ABSTRACT
Infectious diseases are among the strongest selective pressures driving human evolution1,2. This includes the single greatest mortality event in recorded history, the first outbreak of the second pandemic of plague, commonly called the Black Death, which was caused by the bacterium Yersinia pestis3. This pandemic devastated Afro-Eurasia, killing up to 30-50% of the population4. To identify loci that may have been under selection during the Black Death, we characterized genetic variation around immune-related genes from 206 ancient DNA extracts, stemming from two different European populations before, during and after the Black Death. Immune loci are strongly enriched for highly differentiated sites relative to a set of non-immune loci, suggesting positive selection. We identify 245 variants that are highly differentiated within the London dataset, four of which were replicated in an independent cohort from Denmark, and represent the strongest candidates for positive selection. The selected allele for one of these variants, rs2549794, is associated with the production of a full-length (versus truncated) ERAP2 transcript, variation in cytokine response to Y. pestis and increased ability to control intracellular Y. pestis in macrophages. Finally, we show that protective variants overlap with alleles that are today associated with increased susceptibility to autoimmune diseases, providing empirical evidence for the role played by past pandemics in shaping present-day susceptibility to disease.
Subject(s)
DNA, Ancient , Genetic Predisposition to Disease , Immunity , Plague , Selection, Genetic , Yersinia pestis , Humans , Aminopeptidases/genetics , Aminopeptidases/immunology , Plague/genetics , Plague/immunology , Plague/microbiology , Plague/mortality , Yersinia pestis/immunology , Yersinia pestis/pathogenicity , Selection, Genetic/immunology , Europe/epidemiology , Europe/ethnology , Immunity/genetics , Datasets as Topic , London/epidemiology , Denmark/epidemiologyABSTRACT
Malaria is a disease of global significance. Ongoing changes to the earth's climate, antimalarial resistance, insecticide resistance, and socioeconomic decline test the resilience of malaria prevention programs. Museum insect specimens present an untapped resource for studying vector-borne pathogens, spurring the question: Do historical mosquito collections contain Plasmodium DNA, and, if so, can museum specimens be used to reconstruct the historical epidemiology of malaria? In this Perspective, we explore molecular techniques practical to pathogen prospecting, which, more broadly, we define as the science of screening entomological museum specimens for human, animal, or plant pathogens. Historical DNA and pathogen prospecting provide a means of describing the coevolution of human, vector, and parasite, informing the development of insecticides, diagnostics, therapeutics, and vaccines.
Subject(s)
Anopheles , Insecticides , Malaria , Animals , Humans , Museums , Anopheles/genetics , Mosquito Vectors , Malaria/epidemiology , Malaria/prevention & control , Insecticide Resistance , Insecticides/pharmacology , DNA , Mosquito ControlABSTRACT
Brucellosis is a disease caused by the bacterium Brucella and typically transmitted through contact with infected ruminants. It is one of the most common chronic zoonotic diseases and of particular interest to public health agencies. Despite its well-known transmission history and characteristic symptoms, we lack a more complete understanding of the evolutionary history of its best-known species-Brucella melitensis. To address this knowledge gap we fortuitously found, sequenced and assembled a high-quality ancient B. melitensis draft genome from the kidney stone of a 14th-century Italian friar. The ancient strain contained fewer core genes than modern B. melitensis isolates, carried a complete complement of virulence genes, and did not contain any indication of significant antimicrobial resistances. The ancient B. melitensis genome fell as a basal sister lineage to a subgroup of B. melitensis strains within the Western Mediterranean phylogenetic group, with a short branch length indicative of its earlier sampling time, along with a similar gene content. By calibrating the molecular clock we suggest that the speciation event between B. melitensis and B. abortus is contemporaneous with the estimated time frame for the domestication of both sheep and goats. These results confirm the existence of the Western Mediterranean clade as a separate group in the 14th CE and suggest that its divergence was due to human and ruminant co-migration.
