Genetic adaptation and Neandertal admixture shaped the immune system of human populations
Open accessAbstract
Humans differ in the outcome that follows exposure to life-threatening pathogens, yet the extent of population differences in immune responses and their genetic and evolutionary determinants remain undefined. Here, we characterized, using RNA sequencing, the transcriptional response of primary monocytes from Africans and Europeans to bacterial and viral stimuli-ligands activating Toll-like receptor pathways (TLR1/2, TLR4, and TLR7/8) and influenza virus-and mapped expression quantitative trait loci (eQTLs). We identify numerous cis-eQTLs that contribute to the marked differences in immune responses detected within and between populations and a strong trans-eQTL hotspot at TLR1 that decreases expression of pro-inflammatory genes in Europeans only. We find that immune-responsive regulatory variants are enriched in population-specific signals of natural selection and show that admixture with Neandertals introduced regulatory variants into European genomes, affecting preferentially responses to viral challenges. Together, our study uncovers evolutionarily important determinants of differences in host immune responsiveness between human populations.
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Neanderthal variants within immune genes and immune-related CREs have been associated with differential responses to viral infections among present-day Europeans.
“Neanderthal variants within immune genes and immune-related cis-regulatory elements (CREs) have been associated with differential responses to viral infections among present-day Europeans [21, 22].”
From Denisovan introgression has shaped the immune system of present-day Papuans (2022) · cites this paper as [22]
The Results section, “Neandertal Contribution to Transcriptional Responses to Immune Challenges” (page unavailable), links Neandertal-derived variants in Europeans to altered gene-expression responses under influenza-virus and viral-stimulus conditions. The copy does not establish that those specific variants lie within both immune genes and immune-related cis-regulatory elements, as the citing sentence states; it measures cellular transcriptional responses rather than infection outcomes. (LLM, conf=0.82)
Experimental — accuracy not yet measuredThe results presented in this study argue for a potential contribution of Denisovan variants to immune-related phenotypes amongst early modern humans in the region, potentially favouring adaptation to the local environment.
“While further experimental validation of our observations is necessary in order to characterise the genome-wide impact of archaic introgression, the results presented in this study argue for a potential contribution of Denisovan variants to immune-related phenotypes amongst early modern humans in the region, potentially favouring adaptation to the local environment [15, 22].”
From Denisovan introgression has shaped the immune system of present-day Papuans (2022) · cites this paper as [22]
The Introduction says modern Eurasians carry Denisovan or Neandertal ancestry and that archaic admixture has added diversity at immune genes. But the Results and Discussion attribute the paper’s findings on immune responses and possible local adaptation specifically to Neandertal variants in contemporary Europeans, not Denisovan variants in early modern humans in the citing study’s region. (LLM, conf=0.86)
Experimental — accuracy not yet measuredStudies conducted primarily on Neanderthal introgressed DNA have suggested a non-negligible contribution to gene expression variation in modern humans, with repeated examples of Neanderthal archaic variants falling within regulatory elements or the seed region of mature micro-RNAs predicted to affect transcriptional and post-transcriptional regulatory processes.
“Indeed, studies conducted primarily on Neanderthal introgressed DNA have suggested a non-negligible contribution to gene expression variation in modern humans [10, 11, 22], with repeated examples of Neanderthal archaic variants falling within regulatory elements or the seed region of mature micro-RNAs predicted to affect transcriptional and post-transcriptional regulatory processes [11, 62].”
From Denisovan introgression has shaped the immune system of present-day Papuans (2022) · cites this paper as [22]
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredThere 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 [55]
Selected variants can exert their effect by modifying gene expression or by changing the amino acid sequence.
“Selected variants can exert their effect by modifying gene expression or by changing the amino acid sequence [8–12].”
From Functional implications of Neandertal introgression in modern humans (2017) · cites this paper as [10]
A number of instances of adaptive introgression have been described, generally affecting systems that influence immune and metabolic phenotypes.
“a number of instances of adaptive introgression have been described, generally affecting systems that influence immune and metabolic phenotypes [1, 5, 10, 22, 40, 41].”
