The Genomic Landscape of Post-Black Death Epidemics in Northern Europe and the Caucasus

Cameron Robert Ferguson; Åshild J. Vågene‬; Marcel Keller; Caroline Arcini; Eveline Altena; Gorka Lasso; Axel Christophersen; Maria Cinthio; Sean Dexter Denham; Sascha Dreyer; S. Sunna Ebenesersdóttir; Martin R. Ellegaard; Shyam Gopalakrishnan; Agnar Freyr Helgason; Miren Iraeta-Orbegozo; Liam Thomas Lanigan; Xiaodong Liu; Emma Loftus; Maja M. B. Lunn; Ashot Margaryan; Kristjan H. S. Moore; Bente Philippsen; Hannes Schroeder; Hakob Simonyan; Zaruhi Khachatryan; Pooja Swali; Cedric C.S. Tan; Levon Yepiskoposyan; Laurent Frantz; Philip Slavin

doi:10.64898/2026.08.25.746822

bioRxivAug 28, 2026GeneticsPreprint

The Genomic Landscape of Post-Black Death Epidemics in Northern Europe and the Caucasus

Cameron Robert Ferguson iD, Åshild J. Vågene‬iD, Marcel Keller iD, Caroline Arcini iD, Eveline Altena iD, Gorka Lasso iD, Axel Christophersen iD, Maria Cinthio, Sean Dexter Denham iD, Sascha Dreyer iD, S. Sunna Ebenesersdóttir iD, Martin R. Ellegaard iD, Shyam Gopalakrishnan iD, Agnar Freyr Helgason iD, Miren Iraeta-Orbegozo iD, Liam Thomas Lanigan iD, Xiaodong Liu iD, Emma Loftus iD, Maja M. B. Lunn, Ashot Margaryan iD, Kristjan H. S. Moore iD, Bente Philippsen iD, Hannes Schroeder iD, Hakob Simonyan iD, Zaruhi Khachatryan iD, , Lucy van Dorp iD

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Abstract

One of the most devastating events in human history, the Black Death (c.1347-1353), marked the beginning of the Second Plague Pandemic. After initially receding, plague returned in intermittent outbreaks throughout Europe, beginning with the pestis secunda. Despite its significance, the post-Black Death epidemiology of Yersinia pestis remains poorly understood. Here, we report 23 new Y. pestis genomes recovered from Second Plague Pandemic contexts across Scandinavia, the Netherlands, Iceland, and Armenia, spanning approximately 270 years. Applying a reproducible mutation-filtering pipeline to assess genetic diversity, we report both Black Death and post-Black Death lineages and document multiple waves of plague at individual cemetery sites. We identify four pestis secunda genomes, including three from Armenia, supporting the eastward dissemination of this lineage prior to its disappearance from Europe. We also resolve a previously under-characterised Branch 1A sub-lineage of Y. pestis and provide the first genomic evidence of plague in Iceland, resolving longstanding uncertainty over its presence on the island. Finally, by calling variants against a reconstructed ancestral reference, we identify clade-defining mutations, including nonsynonymous changes in metabolic and biofilm-related genes with predicted structural effects that may have contributed to shaping the epidemiological dynamics of the Second Plague Pandemic.

In-depth summary

Claude Opus 5.5 · xhigh effort · 8 Nov 2026 · from the full text of version 1 (28 Aug 2026) · CC BY 4.0

Twenty-three new Yersinia pestis genomes from Scandinavia, the Netherlands, Iceland and Armenia extend the Second Plague Pandemic phylogeny, with the first Icelandic plague genome and eastward-spreading pestis secunda strains.

Post-Black Death plague epidemiology is poorly understood, and genomic sampling is sparse at the northern and eastern margins of medieval Europe. The authors call variants against a reconstructed ancestral genome instead of the modern CO92 reference, which they say exposes mutations that a derived reference masks.