Subject(s)
Brucella melitensis , Brucellosis , Humans , Animals , Sheep , Brucella melitensis/genetics , Brucella abortus/genetics , Phylogeny , Brucellosis/microbiology , Zoonoses , GoatsABSTRACT
[This corrects the article DOI: 10.1371/journal.ppat.1006750.].
ABSTRACT
Hepatitis B virus (HBV) is a ubiquitous viral pathogen associated with large-scale morbidity and mortality in humans. However, there is considerable uncertainty over the time-scale of its origin and evolution. Initial shotgun data from a mid-16th century Italian child mummy, that was previously paleopathologically identified as having been infected with Variola virus (VARV, the agent of smallpox), showed no DNA reads for VARV yet did for hepatitis B virus (HBV). Previously, electron microscopy provided evidence for the presence of VARV in this sample, although similar analyses conducted here did not reveal any VARV particles. We attempted to enrich and sequence for both VARV and HBV DNA. Although we did not recover any reads identified as VARV, we were successful in reconstructing an HBV genome at 163.8X coverage. Strikingly, both the HBV sequence and that of the associated host mitochondrial DNA displayed a nearly identical cytosine deamination pattern near the termini of DNA fragments, characteristic of an ancient origin. In contrast, phylogenetic analyses revealed a close relationship between the putative ancient virus and contemporary HBV strains (of genotype D), at first suggesting contamination. In addressing this paradox we demonstrate that HBV evolution is characterized by a marked lack of temporal structure. This confounds attempts to use molecular clock-based methods to date the origin of this virus over the time-frame sampled so far, and means that phylogenetic measures alone cannot yet be used to determine HBV sequence authenticity. If genuine, this phylogenetic pattern indicates that the genotypes of HBV diversified long before the 16th century, and enables comparison of potential pathogenic similarities between modern and ancient HBV. These results have important implications for our understanding of the emergence and evolution of this common viral pathogen.
Subject(s)
DNA, Ancient/chemistry , Evolution, Molecular , Genome, Viral , Hepatitis B virus/genetics , Models, Genetic , Mummies/virology , Base Sequence , Bayes Theorem , Child, Preschool , Consensus Sequence , DNA, Ancient/isolation & purification , Gene Library , Hepatitis B virus/isolation & purification , Hepatitis B virus/metabolism , Hepatitis B virus/ultrastructure , High-Throughput Nucleotide Sequencing , Humans , Italy , Microscopy, Electron, Scanning , Mutation , Phylogeny , Reproducibility of Results , Sequence Alignment , Virion/genetics , Virion/isolation & purification , Virion/metabolism , Virion/ultrastructureABSTRACT
Identification of the nucleotide sequences encoding antibiotic resistance elements and determination of their association with antibiotic resistance are critical to improve surveillance and monitor trends in antibiotic resistance. Current methods to study antibiotic resistance in various environments rely on extensive deep sequencing or laborious culturing of fastidious organisms, both of which are heavily time-consuming operations. An accurate and sensitive method to identify both rare and common resistance elements in complex metagenomic samples is needed. Referencing the sequences in the Comprehensive Antibiotic Resistance Database, we designed a set of 37,826 probes to specifically target over 2,000 nucleotide sequences associated with antibiotic resistance in clinically relevant bacteria. Testing of this probe set on DNA libraries generated from multidrug-resistant bacteria to selectively capture resistance genes reproducibly produced higher numbers of reads on target at a greater length of coverage than shotgun sequencing. We also identified additional resistance gene sequences from human gut microbiome samples that sequencing alone was not able to detect. Our method to capture the resistome enables a sensitive means of gene detection in diverse environments where genes encoding antibiotic resistance represent less than 0.1% of the metagenome.
