas, L., Ferreira, M.A.R., Bender, D., Maller, J., Sklar, P., de Bakker, P.I.W., Daly, M.J., et al. (2007). PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81, 559–575.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ramos-Lopez, O., Riezu-Boj, J.I., Milagro, F.I., Zulet, M.A., Santos, J.L., and Martinez, J.A. (2019). Associations between olfactory pathway gene methylation marks, obesity features and dietary intakes. Genes Nutr 14, 11.

    Article  PubMed  PubMed Central  Google Scholar 

  • Rand, A.C., Jain, M., Eizenga, J.M., Musselman-Brown, A., Olsen, H.E., Akeson, M., and Paten, B. (2017). Mapping DNA methylation with high-throughput nanopore sequencing. Nat Methods 14, 411–413.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rawlik, K., Rowlatt, A., Sanabria-Salas, M.C., Hernández-Suárez, G., Serrano López, M.L., Zabaleta, J., and Tenesa, A. (2017). Evidence of epigenetic admixture in the Colombian population. Hum Mol Genet 26, 501–508.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Reinius, L.E., Acevedo, N., Joerink, M., Pershagen, G., Dahlén, S.E., Greco, D., Söderhäll, C., Scheynius, A., and Kere, J. (2012). Differential DNA methylation in purified human blood cells: implications for cell lineage and studies on disease susceptibility. PLoS One, 7, e41361.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sandoval, J., Heyn, H., Moran, S., Serra-Musach, J., Pujana, M.A., Bibikova, M., and Esteller, M. (2011). Validation of a DNA methylation microarray for 450,000 CpG sites in the human genome. Epigenetics 6, 692–702.

    Article  CAS  PubMed  Google Scholar 

  • Schmitz, R.J., Lewis, Z.A., and Goll, M.G. (2019). DNA methylation: shared and divergent features across eukaryotes. Trends Genet 35, 818–827.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Simonson, T.S., Yang, Y., Huff, C.D., Yun, H., Qin, G., Witherspoon, D.J., Bai, Z., Lorenzo, F.R., Xing, J., Jorde, L.B., et al. (2010). Genetic evidence for high-altitude adaptation in Tibet. Science 329, 72–75.

    Article  CAS  PubMed  Google Scholar 

  • Simpson, J.T., Workman, R.E., Zuzarte, P.C., David, M., Dursi, L.J., and Timp, W. (2017). Detecting DNA cytosine methylation using nanopore sequencing. Nat Methods 14, 407–410.

    Article  CAS  PubMed  Google Scholar 

  • Stamatakis, A. (2014). RAxML version 8: a tool for phylogenetic analysis and post-analysis of large phylogenies. Bioinformatics 30, 1312–1313.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Villicaña, S., and Bell, J.T. (2021). Genetic impacts on DNA methylation: research findings and future perspectives. Genome Biol 22, 127.

    Article  PubMed  PubMed Central  Google Scholar 

  • Wang, Z., and Zhang, L.H. (2019). The spatial distribution of population in 31 Chinese provinces: 1990–2010 (in Chinese). Northwest Popul 40, 29–39.

    Google Scholar 

  • Wolffe, A.P., and Matzke, M.A. (1999). Epigenetics: regulation through repression. Science 286, 481–486.

    Article  CAS  PubMed  Google Scholar 

  • Wu, T., and Kayser, B. (2006). High altitude adaptation in Tibetans. High Alt Med Biol 7, 193–208.

    Article  PubMed  Google Scholar 

  • Xi, Y., and Li, W. (2009). BSMAP: whole genome bisulfite sequence MAPping program. BMC Bioinformatics 10, 232.

    Article  PubMed  PubMed Central  Google Scholar 

  • Xin, J., Zhang, H., He, Y., Duren, Z., Bai, C., Chen, L., Luo, X., Yan, D.S., Zhang, C., Zhu, X., et al. (2020). Chromatin accessibility landscape and regulatory network of high-altitude hypoxia adaptation. Nat Commun 11, 4928.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xu, S., Li, S., Yang, Y., Tan, J., Lou, H., Jin, W., Yang, L., Pan, X., Wang, J., Shen, Y., et al. (2010). A genome-wide search for signals of high-altitude adaptation in Tibetans. Mol Biol Evol 28, 1003–1011.

    Article  PubMed  Google Scholar 

  • Yang, J., Jin, Z.B., Chen, J., Huang, X.F., Li, X.M., Liang, Y.B., Mao, J.Y., Chen, X., Zheng, Z., Bakshi, A., et al. (2017). Genetic signatures of high-altitude adaptation in Tibetans. Proc Natl Acad Sci USA 114, 4189–4194.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang, F.F., Cardarelli, R., Carroll, J., Fulda, K.G., Kaur, M., Gonzalez, K., Vishwanatha, J.K., Santella, R.M., and Morabia, A. (2011a). Significant differences in global genomic DNA methylation by gender and race/ethnicity in peripheral blood. Epigenetics 6, 623–629.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang, F.F., Morabia, A., Carroll, J., Gonzalez, K., Fulda, K., Kaur, M., Vishwanatha, J.K., Santella, R.M., and Cardarelli, R. (2011b). Dietary patterns are associated with levels of global genomic DNA methylation in a cancer-free population. J Nutr 141, 1165–1171.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang, L., Rong, W., Ma, J., Li, H., Tang, X., Xu, S., Wang, L., Wan, L., Zhu, Q., Jiang, B., et al. (2022). Comprehensive analysis of DNA 5-methylcytosine and N6-adenine methylation by nanopore sequencing in hepatocellular carcinoma. Front Cell Dev Biol 10, 827391.

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by the National Key Research and Development Program of China (2016YFC0900402), the Basic Science Center Program (32288101), the National Natural Science Foundation of China (32030020 and 31961130380), and the Shanghai Municipal Science and Technology Major Project (2017SHZDZX01).

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Authors and Affiliations

  1. School of Ecology and Environment, Northwestern Polytechnical University, Xi’an, 710072, China

    Zeshan Lin, Bao Wang & Wen Wang

  2. State Key Laboratory of Genetic Engineering, Center for Evolutionary Biology, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai, 200438, China

    Yan Lu & Shuhua Xu

  3. GrandOmics Biosciences, Beijing, 102200, China

    Guoliang Yu

  4. Department of Radiation Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, 100142, China

    Huajing Teng

  5. Human Phenome Institute, Zhangjiang Fudan International Innovation Center, and Ministry of Education Key Laboratory of Contemporary Anthropology, Fudan University, Shanghai, 201203, China

    Yajun Yang & Shuhua Xu

  6. Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing, 100101, China

    Qinglan Li & Zhongsheng Sun

  7. School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China

    Shuhua Xu

  8. Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, 650223, China

    Shuhua Xu & Wen Wang

  9. State Key Laboratory of Crop Stress Biology for Arid Areas and College of Agronomy, Northwest A&F University, Yangling, 712100, China

    Peng Tian

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  1. Zeshan Lin
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Correspondence to Shuhua Xu, Wen Wang or Peng Tian.

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Lin, Z., Lu, Y., Yu, G. et al. Genome-wide DNA methylation landscape of four Chinese populations and epigenetic variation linked to Tibetan high-altitude adaptation. Sci. China Life Sci. 66, 2354–2369 (2023). https://doi.org/10.1007/s11427-022-2284-8

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