Ancient pathogen genomics as an emerging tool for infectious disease research


Over the past decade, a genomics revolution, made possible through the development of high-throughput sequencing, has triggered considerable progress in the study of ancient DNA, enabling complete genomes of past organisms to be reconstructed. A newly established branch of this field, ancient pathogen genomics, affords an in-depth view of microbial evolution by providing a molecular fossil record for a number of human-associated pathogens. Recent accomplishments include the confident identification of causative agents from past pandemics, the discovery of microbial lineages that are now extinct, the extrapolation of past emergence events on a chronological scale and the characterization of long-term evolutionary history of microorganisms that remain relevant to public health today. In this Review, we discuss methodological advancements, persistent challenges and novel revelations gained through the study of ancient pathogen genomes.

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Fig. 1: Selected cultural time periods and epidemics or pandemics of human history.
Fig. 2: Methods for the detection and isolation of pathogen DNA from ancient metagenomic specimens.
Fig. 3: Methods for whole-genome analysis of clonal and recombining pathogens.
Fig. 4: Map of published modern and ancient Yersinia pestis genomes.
Fig. 5: Yersinia pestis ecology and transmission cycle.
Fig. 6: Evolutionary history of Yersinia pestis.


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The authors thank C. Warinner for her valuable comments to the manuscript and M. Keller for his contributions in assembling comprehensive meta-information for the Y. pestis modern genomic data set. In addition, the authors thank all members of the Molecular Paleopathology and Computational Pathogenomics groups at the Max Planck Institute for the Science of Human History for insightful discussions during meetings. Moreover, they are grateful to M. O’Reilly, H. Shell and R. Barquera for extensive assistance with the graphics. This work was supported by the Max Planck Society.

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Nature Reviews Genetics thanks E. Willerslev and other anonymous reviewer(s) for their contribution to the peer review of this work.

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M.A.S. researched the literature and wrote the article. All authors provided substantial contributions to discussions of the content and reviewed and/or edited the manuscript.

Correspondence to Maria A. Spyrou or Johannes Krause.

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Ancient pathogen genomics

A scientific field focused on the study of whole pathogen genomes retrieved from ancient human, animal or plant remains.

Neolithic revolution

The cultural transition associated with the adoption of farming, animal husbandry and domestication as well as the practice of a sedentary lifestyle among human populations.

Zoonotic transmission

The infectious disease transmission from animals to humans.


Refers to increased, often sudden, disease occurrence within populations across more than one region or continent, whereas epidemics refers to increased disease occurrences within a confined region or country.

Palaeopathological assessment

The evaluation of the health status of ancient individuals or populations, usually through the analysis of disease marker presence on skeletal assemblages.

Ancient DNA

(aDNA). The DNA that has been retrieved from historical, archaeological or palaeontological remains.


Refers to the type of tissue or cell in which infection is established and supported.

Pulp chamber

The highly vascularized inner tooth cavity that is contained within the crown and root portions.

Dental calculus

Calcified dental plaque.


A term used to describe a specimen or data set that includes nucleic acid sequences from all organisms within the sampled proportion.

Taxonomic binning

An algorithm that assigns metagenomic DNA reads to a species or a higher taxonomic rank (for example, genus or family) based on the sequence specificity.

k-mer matching

The matching, for each read, of multiple subsequences of length k without mismatches to a database.


A hydrolytic reaction in which the β-N-glycosidic bond of a purine (adenine or guanine) is cleaved, causing its excision from a DNA strand.


The hydrolytic removal of an amine group (NH2) from a molecule. In ancient DNA studies, the term deamination most often refers to the deamination of cytosine residues into uracils.

Variant calling

The identification of polymorphisms (nucleotide differences) in sequenced data by comparison to a reference.

Molecular clock

A term used to describe that genome evolution occurs as a function of time and, therefore, the genetic distance between two living forms is proportional to the time of their divergence.

Radiocarbon dating

A technique to estimate the age of a specimen on the basis of the amount of incorporated radiocarbon (14C) that after the death of an organism gradually becomes lost over time.

Nucleotide substitution rate

Denotes the frequency of substitution accumulation in an organism within a given time; usually represented as substitutions per site per year.

Divergence dates

The dates of separation between two phylogenetic lineages, for example, the split between two species.

Date randomization

A test that involves random shuffling of calibration points (tip dates) across a molecular phylogeny to evaluate the effect of randomizations compared to true data on the nucleotide substitution rate estimates.

Root-to-tip regression

A test that uses a linear correlation to determine the relationship between branch lengths and sampling times within a time-dependent phylogeny.

Demographic model

A mathematical model that aims to explain the size and density of a population over time.

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Spyrou, M.A., Bos, K.I., Herbig, A. et al. Ancient pathogen genomics as an emerging tool for infectious disease research. Nat Rev Genet 20, 323–340 (2019) doi:10.1038/s41576-019-0119-1

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