Subject(s)
Drug Resistance, Bacterial/genetics , Metagenome , Bacteria/drug effects , Bacteria/genetics , Bacteria/isolation & purification , DNA Probes/genetics , Databases, Genetic , Drug Resistance, Multiple, Bacterial/genetics , Feces/microbiology , Gastrointestinal Microbiome/drug effects , Gastrointestinal Microbiome/genetics , Genome, Bacterial , Humans , Metagenomics/methods , Microbiota/drug effects , Microbiota/genetics , Whole Genome SequencingABSTRACT
OBJECTIVES: In the 14th century AD, medieval Europe was severely affected by the Great European Famine as well as repeated bouts of disease, including the Black Death, causing major demographic shifts. This high volatility led to increased mobility and migration due to new labor and economic opportunities, as evidenced by documentary and stable isotope data. This study uses ancient DNA (aDNA) isolated from skeletal remains to examine whether evidence for large-scale population movement can be gleaned from the complete mitochondrial genomes of 264 medieval individuals from England (London) and Denmark. MATERIALS AND METHODS: Using a novel library-conserving approach to targeted capture, we recovered 264 full mitochondrial genomes from the petrous portion of the temporal bones and teeth and compared genetic diversity across the medieval period within and between English (London) and Danish populations and with contemporary populations through population pairwise ΦST analysis. RESULTS: We find no evidence of significant differences in genetic diversity spatially or temporally in our dataset, yet there is a high degree of haplotype diversity in our medieval samples with little exact sequence sharing. DISCUSSION: The mitochondrial genomes of both medieval Londoners and medieval Danes suggest high mitochondrial diversity before, during and after the Black Death. While our mitochondrial genomic data lack geographically correlated signals, these data could be the result of high, continual female migration before and after the Black Death or may simply indicate a large female effective population size unaffected by the upheaval of the medieval period. Either scenario suggests a genetic resiliency in areas of northwestern medieval Europe.
Subject(s)
Genetic Variation/genetics , Genome, Mitochondrial/genetics , Plague/history , Bone and Bones/chemistry , DNA, Ancient/analysis , DNA, Mitochondrial/analysis , Denmark , Female , History, Medieval , Human Migration/history , Humans , London , Male , Tooth/chemistryABSTRACT
Yersinia pestis, the causative agent of plague, evolved from the closely related pathogen Yersinia pseudotuberculosis During its emergence, Y. pestis is believed to have acquired its unique pathogenic characteristics through numerous gene gains/losses, genomic rearrangements, and single nucleotide polymorphism (SNP) changes. One such SNP creates a single amino acid variation in the DNA binding domain of PhoP, the response regulator in the PhoP/PhoQ two-component system. Y. pseudotuberculosis and the basal human-avirulent strains of Y. pestis harbor glycines at position 215 of PhoP, whereas the modern human-virulent strains (e.g., KIM and CO92) harbor serines at this residue. Since PhoP plays multiple roles in the adaptation of Y. pestis to stressful host conditions, we tested whether this amino acid substitution affects PhoP activity or the ability of Y. pestis to survive in host environments. Compared to the parental KIM6+ strain carrying the modern allele of phoP (phoP-S215), a derivative carrying the basal allele (phoP-G215) exhibited slightly defective growth under a low-Mg2+ condition and decreased transcription of a PhoP target gene, ugd, as well as an â¼8-fold increase in the susceptibility to the antimicrobial peptide polymyxin B. The phoP-G215 strain showed no apparent defect in flea colonization, although a phoP-null mutant showed decreased flea infectivity in competition experiments. Our results suggest that the amino acid variation at position 215 of PhoP causes subtle changes in the PhoP activity and raise the possibility that the change in this residue have contributed to the evolution of increased virulence in Y. pestisIMPORTANCEY. pestis acquired a single nucleotide polymorphism (SNP) in phoP when the highly human-virulent strains diverged from less virulent basal strains, resulting in an amino acid substitution in the DNA binding domain of the PhoP response regulator. We show that Y. pestis carrying the modern phoP allele has an increased ability to induce the PhoP-regulated ugd gene and resist antimicrobial peptides compared to an isogenic strain carrying the basal allele. Given the important roles PhoP plays in host adaptation, the results raise an intriguing possibility that this amino acid substitution contributed to the evolution of increased virulence in Y. pestis Additionally, we present the first evidence that phoP confers a survival fitness advantage to Y. pestis inside the flea midgut.
