Inferred divergent gene regulation in archaic hominins reveals potential phenotypic differences
Open accessAbstract
Sequencing DNA derived from archaic bones has enabled genetic comparison of Neanderthals and anatomically modern humans (AMHs), and revealed that they interbred. However, interpreting what genetic differences imply about their phenotypic differences remains challenging. Here, we introduce an approach for identifying divergent gene regulation between archaic hominins, such as Neanderthals, and AMH sequences, and find 766 genes that are likely to have been divergently regulated (DR) by Neanderthal haplotypes that do not remain in AMHs. DR genes include many involved in phenotypes known to differ between Neanderthals and AMHs, such as the structure of the rib cage and supraorbital ridge development. They are also enriched for genes associated with spontaneous abortion, polycystic ovary syndrome, myocardial infarction and melanoma. Phenotypes associated with modern human variation in these genes’ regulation in ~23,000 biobank patients further support their involvement in immune and cardiovascular phenotypes. Comparing DR genes between two Neanderthals and a Denisovan revealed divergence in the immune system and in genes associated with skeletal and dental morphology that are consistent with the archaeological record. These results establish differences in gene regulatory architecture between AMHs and archaic hominins, and provide an avenue for exploring phenotypic differences between archaic groups from genomic information alone. This study presents a method to identify divergent gene regulation between archaic hominin and anatomically modern human sequences, and shows differences in gene regulatory architecture between the two groups.
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The PrediXcan approach has a modest decrease in performance when applied to Neanderthals, but can accurately be applied between humans and Neanderthals for thousands of genes.
“Previous work demonstrated that this approach has a modest decrease in performance when applied to Neanderthals, but that it can accurately applied between humans and Neanderthals for thousands of genes.”
From Archaic Introgression Shaped Human Circadian Traits (2023) · cites this paper as Colbran et al. 2019
The Results section, “Quantifying gene regulatory divergence with PrediXcan” (page unavailable), reports a 12% reduction in models with significant accuracy in skeletal muscle and a median accuracy decrease of 23–35% across tissues. The Results also report applying the models to more than 17,000 Neanderthal gene regulatory regions. However, the Methods section, “Assessment of Imputation Accuracy on Neanderthal Sequences” (page unavailable), says accuracy on Neanderthal sequences cannot be assessed directly; the paper estimates it using introgressed sequences in modern humans. The claim overstates that estimate as demonstrated accuracy for thousands of genes. (LLM, conf=0.84)
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References 44 · Cited by 50
Research works printed but not linked: 2
- [31]Gokhman D Extensive Regulatory Changes in Genes Affecting Vocal and Facial Anatomy Separate Modern from Archaic Humans. bioRxiv (2017). doi: 10.1101/106955 · DOI · Paper page
- [34]Hernandez RD Singleton Variants Dominate the Genetic Architecture of Human Gene Expression. bioRxiv 219238 (2017).
- Authors
- Colbran, L. L., Gamazon, E. R., Zhou, D., Evans, P., Cox, N. J., & Capra, J. A.
- Affiliations
- Vanderbilt University Medical Center (US)
- University of Cambridge (GB)
- Vanderbilt University (US)
- Corresponding author
- Capra, John A.
- Venue
- Nature Ecology & Evolution
- Published
- 2019-10-07
- Volume
- 3
- Issue
- 11
- Pages
- 1598-1606
- ISSN
- 2397-334X (ISSN-L)
- PMC
- PMC7046098
- OpenAlex
- W2978387981
- Semantic Scholar
- b010becf1e408bc419ae7da92f685fb5e38da916
- Cited by
- 50
- References
- 44
- Citations by year
- 2026: 4 · 2025: 2 · 2024: 8 · 2023: 8 · 2022: 11 · 2021: 9 · 2020: 6 · 2019: 2
- FWCI
- 32.07
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature Ecology & Evolution (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (T32GM080178, R35GM127087)
- U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (R01MH101820, R01MH113362)
- U.S. Department of Health & Human Services | National Institutes of Health (R01MH090937, R01GM115836)
- Burroughs Wellcome Fund (Preterm Birth Initiative)
- March of Dimes | March of Dimes Prematurity Research Center Ohio Collaborative
- Topics
- Social Sciences › Anthropology › Pleistocene-Era Hominins and Archaeology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Forensic and Genetic Research
- Keywords
- Neanderthals, Denisovans, archaic humans, anatomically modern humans, phenotypic differences, miscarriage, polycystic ovary syndrome, myocardial infarction, melanoma, immune system genes
- MeSH terms
- Animals, Female, Haplotypes, Humans, Phenotype, Hominidae, Genome, Human, Neanderthals
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