Natural selection contributed to immunological differences between hunter-gatherers and agriculturalists

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The shift from a hunter-gatherer to an agricultural mode of subsistence is believed to have been associated with profound changes in the burden and diversity of pathogens across human populations. Yet, the extent to which the advent of agriculture affected the evolution of the human immune system remains unknown. Here we present a comparative study of variation in the transcriptional responses of peripheral blood mononuclear cells to bacterial and viral stimuli between Batwa rainforest hunter-gatherers and Bakiga agriculturalists from Uganda. We observed increased divergence between hunter-gatherers and agriculturalists in the early transcriptional response to viruses compared with that for bacterial stimuli. We demonstrate that a significant fraction of these transcriptional differences are under genetic control and we show that positive natural selection has helped to shape population differences in immune regulation. Across the set of genetic variants underlying inter-population immune-response differences, however, the signatures of positive selection were disproportionately observed in the rainforest hunter-gatherers. This result is counter to expectations on the basis of the popularized notion that shifts in pathogen exposure due to the advent of agriculture imposed radically heightened selective pressures in agriculturalist populations.

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Fig. 1: Transcriptional differences between Batwa-HG and Bakiga-AG populations.
Fig. 2: Differences in immune response between HG and AG populations.
Fig. 3: Analysis of the contribution of genetics to differences in immune response between the HG-Batwa and the AG-Bakiga.
Fig. 4: Evidence of selection driving population differences in immune response.

Data availability

The data that support the findings of this study are available at

Code availability

All scripts required to run the analyses described in the manuscript can be found at


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The authors thank the Batwa and Bakiga communities and all individuals who participated in this study; also the Batwa Development Program, J. Byaruhanga, M. Magambo, P. Byamugisha, S. Twesigomwe, J. Safari and L. Busingye for expert assistance during the sample collection process in Uganda. We thank S. Nanyunja for technical laboratory assistance. We thank J. Tung and L.B.B. laboratory members for critical reading of the manuscript. We thank Calcul Québec and Compute Canada for providing access to the supercomputer Briaree from the University of Montreal. This work was supported by NIH R01-GM115656 to G.H.P and L.B.B., a fellowship from the Réseau de Médecine Génétique Appliquée and the Fonds de Recherche du Québec−Santé to G.F.H, and 1 F32 GM125228-638 01A1 to C.M.B. RNA-seq data have been deposited in Gene Expression Omnibus (accession number GSE120502). The 1M SNP genotype data are available at the European Genome–Phenome archive, (accession numbers EGAS00001000605 and EGAS00001000908).

Author information

L.B.B. and G.H.P conceived and coordinated the study, and performed field work in Uganda. S.L.N facilitated samples collection. J.B., A.D. and V.Y. performed cell culture experiments. G.F.H. and J.S. conducted most data analysis, with support from F.C.G. and C.M.B and input from co-authors. M.J.M, Y.L. and S.J.E. generated VirScan data. E.S. and L.Q.M. contributed to data generation. G.F.H, L.B.B. and G.H.P. wrote the paper with input from all co-authors.

Correspondence to Luis B. Barreiro.

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The authors declare no competing interests.

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Supplementary information

Supplementary Figures

Supplementary Figs. 1–11.

Reporting Summary

Supplementary Table 1

Metadata for samples used in the study.

Supplementary Table 2

Results for identifying PopDE and PopDR genes.

Supplementary Table 3

Results from GSEA for popDE and PopDR genes.

Supplementary Table 4

Results from VirScan analysis.

Supplementary Table 5

Results from mapping of cis-eQTL.

Supplementary Table 6

Delta-PVE among PopDE genes.

Supplementary Table 7

Selection statistics for SNPs that are mapped cis-eQTL.

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