Subject(s)
Amino Acid Substitution , Anti-Bacterial Agents/pharmacology , Bacterial Proteins/genetics , Polymyxin B/pharmacology , Yersinia pestis/drug effects , Yersinia pestis/genetics , Animals , Evolution, Molecular , Glycine/metabolism , Macrophages/microbiology , Mice , Mutation , Serine/metabolism , Siphonaptera/microbiology , Transcription, Genetic , Virulence , Yersinia pestis/pathogenicityABSTRACT
Mylodon darwinii is the extinct giant ground sloth named after Charles Darwin, who first collected its remains in South America. We have successfully obtained a high-quality mitochondrial genome at 99-fold coverage using an Illumina shotgun sequencing of a 12 880-year-old bone fragment from Mylodon Cave in Chile. Low level of DNA damage showed that this sample was exceptionally well preserved for an ancient subfossil, probably the result of the dry and cold conditions prevailing within the cave. Accordingly, taxonomic assessment of our shotgun metagenomic data showed a very high percentage of endogenous DNA with 22% of the assembled metagenomic contigs assigned to Xenarthra. Additionally, we enriched over 15 kb of sequence data from seven nuclear exons, using target sequence capture designed against a wide xenarthran dataset. Phylogenetic and dating analyses of the mitogenomic dataset including all extant species of xenarthrans and the assembled nuclear supermatrix unambiguously place Mylodon darwinii as the sister-group of modern two-fingered sloths, from which it diverged around 22 million years ago. These congruent results from both the mitochondrial and nuclear data support the diphyly of the two modern sloth lineages, implying the convergent evolution of their unique suspensory behaviour as an adaption to arboreality. Our results offer promising perspectives for whole-genome sequencing of this emblematic extinct taxon.
Subject(s)
DNA, Ancient/analysis , Genome, Mitochondrial , Xenarthra/classification , Animals , Chile , DNA, Mitochondrial/analysis , Exons/genetics , Fossils , Phylogeny , Sloths/classification , Sloths/genetics , Xenarthra/geneticsABSTRACT
Xenarthra (armadillos, sloths, and anteaters) constitutes one of the four major clades of placental mammals. Despite their phylogenetic distinctiveness in mammals, a reference phylogeny is still lacking for the 31 described species. Here we used Illumina shotgun sequencing to assemble 33 new complete mitochondrial genomes, establishing Xenarthra as the first major placental clade to be fully sequenced at the species level for mitogenomes. The resulting data set allowed the reconstruction of a robust phylogenetic framework and timescale that are consistent with previous studies conducted at the genus level using nuclear genes. Incorporating the full species diversity of extant xenarthrans points to a number of inconsistencies in xenarthran systematics and species definition. We propose to split armadillos into two distinct families Dasypodidae (dasypodines) and Chlamyphoridae (euphractines, chlamyphorines, and tolypeutines) to better reflect their ancient divergence, estimated around 42 Ma. Species delimitation within long-nosed armadillos (genus Dasypus) appeared more complex than anticipated, with the discovery of a divergent lineage in French Guiana. Diversification analyses showed Xenarthra to be an ancient clade with a constant diversification rate through time with a species turnover driven by high but constant extinction. We also detected a significant negative correlation between speciation rate and past temperature fluctuations with an increase in speciation rate corresponding to the general cooling observed during the last 15 My. Biogeographic reconstructions identified the tropical rainforest biome of Amazonia and the Guiana Shield as the cradle of xenarthran evolutionary history with subsequent dispersions into more open and dry habitats.
Subject(s)
Evolution, Molecular , Genome, Mitochondrial , Genomics , Phylogeny , Xenarthra/classification , Xenarthra/genetics , Animals , Bayes Theorem , Biological Evolution , Computational Biology , High-Throughput Nucleotide SequencingABSTRACT
In the 19th century, there were several major cholera pandemics in the Indian subcontinent, Europe, and North America. The causes of these outbreaks and the genomic strain identities remain a mystery. We used targeted high-throughput sequencing to reconstruct the Vibrio cholerae genome from the preserved intestine of a victim of the 1849 cholera outbreak in Philadelphia, part of the second cholera pandemic. This O1 biotype strain has 95 to 97% similarity with the classical O395 genome, differing by 203 single-nucleotide polymorphisms (SNPs), lacking three genomic islands, and probably having one or more tandem cholera toxin prophage (CTX) arrays, which potentially affected its virulence. This result highlights archived medical remains as a potential resource for investigations into the genomic origins of past pandemics.