From Functional implications of Neandertal introgression in modern humans (2017) · cites this paper as [10]
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Kukurba, K. R., Zhang, R., Li, X., Smith, K. S., Knowles, D. A., Tan, M. H., Piskol, R., Lek, M., Snyder, M. P., MacArthur, D. G., et al. (2014) · PLoS Genetics · doi:10.1371/journal.pgen.1004304 · Cited by 62 · see citing works
Gladue, R. P., Cole, S. H., Roach, M. L., et al. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.176.5.3141 · Cited by 55 · see citing works
Kitai, Y., Takeuchi, O., Kawasaki, T., et al. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.611053 · Cited by 21 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
New insights into the genetic etiology of Alzheimer’s disease and related dementias
Bellenguez, C., Küçükali, F., Jansen, I. E., Kleineidam, L., Moreno-Grau, S., Amin, N., Naj, A. C., Campos-Martin, R., Grenier-Boley, B., Andrade, V., et al. (2022) · Nature Genetics · doi:10.1038/s41588-022-01024-z · Cited by 2,498 · see citing works
Self-citationWightman, D. P., Jansen, I. E., Savage, J. E., Shadrin, A. A., Bahrami, S., Holland, D., Rongve, A., Børte, S., Winsvold, B. S., Drange, O. K., et al. (2021) · Nature Genetics · doi:10.1038/s41588-021-00921-z · Cited by 1,011 · see citing works
Impact of Genetic Polymorphisms on Human Immune Cell Gene Expression
Schmiedel, B. J., Singh, D., Madrigal, A., Valdovino-Gonzalez, A. G., White, B. M., Zapardiel-Gonzalo, J., Ha, B., Altay, G., Greenbaum, J. A., McVicker, G., et al. (2018) · Cell · doi:10.1016/j.cell.2018.10.022 · Cited by 867 · see citing works
A high-coverage Neandertal genome from Vindija Cave in Croatia
Prüfer, K., de Filippo, C., Grote, S., Mafessoni, F., Korlević, P., Hajdinjak, M., Vernot, B., Skov, L., Hsieh, P., Peyrégne, S., et al. (2017) · Science · doi:10.1126/science.aao1887 · Cited by 719 · see citing works
Self-citationSchwartzentruber, J., Cooper, S., Liu, J. Z., Barrio-Hernandez, I., Bello, E., Kumasaka, N., Young, A. M. H., Franklin, R. J. M., Johnson, T., Estrada, K., et al. (2021) · Nature Genetics · doi:10.1038/s41588-020-00776-w · Cited by 532 · see citing works
Analysis of Human Sequence Data Reveals Two Pulses of Archaic Denisovan Admixture
Browning, S. R., Browning, B. L., Zhou, Y., Tucci, S., & Akey, J. M. (2018) · Cell · doi:10.1016/j.cell.2018.02.031 · Cited by 381 · see citing works
The influence of evolutionary history on human health and disease
Benton, M. L., Abraham, A., LaBella, A. L., Abbot, P., Rokas, A., & Capra, J. A. (2021) · Nature Reviews Genetics · doi:10.1038/s41576-020-00305-9 · Cited by 291 · see citing works
Neanderthal language revisited: not only us
Dediu, D., & Levinson, S. C. (2018) · Current Opinion in Behavioral Sciences · doi:10.1016/j.cobeha.2018.01.001 · Cited by 218 · see citing works
Discovery of target genes and pathways at GWAS loci by pooled single-cell CRISPR screens
Morris, J. A., Caragine, C., Daniloski, Z., Domingo, J., Barry, T., Lu, L., Davis, K., Ziosi, M., Glinos, D. A., Hao, S., et al. (2023) · Science · doi:10.1126/science.adh7699 · Cited by 208 · see citing works
Evidence that RNA Viruses Drove Adaptive Introgression between Neanderthals and Modern Humans
Enard, D., & Petrov, D. A. (2018) · Cell · doi:10.1016/j.cell.2018.08.034 · Cited by 208 · see citing works
Impacts of Neanderthal-Introgressed Sequences on the Landscape of Human Gene Expression
McCoy, R. C., Wakefield, J., & Akey, J. M. (2017) · Cell · doi:10.1016/j.cell.2017.01.038 · Cited by 200 · see citing works
The Contribution of Neanderthals to Phenotypic Variation in Modern Humans
Dannemann, M., & Kelso, J. (2017) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2017.09.010 · Cited by 193 · see citing works
Self-citationHuman immune diversity: from evolution to modernity
Liston, A., Humblet-Baron, S., Duffy, D., & Goris, A. (2021) · Nature Immunology · doi:10.1038/s41590-021-01058-1 · Cited by 187 · see citing works
Self-citationFunctional implications of Neandertal introgression in modern humans
Dannemann, M., Prüfer, K., & Kelso, J. (2017) · Genome biology · doi:10.1186/s13059-017-1181-7 · Cited by 92 · see citing works
“Despite these general patterns, a number of instances of adaptive introgression have been described, generally affecting systems that influence immune and metabolic phenotypes [1, 5, 10, 22, 40, 41].”
