Altitude adaptation in Tibetans caused by introgression of Denisovan-like DNA
Open accessAbstract
As modern humans migrated out of Africa, they encountered many new environmental conditions, including greater temperature extremes, different pathogens and higher altitudes. These diverse environments are likely to have acted as agents of natural selection and to have led to local adaptations. One of the most celebrated examples in humans is the adaptation of Tibetans to the hypoxic environment of the high-altitude Tibetan plateau. A hypoxia pathway gene, EPAS1, was previously identified as having the most extreme signature of positive selection in Tibetans, and was shown to be associated with differences in haemoglobin concentration at high altitude. Re-sequencing the region around EPAS1 in 40 Tibetan and 40 Han individuals, we find that this gene has a highly unusual haplotype structure that can only be convincingly explained by introgression of DNA from Denisovan or Denisovan-related individuals into humans. Scanning a larger set of worldwide populations, we find that the selected haplotype is only found in Denisovans and in Tibetans, and at very low frequency among Han Chinese. Furthermore, the length of the haplotype, and the fact that it is not found in any other populations, makes it unlikely that the haplotype sharing between Tibetans and Denisovans was caused by incomplete ancestral lineage sorting rather than introgression. Our findings illustrate that admixture with other hominin species has provided genetic variation that helped humans to adapt to new environments.
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Archaic alleles have been associated with differences in hemoglobin levels at higher altitude in Tibetans, immune resistance to new pathogens, levels of skin pigmentation, and fat composition.
“For example, archaic alleles have been associated with differences in hemoglobin levels at higher altitude in Tibetans, immune resistance to new pathogens, levels of skin pigmentation, and fat composition (Huerta-Sánchez et al. 2014; Racimo et al. 2015; Racimo, Gokhman, et al. 2017; Dannemann and Kelso 2017; Racimo, Marnetto, and Huerta-Sánchez 2017; McArthur et al. 2021).”
From Archaic Introgression Shaped Human Circadian Traits (2023) · cites this paper as Huerta-Sánchez et al. 2014
The opening section (page not supplied) links a Denisovan-like EPAS1 haplotype in Tibetans to differences in hemoglobin levels at high altitude. The Discussion (page not supplied) mentions earlier work on archaic introgression in immunity- and pigmentation-related genes, but does not establish resistance to new pathogens or pigmentation levels. The supplied passages do not address fat composition. (LLM, conf=0.86)
Experimental — accuracy not yet measuredSome archaic alleles and haplotypes are adaptive and persist at high frequencies in human populations.
“For instance, substantial evidence suggests that some archaic alleles and haplotypes are adaptive and persist at high frequencies in human populations [10, 13–19].”
From A refined analysis of Neanderthal-introgressed sequences in modern humans with a complete reference genome (2025) · cites this paper as [15]
There are exceptions to the general neutral or near-neutral pattern of archaic introgression, with examples of adaptive introgression related to the immune system, skin pigmentation, and altitude.
“However, there are exceptions to this general pattern, with examples of adaptive introgression related to the immune system (54, 55), skin pigmentation (9), and altitude (56)”
From Past human expansions shaped the spatial pattern of Neanderthal ancestry (2023) · cites this paper as [56]
The very unusual haplotype structure of the EPAS1 advantageous allele can now best be explained by introgression of DNA from Denisovans.
“For example, the very unusual haplotype structure of the EPAS1 advantageous allele can now best be explained by introgression of DNA from Denisovans [41].”
From Ancient DNA and the rewriting of human history: be sparing with Occam’s razor (2016) · cites this paper as [41]
Archaic admixture appears to have introduced a few beneficial alleles, such as EPAS1.
“On the other hand, archaic admixture appears to have also introduced a few beneficial alleles, such as EPAS1.”
From Ancient DNA and the rewriting of human history: be sparing with Occam’s razor (2016) · cites this paper as [41]
Some archaic alleles have been shown to confer an adaptive advantage for modern humans.
“Some archaic alleles have been shown to confer an adaptive advantage for modern humans”
From Functional implications of Neandertal introgression in modern humans (2017) · cites this paper as [3]
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Zhang, X., Kim, B., Singh, A., Sankararaman, S., Durvasula, A., & Lohmueller, K. E. (2023) · Molecular Biology and Evolution · doi:10.1093/molbev/msad001 · Cited by 29 · see citing works
Self-citationEvolutionary and medical consequences of archaic introgression into modern human genomes
Dolgova, O., & Lao, O. (2018) · Genes · doi:10.3390/genes9070358 · Cited by 34 · see citing works
Koller, D., Wendt, F. R., Pathak, G. A., De Lillo, A., De Angelis, F., Cabrera-Mendoza, B., Tucci, S., & Polimanti, R. (2022) · BMC Biology · doi:10.1186/s12915-022-01449-2 · Cited by 27 · see citing works
“Huerta‑Sánchez E, Jin X, Null A, Bianba Z, Peter BM, Vinckenbosch N, et al. Altitude adaptation in Tibetans caused by introgression of Denisovan‑like DNA.”