Subject(s)
Cholera/history , Pandemics/history , Vibrio cholerae/genetics , Bacterial Typing Techniques , Cholera/epidemiology , Cholera/microbiology , DNA, Bacterial/isolation & purification , DNA, Mitochondrial/analysis , Evolution, Molecular , Genome, Bacterial , Genomic Islands , History, 19th Century , Humans , Intestines/microbiology , Intestines/pathology , Male , Philadelphia/epidemiology , Phylogeny , Polymorphism, Single Nucleotide , Sequence Analysis, DNA , Vibrio cholerae/classification , Vibrio cholerae/pathogenicity , Virulence , Virulence Factors/analysisABSTRACT
The discovery of antibiotics more than 70 years ago initiated a period of drug innovation and implementation in human and animal health and agriculture. These discoveries were tempered in all cases by the emergence of resistant microbes. This history has been interpreted to mean that antibiotic resistance in pathogenic bacteria is a modern phenomenon; this view is reinforced by the fact that collections of microbes that predate the antibiotic era are highly susceptible to antibiotics. Here we report targeted metagenomic analyses of rigorously authenticated ancient DNA from 30,000-year-old Beringian permafrost sediments and the identification of a highly diverse collection of genes encoding resistance to ß-lactam, tetracycline and glycopeptide antibiotics. Structure and function studies on the complete vancomycin resistance element VanA confirmed its similarity to modern variants. These results show conclusively that antibiotic resistance is a natural phenomenon that predates the modern selective pressure of clinical antibiotic use.
Subject(s)
Genes, Bacterial/genetics , Metagenomics , Vancomycin Resistance/genetics , Animals , Anti-Bacterial Agents/pharmacology , Bacteria/classification , Bacteria/enzymology , Bacteria/genetics , Bayes Theorem , Crystallography, X-Ray , DNA, Chloroplast/genetics , Freezing , Genes, Mitochondrial/genetics , Genes, Plant/genetics , Geologic Sediments/microbiology , History, Ancient , Hydrogen Bonding , Models, Molecular , Molecular Sequence Data , Phylogeny , Protein Conformation , RNA, Ribosomal/genetics , RNA, Ribosomal, 16S/genetics , Siberia , Vancomycin Resistance/drug effects , Vertebrates/genetics , beta-Lactamases/geneticsABSTRACT
Technological advances in DNA recovery and sequencing have drastically expanded the scope of genetic analyses of ancient specimens to the extent that full genomic investigations are now feasible and are quickly becoming standard. This trend has important implications for infectious disease research because genomic data from ancient microbes may help to elucidate mechanisms of pathogen evolution and adaptation for emerging and re-emerging infections. Here we report a reconstructed ancient genome of Yersinia pestis at 30-fold average coverage from Black Death victims securely dated to episodes of pestilence-associated mortality in London, England, 1348-1350. Genetic architecture and phylogenetic analysis indicate that the ancient organism is ancestral to most extant strains and sits very close to the ancestral node of all Y. pestis commonly associated with human infection. Temporal estimates suggest that the Black Death of 1347-1351 was the main historical event responsible for the introduction and widespread dissemination of the ancestor to all currently circulating Y. pestis strains pathogenic to humans, and further indicates that contemporary Y. pestis epidemics have their origins in the medieval era. Comparisons against modern genomes reveal no unique derived positions in the medieval organism, indicating that the perceived increased virulence of the disease during the Black Death may not have been due to bacterial phenotype. These findings support the notion that factors other than microbial genetics, such as environment, vector dynamics and host susceptibility, should be at the forefront of epidemiological discussions regarding emerging Y. pestis infections.