BackgroundSelf-citationSomething old, something borrowed: admixture and adaptation in human evolution
Dannemann, M., & Racimo, F. (2018) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2018.05.009 · Cited by 87 · see citing works
Self-citationQuantifying the contribution of Neanderthal introgression to the heritability of complex traits
McArthur, E., Rinker, D. C., & Capra, J. A. (2021) · Nature Communications · doi:10.1038/s41467-021-24582-y · Cited by 71 · see citing works
Gouy, A., & Excoffier, L. (2020) · Molecular Biology and Evolution · doi:10.1093/molbev/msz306 · Cited by 63 · see citing works
Costas, J. (2018) · American Journal of Medical Genetics Part B: Neuropsychiatric Genetics · doi:10.1002/ajmg.b.32545 · Cited by 58 · see citing works
Silvert, M., Quintana-Murci, L., & Rotival, M. (2019) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2019.04.016 · Cited by 58 · see citing works
Selection against archaic hominin genetic variation in regulatory regions
Telis, N., Aguilar, R., & Harris, K. (2020) · Nature Ecology & Evolution · doi:10.1038/s41559-020-01284-0 · Cited by 51 · see citing works
The lingering effects of Neanderthal introgression on human complex traits
Wei, X., Robles, C. R., Pazokitoroudi, A., Ganna, A., Gusev, A., Durvasula, A., Gazal, S., Loh, P.-R., Reich, D., & Sankararaman, S. (2023) · eLife · doi:10.7554/elife.80757 · Cited by 43 · see citing works
“While our results do not directly support this hypothesis, they pinpoint introgressed alleles in immunerelated genes that could have and continue to modulate human phenotypes consistent with findings from prior studies (AbiRached et al., 2011; Mendez et al., 2012; Quach et al., 2016; Nédélec et al., 2016; Enard and Pe…”
ResultDenisovan introgression has shaped the immune system of present-day Papuans
Vespasiani, D. M., Jacobs, G. S., Cook, L. E., Brucato, N., Leavesley, M., Kinipi, C., Ricaut, F.-X., Cox, M. P., & Gallego Romero, I. (2022) · PLOS Genetics · doi:10.1371/journal.pgen.1010470 · Cited by 46 · see citing works
“As above, repeating this analysis in Neanderthal aSNPs segregating within Europeans also identified significant enrichments of Neanderthal aSNPs within CREs active in mesenchymal and blood & T cells (S6(B) Fig).”
