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Inferred divergent gene regulation in archaic hominins reveals potential phenotypic differences


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.

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Fig. 1: Identifying divergent gene regulation between individuals using PrediXcan.
Fig. 2: Neanderthal sequences drive substantial divergent regulation compared with modern humans.
Fig. 3: Modern human variation in the regulation of GWARRs is associated with clinical phenotypes.
Fig. 4: Genes in introgression deserts exhibit divergent regulation between modern humans and Neanderthals.
Fig. 5: Comparison of genome-wide regulatory profiles between two Neanderthals, a Denisovan and modern humans.

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All data reported in this paper are available from the project’s GitHub repository (

Code availability

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We thank C. Simonti, D. Rinker, M. L. Benton, N. Creanza, E. Hodges and S. Francis for helpful discussions and comments on the manuscript. L.L.C. was funded by NIH grant T32GM080178 to Vanderbilt University. J.A.C. was funded by NIH grants R01GM115836 and R35GM127087, the March of Dimes Prematurity Research Center Ohio Collaborative and the Burroughs Wellcome Fund. E.R.G. acknowledges support from R01MH101820, R01MH090937 and R01MH113362. E.R.G. is grateful to the President and Fellows of Clare Hall, University of Cambridge for fellowship support and is supported by the National Human Genome Research Institute of the National Institutes of Health under Award Number R35HG010718. This work was conducted in part using the resources of the Advanced Computing Center for Research and Education at Vanderbilt University, and was based in part on data from the PredixVU system of Vanderbilt University Medical Center. This research is solely the responsibility of the authors and does not necessarily represent the views of Vanderbilt University Medical Center.

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Authors and Affiliations



L.L.C. and J.A.C. designed and conducted the experiments. E.R.G. was responsible for the technical design and implementation of the PrediXcan system, and performed the cross-population validation analysis. E.R.G. and D.Z. retrained the models and performed the analysis of predictive power by introgression status. E.R.G., P.E. and N.J.C. designed the PredixVU system and advised on its use. L.L.C. and J.A.C. wrote the manuscript. All authors revised and approved the manuscript for publication.

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Correspondence to John A. Capra.

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Supplementary text, Figs. 1–13 and Tables 1–4.

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Colbran, L.L., Gamazon, E.R., Zhou, D. et al. Inferred divergent gene regulation in archaic hominins reveals potential phenotypic differences. Nat Ecol Evol 3, 1598–1606 (2019).

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