Subject(s)
Genome, Bacterial/genetics , Plague/microbiology , Yersinia pestis/genetics , Yersinia pestis/isolation & purification , Chromosomes, Bacterial/genetics , Contig Mapping , Dental Pulp/microbiology , Evolution, Molecular , History, Medieval , Humans , London/epidemiology , Molecular Sequence Data , Phylogeny , Plague/epidemiology , Plague/transmission , Plasmids/genetics , Sequence Alignment , Sequence Analysis, DNA , Virulence/genetics , Yersinia pestis/classificationABSTRACT
We report metrics from complete genome capture of nuclear DNA from extinct mammoths using biotinylated RNAs transcribed from an Asian elephant DNA extract. Enrichment of the nuclear genome ranged from 1.06- to 18.65-fold, to an apparent maximum threshold of â¼80% on-target. This projects an order of magnitude less costly complete genome sequencing from long-dead organisms, even when a reference genome is unavailable for bait design.
Subject(s)
Genome , Genomics/methods , Mammoths/genetics , Sequence Analysis, DNA/methods , Animals , DNA/genetics , DNA/isolation & purification , Elephants/genetics , Fossils , History, Ancient , Sequence Alignment/methodsABSTRACT
High-throughput sequencing (HTS) has radically altered approaches to human evolutionary research. Recent contributions highlight that HTS is able to reach depths of the human lineage previously thought to be impossible. In this paper, we outline the methodological advances afforded by recent developments in DNA recovery, data output, scalability, speed, and resolution of the current sequencing technology. We review and critically evaluate the 'DNA pipeline' for ancient samples: from DNA extraction, to constructing immortalized sequence libraries, to enrichment strategies (e.g., polymerase chain reaction [PCR] and hybridization capture), and finally, to bioinformatic analyses of sequence data. We argue that continued evaluations and improvements to this process are essential to ensure sequence data validity. Also, we highlight the role of contamination and authentication in ancient DNA-HTS, which is particularly relevant to ancient human genomics, since sequencing the genomes of hominins such as Homo erectus and Homo heidelbergensis may soon be within the realm of possibility.
Subject(s)
Biological Evolution , Fossils , Genomics , High-Throughput Nucleotide Sequencing , Hominidae/genetics , Animals , Anthropology, Physical , DNA/analysis , DNA/genetics , HumansABSTRACT
The present erratum is in regards to our article entitled 'Ancient DNA and the tropics: a rodent's tale'. We were made aware of problems with some of the ancient sequences submitted to GenBank and conducted a systematic review of all the files used in our study. We discovered that, unfortunately, an incorrect file was sent to GenBank and was also used in some of our downstream analyses. We immediately contacted GenBank, explained the situation and corrected the file. We have redone some analyses with the correct file and describe these changes below.
ABSTRACT
Most genetic studies of Holocene fauna have been performed with ancient samples from dry and cold regions, in which preservation of fossils is facilitated and molecular damage is reduced. Ancient DNA work from tropical regions has been precluded owing to factors that limit DNA preservation (e.g. temperature, hydrolytic damage). We analysed ancient DNA from rodent jawbones identified as Ototylomys phyllotis, found in Holocene and Late Pleistocene stratigraphic layers from Loltún, a humid tropical cave located in the Yucatan peninsula. We extracted DNA and amplified six short overlapping fragments of the cytochrome b gene, totalling 666 bp, which represents an unprecedented success considering tropical ancient DNA samples. We performed genetic, phylogenetic and divergence time analyses, combining sequences from ancient and modern O. phyllotis, in order to assess the ancestry of the Loltún samples. Results show that all ancient samples fall into a unique clade that diverged prior to the divergence of the modern O. phyllotis, supporting it as a distinct Pleistocene form of the Ototylomys genus. Hence, this rodent's tale suggests that the sister group to modern O. phyllotis arose during the Miocene-Pliocene, diversified during the Pleistocene and went extinct in the Holocene.