InfluentialNeanderthal introgression reintroduced functional ancestral alleles lost in Eurasian populations
Rinker, D. C., Simonti, C. N., McArthur, E., Shaw, D., Hodges, E., & Capra, J. A. (2020) · Nature Ecology & Evolution · doi:10.1038/s41559-020-1261-z · Cited by 44 · see citing works
Evolutionary 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
The 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
Dannemann, M., Milaneschi, Y., Yermakovich, D., Stiglbauer, V., Kariis, H. M., Krebs, K., Friese, M. A., Otte, C., Estonian Biobank Research Team, Esko, T., et al. (2022) · Translational Psychiatry · doi:10.1038/s41398-022-02196-2 · Cited by 23 · see citing works
“Testing for the proportional association strength to phenotypes In order to quantify the association strength of archaic variants, we compared their number of significantly associated tag aSNPs to the number of frequency-matched non-archaic tag SNPs following similar approaches that have previously been used for such…”
ResultSelf-citationSellayah, D. (2019) · Journal of the Endocrine Society · doi:10.1210/js.2018-00363 · Cited by 21 · see citing works
Enabling multiplexed testing of pooled donor cells through whole-genome sequencing
Chan, Y., Chan, Y. K., Goodman, D. B., Guo, X., Chavez, A., Lim, E. T., & Church, G. M. (2018) · Genome Medicine · doi:10.1186/s13073-018-0541-6 · Cited by 17 · see citing works
A signature of Neanderthal introgression on molecular mechanisms of environmental responses
Findley, A. S., Zhang, X., Boye, C., Lin, Y. L., Kalita, C. A., Barreiro, L., Lohmueller, K. E., Pique-Regi, R., & Luca, F. (2021) · PLoS Genetics · doi:10.1371/journal.pgen.1009493 · Cited by 14 · see citing works
Past human expansions shaped the spatial pattern of Neanderthal ancestry
Quilodrán, C. S., Rio, J., Tsoupas, A., & Currat, M. (2023) · Science Advances · doi:10.1126/sciadv.adg9817 · Cited by 12 · see citing works
Africa, Virus and Vulnerability: COVID-19 Pandemic in Africa
Onuoha, F. C., & Mbaegbu, C. C. (2022) · New Security Challenges · doi:10.1007/978-3-030-82230-9_5 · Cited by 5 · see citing works
- Authors
- Quach, H., Rotival, M., Pothlichet, J., Loh, Y.-H. E., Dannemann, M., Zidane, N., Laval, G., Patin, E., Harmant, C., Lopez, M., Deschamps, M., Naffakh, N., Duffy, D., Coen, A., Leroux-Roels, G., Clément, F., Boland, A., Deleuze, J.-F., Kelso, J., Albert, M. L., & Quintana-Murci, L.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Max Planck Institute for Evolutionary Anthropology (DE)
- Institut Pasteur (FR)
- Ghent University Hospital (BE)
- Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR)
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2016-10
- Volume
- 167
- Issue
- 3
- Pages
- 643-656.e17
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC5075285
- OpenAlex
- W2532435486
- Cited by
- 475
- References
- 85
- Citations by year
- 2026: 41 · 2025: 30 · 2024: 51 · 2023: 52 · 2022: 56 · 2021: 65 · 2020: 56 · 2019: 46 · 2018: 42 · 2017: 33 · 2016: 2 · 2015: 1
- FWCI
- 33.09
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cell (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- HAL (submittedVersion, cc-by-nc-nd)
- Max Planck Digital Library (submittedVersion, other-oa)
- MPG.PuRe (Max Planck Society) (submittedVersion, cc-by-nc-nd)
- Funders
- European Commission (2007–2013, 655417, FP/2007-2013)/ERC, FP/2007/2013)
- Deutsche Forschungsgemeinschaft (FP/2007-2013)
- Max-Planck-Gesellschaft
- FP7 Ideas: European Research Council (281297)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- Toll-like receptors, TLR1, TLR4, TLR7/8, expression quantitative trait loci, cis-eQTL, regulatory variants, natural selection, pro-inflammatory gene expression
- MeSH terms
- Adaptation, Physiological, Alleles, Animals, Bacterial Infections, Base Sequence, Biological Evolution, Gene Expression Regulation, Humans, Immune System, RNA, Selection, Genetic, Transcription, Genetic, Genetic Variation, Virus Diseases, Sequence Analysis, RNA, Quantitative Trait Loci, Black People, White People, Toll-Like Receptors, Adaptive Immunity, Neanderthals
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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