BackgroundThe Spatial Signature of Introgression After a Biological Invasion With Hybridization
Quilodrán, C. S., Tsoupas, A., & Currat, M. (2020) · Frontiers in Ecology and Evolution · doi:10.3389/fevo.2020.569620 · Cited by 31 · see citing works
A Chronological Atlas of Natural Selection in the Human Genome during the Past Half-million Years
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<i>DLX5/6</i> GABAergic Expression Affects Social Vocalization: Implications for Human Evolution
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The Impact of Modern Admixture on Archaic Human Ancestry in Human Populations
Witt, K. E., Funk, A., Añorve-Garibay, V., Fang, L. L., & Huerta-Sánchez, E. (2023) · Genome Biology and Evolution · doi:10.1093/gbe/evad066 · Cited by 29 · see citing works
Self-citationThe evolutionary history of human spindle genes includes back-and-forth gene flow with Neandertals
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Archaic Introgression Shaped Human Circadian Traits
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Human Evolution: Genomic Gifts from Archaic Hominins
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Past human expansions shaped the spatial pattern of Neanderthal ancestry
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“However, there are exceptions to this general pattern, with examples of adaptive introgression related to the immune system ( 54 , 55 ), skin pigmentation ( 9 ), and altitude ( 56 ), providing a better adaptation to local environmental conditions and pathogens ( 57 ).”
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Human genetic adaptation related to cellular zinc homeostasis
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“…shared with archaic humans due to incomplete lineage sorting (ILS) was calculated following the same procedure as in Huerta-Sa´nchez et al. (2014) [66] considering the generation (g = 25 years) and split times as in Dannemann et al. (2016) [67] and the average recombination rate of the putatively…”
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Effects of introgressed Neanderthal alleles on present-day brain morphology
Zeloni, R., Amaolo, A., Morez Jacobs, A., Zapparoli, E., Akl, Y., Shafie, M., Huerta-Sanchez, E., Pizzagalli, F., Provero, P., Pagani, L., et al. (2026) · bioRxiv · doi:10.64898/2026.04.14.718380
“Although some examples of adaptive introgression from archaic humans have been identified 7–10 , most introgressed haplotypes are expected to be neutral, or even fitness-reducing due to a) critical demographic conditions of late Neanderthals leading to accumulation of deleterious variants 6,11 and…”
Self-citation
- Authors
- Huerta-Sánchez, E., Jin, X., Asan, Bianba, Z., Peter, B. M., Vinckenbosch, N., Liang, Y., Yi, X., He, M., Somel, M., Ni, P., Wang, B., Ou, X., Huasang, Luosang, J., Cuo, Z. X. P., Li, K., Gao, G., Yin, Y., Wang, W., Zhang, X., Xu, X., Yang, H., Li, Y., Wang, J., Wang, J., & Nielsen, R.
- Affiliations
- BGI Group (China) (CN)
- Tibet Autonomous Region People's Hospital (CN)
- University of California, Berkeley (US)
- Middle East Technical University (TR)
- Macau University of Science and Technology (MO)
- Corresponding author
- Wang, Jian
- Wang, Jun
- Nielsen, Rasmus
- ORCID
- Venue
- Nature
- Published
- 2014-07-02
- Volume
- 512
- Issue
- 7513
- Pages
- 194-197
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4134395
- OpenAlex
- W1999623479
- Cited by
- 1,208
- References
- 42
- Citations by year
- 2026: 88 · 2025: 86 · 2024: 168 · 2023: 102 · 2022: 88 · 2021: 144 · 2020: 96 · 2019: 86 · 2018: 95 · 2017: 83 · 2016: 89 · 2015: 62 · 2014: 21
- FWCI
- 55.83
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc-nd)
- Digital Commons - University of South Florida (University of South Florida) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- OpenMETU (Middle East Technical University) (submittedVersion, cc-by-nc-nd)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Funders
- National Institutes of Health
- National Key Research and Development Program of China (2012CB518201, 2011CB809202, 2011CB809201)
- National Human Genome Research Institute (R01HG003229)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › High Altitude and Hypoxia
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Forensic and Genetic Research
- Social Sciences › Anthropology › Pleistocene-Era Hominins and Archaeology
- Keywords
- Denisovans, Denisovan introgression, EPAS1, high-altitude adaptation, Tibetan Plateau, hypoxia pathway, haplotype structure, admixture, positive selection, Han Chinese, natural selection, hypoxia tolerance, hemoglobin levels, Tibetans, resequencing, incomplete lineage sorting, Neanderthals
- MeSH terms
- Endothelial PAS Domain-Containing Protein 1, Adaptation, Physiological, Altitude, Animals, DNA, Gene Frequency, Haplotypes, Humans, Genetic Variation, Hominidae, Tibet, Polymorphism, Single Nucleotide, Asian People, Basic Helix-Loop-Helix Transcription Factors, Basic Helix-Loop-Helix Proteins
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