This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
27,99 € / 30 days
cancel any time
Subscribe to this journal
Receive 51 print issues and online access
199,00 € per year
only 3,90 € per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Data availability
New genotype data were generated for 32 individuals for whom we had previously generated functional data and genotyped at the putatively selected ERAP2 variant. These genotype data are available from the GitHub repository for this project (https://github.com/TaurVil/VilgalysKlunk_response_to_commentary/functional analyses/DATA/genotypes_for_functional_analyses.txt).
Code availability
The code to replicate the analyses described here is available at https://github.com/TaurVil/VilgalysKlunk_response_to_commentary.
References
Barton, A. R. et al. Insufficient evidence for natural selection associated with the Black Death. Nature https://doi.org/10.1038/s41586-024-08496-5 (2025).
Klunk, J. et al. Evolution of immune genes is associated with the Black Death. Nature 611, 312–319 (2022).
Hamilton, F. et al. Variation in ERAP2 has opposing effects on severe respiratory infection and autoimmune disease. Am. J. Hum. Genet. https://doi.org/10.1016/j.ajhg.2023.02.008 (2023).
Klunk, J. et al. Author Correction: Evolution of immune genes is associated with the Black Death. Nature https://doi.org/10.1038/s41586-024-08522-6 (2025).
International HapMap Consortium. A second generation human haplotype map of over 3.1 million SNPs. Nature 449, 851–861 (2007).
Voight, B. F., Kudaravalli, S., Wen, X. & Pritchard, J. K. A map of recent positive selection in the human genome. PLoS Biol. 4, e72 (2006).
1000 Genomes Project Consortium. A global reference for human genetic variation. Nature 526, 68–74 (2015).
Hui, R. et al. Genetic history of Cambridgeshire before and after the Black Death. Sci. Adv. 10, eadi5903 (2024).
Mathieson, I. & Terhorst, J. Direct detection of natural selection in Bronze Age Britain. Genome Res. 32, 2057–2067 (2022).
Nait Saada, J. et al. Identity-by-descent detection across 487,409 British samples reveals fine scale population structure and ultra-rare variant associations. Nat. Commun. 11, 6130 (2020).
Andrés, A. M. et al. Balancing selection maintains a form of ERAP2 that undergoes nonsense-mediated decay and affects antigen presentation. PLoS Genet. 6, e1001157 (2010).
Ye, C. J. et al. Genetic analysis of isoform usage in the human anti-viral response reveals influenza-specific regulation of ERAP2 transcripts under balancing selection. Genome Res. 28, 1812–1825 (2018).
Laval, G., Patin, E., Quintana-Murci, L. & Kerner, G. Deep estimation of the intensity and timing of natural selection from ancient genomes. Mol. Ecol. Resour. 24, e14015 (2024).
Danecek, P. et al. Twelve years of SAMtools and BCFtools. GigaScience 10, giab008 (2021).
Korneliussen, T. S., Albrechtsen, A. & Nielsen, R. ANGSD: analysis of next generation sequencing data. BMC Bioinf. 15, 356 (2014).
Acknowledgements
We thank all members of the Barreiro and Poinar laboratories for their constructive comments and feedback. We thank J. Berg, R. Blekhman, Y. Gilad, N. Gonzales, E. Patin, G. Perry, L. Quintana-Murci and J. Tung for their comments on the paper. Computational resources were provided by the University of Chicago Research Computing Center. This study was supported by grant no. R01-GM134376 to L.B.B., H.N.P. and J.P.-C.; a grant from the Wenner-Gren Foundation to J.F.B. (grant no. 8702); and the Center for Interdisciplinary Study of Inflammatory Intestinal Disorders (grant no. NIDDK P30 DK042086). H.N.P. was supported by an Insight Grant no. 20008499 from the Social Sciences and Humanities Research Council of Canada and The Canadian Institute for Advanced Research under the Humans & the Microbiome programme. T.P.V. was supported by grant nos. F32GM140568 and K99HG013351. X.C. and M. Steinrücken were supported by grant no. R01GM146051.
Author information
Authors and Affiliations
Contributions
L.B.B., T.P.V. and H.N.P. directed this study. T.P.V. completed all analyses except for the estimation of selection coefficients, which was performed by X.C. and M. Steinrücken. T.P.V., H.N.P. and L.B.B. wrote the paper, with input from all authors (including J.K., C.E.D., M. Shiratori, J.M., R.B., D.E., M.I.P., R.R., S.N.D., J.A.G., J.L.B., A.C., N.V., K.E., J.-C.G., G.B.G., A.D., J.-M.R., V.Y., R.S., C.J.Y., M.B., A.D., J.F.B., D.M., G.A.R. and J.P.-C.). Contributions of all authors to the original publication can be found in ref. 2.
Corresponding authors
Ethics declarations
Competing interests
J.K., A. Devault and J.-M.R. declare financial interest in Daicel Arbor Biosciences, who provided the myBaits hybridization capture kits for this study. The other authors declare no competing interests.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Extended data figures and tables
Extended Data Fig. 1 Maximum likelihood allele frequency estimates are not biased by coverage.
The difference between simulated “true” allele frequencies and the allele frequency estimated using either the genotype likelihoods (GL) in Klunk et al. or the maximum likelihood (ML) approach outlined by Barton et al. The GL approach shows a bias towards overestimating the frequency of rare variants, which is exaggerated at lower coverages. No similar bias is apparent using the ML approach.
Extended Data Fig. 2 Candidate loci for positive selection, based on the proportion of permutations exceeding the observed patterns.
Loci ranked by evidence for positive selection, shown on the y-axis as the -log10 proportion of permutations where the FST was greater than the observed FST in both London and Denmark, the allele frequency change between pre- and post-Black Death was in the same direction for both London and Denmark, and the allele frequency change between pre- and during-Black Death in London was in the opposite direction. Candidate immune loci (n = 290) are shown in green, and values are jittered along the x-axis to limit overlapping points. Among our 4 original candidate loci, rs2549794 (ERAP2) and rs1052025 (NFATC1) are shown in red. The other two variants failed to meet the criteria where the changes in allele frequency between pre- vs post-Black Death and pre- vs during-Black Death should be in the opposite direction. This plot differs from Fig. 2a in that it shows the proportion of permutations on the y-axis rather than the multivariate p-value used in Fig. 2a.
Supplementary information
Supplementary Tables
This file contains Supplementary Tables 1–4.
Rights and permissions
About this article
Cite this article
Vilgalys, T.P., Klunk, J., Demeure, C.E. et al. Reply to: Insufficient evidence for natural selection associated with the Black Death. Nature 638, E23–E29 (2025). https://doi.org/10.1038/s41586-024-08497-4
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41586-024-08497-4