Key results

Shown23 Y. pestis genomes were recovered from five sites, 14 of them above 5x coverage. Together with published data they give a maximum likelihood tree of 288 genomes (84 ancient, 204 modern); all high-coverage new genomes fall in Branch 1.
All 23 genomes had at least 1x coverage and 15 exceeded 3x. The tree used 2,804 high-confidence SNPs after a custom filtering pipeline. Three previously published ancient genomes were excluded for likely non-Yersinia mutations. · Recovery of Y. pestis genomes from the Black…; Phylogenetic reconstruction of Black Death and…
SuggestedArmenian genomes support an eastward spread of the pestis secunda lineage. CB045 from Armenia is identical to Bolgar 2370 from Tatarstan, and the two low-coverage Armenian genomes were placed in the same clade. A new Swedish pestis secunda genome (LUN132) is identical to German KRA018.
CB045 (5.4x) is identical to Bolgar 2370. CB010 (1.41x) and CB044 (1.50x) were placed by pathPhynder. LUN132 (73.6x) from Lund is identical to the German KRA018. · Phylogenetic reconstruction of Black Death and…; Phylogenetic placement of lower coverage Y…; Discussion
SuggestedThe Icelandic genome USK13 falls in a previously under-characterised sub-lineage of basal Branch 1A. This is the first genomic evidence of plague in Iceland, and the lineage is dated to the late 14th century and shared with Germany, Denmark and Sweden.
USK13 (~2.5x) carries nine substitutions relative to Lund genomes LUN363U and LUN214, seven of them at ≥3x. The clade's most recent common ancestor is dated to 1375-1385. A mutation-rate estimate gives USK13 a date of 1436-1503, closer to the 1494-1495 outbreak. · Recovery of Y. pestis genomes from the Black…; Phylogenetic placement of lower coverage Y…; Discussion
SuggestedPlague in Lund appears to have recurred through repeated introductions rather than persisting from one local source. Diversity across the seven Lund clades was not significantly different from that of pooled Black Death and basal Branch 1A genomes.
Seven distinct clades across branches 1A and 1B over about 270 years. Median pairwise distance was ~15.7 substitutions in Lund vs ~18.35 across all Black Death and basal 1A genomes (permutation test, n = 100000, Δmedian = -2.65, p = 0.136). · Phylogenetic reconstruction of Black Death and…; Recovery of Y. pestis genomes from the Black…
SuggestedAncestral Reference Mapping (ARM) found 16 mutations between the Great Polytomy and the pestis secunda. Three non-synonymous ones were acquired and retained: pabA Cys140Arg, YPO_RS10940 Arg401Leu and hmsR Val50Gly. AlphaFold3 and Rosetta modelling suggest local structural effects.
16 mutations (five substitutions, 11 indels), six non-synonymous after excluding intergenic ones. hmsR is present in about 92% of 1272 Branch 1 genomes, which the authors say suggests its non-core designation may warrant reevaluation. AlphaFold3 pTM was 0.96 for PabA, 0.81 for YPO_RS10940 and 0.93 for hmsR. · Identification of mutational signatures defining…; Ancestral Reference Mapping (ARM) and Mutation…; Protein modelling and interface prediction; In-silico prediction of stability changes (ddG)…

Methods, data and reproducibility

Ancient shotgun data were screened for Y. pestis with MALT/HOPS and enriched by capture. Genomes were mapped, filtered and placed on a maximum likelihood tree, with low-coverage genomes placed by pathPhynder. Variants were then called against a reconstructed Great Polytomy genome and assigned to branches by parsimony.

Y. pestis genomes from Trinitatis Church, Lund (c. 1270-1536) · Yersinia pestis (from human remains) · n = 14 genomes (12 above 3x)
Y. pestis genomes from Trondheim, Norway (1275-1600) · Yersinia pestis (from human remains) · n = 4 genomes
Y. pestis genomes from Aghtsk, Armenia (c. 1260-1365) · Yersinia pestis (from human remains) · n = 3 genomes
Y. pestis genomes from Eindhoven (Netherlands) and Útskála (Iceland) · Yersinia pestis (from human remains) · n = 1 genome each
Ancient (84, including this study's high-coverage genomes) and modern (204) Y. pestis genomes used for the phylogeny · Yersinia pestis · n = 288 genomes in total (84 ancient, 204 modern)
Published Branch 1 assemblies used in a BLAST check of hmsR presence · Yersinia pestis · n = 1272 genomes

Methods & tools: MALT, HOPS, nf-core eager, GATK Unified Genotyper, MultiVCFAnalyzer, IQ-TREE 2, BactDating, pathPhynder, SnpEff, AlphaFold3, Rosetta, AncientMetagenomeDir
Code: https://github.com/theHatIsBack/The-Genomic-Landscape-of-Post-Black-Death-Epidemics-in-Northern-Europe-and-the-Caucasus-scripts
Software & environment: Versions are given for most tools, e.g. nf-core eager v2.4.7, Nextflow v22.10.0, IQ-TREE 2 v2.4.0, pathPhynder v1.2.3, BactDating v1.1.2, SnpEff v5.3a. No container or lockfile is mentioned.
Reproducibility gaps: Raw reads and aligned reads are said to be in the European Nucleotide Archive, but the accession is a placeholder (PRJXXXXXXX). Many details are in supplementary notes and tables that are not in the text.

Limitations (5)

The functional consequences of the pabA, YPO_RS10940 and hmsR substitutions are unknown. The structural predictions are computational, and the authors say experimental validation is needed. · stated by the authors
USK13 has low coverage, so missing SNPs on its terminal branch cannot be counted. The authors say its estimated date is likely an underestimate. · stated by the authors
Sampling remains geographically uneven, and the authors list the northern and eastern peripheries of medieval Europe as sparsely sampled. · stated by the authors
The Lund recurrence inference rests on a non-significant permutation test (p = 0.136), which shows no detectable difference from pooled diversity and does not directly test a model of introduction. · noted in this summary
Assigning genomes to specific historical outbreaks relies on radiocarbon dates and documentary records, and some genomes map to several candidate outbreaks. · noted in this summary