Subject(s)
Arvicolinae/genetics , Evolution, Molecular , Fossils , Animals , Cytochromes b/genetics , DNA/genetics , Mexico , Phylogeny , Sequence Analysis, DNA , Time Factors , Tropical ClimateABSTRACT
Although investigations of medieval plague victims have identified Yersinia pestis as the putative etiologic agent of the pandemic, methodological limitations have prevented large-scale genomic investigations to evaluate changes in the pathogen's virulence over time. We screened over 100 skeletal remains from Black Death victims of the East Smithfield mass burial site (1348-1350, London, England). Recent methods of DNA enrichment coupled with high-throughput DNA sequencing subsequently permitted reconstruction of ten full human mitochondrial genomes (16 kb each) and the full pPCP1 (9.6 kb) virulence-associated plasmid at high coverage. Comparisons of molecular damage profiles between endogenous human and Y. pestis DNA confirmed its authenticity as an ancient pathogen, thus representing the longest contiguous genomic sequence for an ancient pathogen to date. Comparison of our reconstructed plasmid against modern Y. pestis shows identity with several isolates matching the Medievalis biovar; however, our chromosomal sequences indicate the victims were infected with a Y. pestis variant that has not been previously reported. Our data reveal that the Black Death in medieval Europe was caused by a variant of Y. pestis that may no longer exist, and genetic data carried on its pPCP1 plasmid were not responsible for the purported epidemiological differences between ancient and modern forms of Y. pestis infections.
Subject(s)
DNA, Bacterial/genetics , Plague/microbiology , Plasmids/genetics , Yersinia pestis/genetics , Adult , Bacterial Typing Techniques , Base Sequence , Bone and Bones/metabolism , Bone and Bones/microbiology , DNA, Bacterial/chemistry , DNA, Mitochondrial/chemistry , DNA, Mitochondrial/genetics , Europe/epidemiology , Female , Genetic Variation , History, Medieval , Humans , Male , Molecular Sequence Data , Pandemics/history , Plague/epidemiology , Plague/genetics , Sequence Analysis, DNA , Sequence Homology, Nucleic Acid , Species Specificity , Tooth/metabolism , Tooth/microbiology , Virulence/genetics , Yersinia pestis/classification , Yersinia pestis/pathogenicityABSTRACT
Plague has an enigmatic history as a zoonotic pathogen. This infectious disease will unexpectedly appear in human populations and disappear just as suddenly. As a result, a long-standing line of inquiry has been to estimate when and where plague appeared in the past. However, there have been significant disparities between phylogenetic studies of the causative bacterium, Yersinia pestis, regarding the timing and geographic origins of its reemergence. Here, we curate and contextualize an updated phylogeny of Y. pestis using 601 genome sequences sampled globally. Through a detailed Bayesian evaluation of temporal signal in subsets of these data we demonstrate that a Y. pestis-wide molecular clock is unstable. To resolve this, we developed a new approach in which each Y. pestis population was assessed independently, enabling us to recover substantial temporal signal in five populations, including the ancient pandemic lineages which we now estimate may have emerged decades, or even centuries, before a pandemic was historically documented from European sources. Despite this methodological advancement, we only obtain robust divergence dates from populations sampled over a period of at least 90 years, indicating that genetic evidence alone is insufficient for accurately reconstructing the timing and spread of short-term plague epidemics.
Subject(s)
Plague , Yersinia pestis , Humans , Plague/epidemiology , Plague/genetics , Plague/microbiology , Yersinia pestis/genetics , Phylogeny , Bayes Theorem , Genome, BacterialABSTRACT
The historical epidemiology of plague is controversial due to the scarcity and ambiguity of available data.1,2 A common source of debate is the extent and pattern of plague re-emergence and local continuity in Europe during the 14th-18th century CE.3 Despite having a uniquely long history of plague (â¼5,000 years), Scandinavia is relatively underrepresented in the historical archives.4,5 To better understand the historical epidemiology and evolutionary history of plague in this region, we performed in-depth (n = 298) longitudinal screening (800 years) for the plague bacterium Yersinia pestis (Y. pestis) across 13 archaeological sites in Denmark from 1000 to 1800 CE. Our genomic and phylogenetic data captured the emergence, continuity, and evolution of Y. pestis in this region over a period of 300 years (14th-17th century CE), for which the plague-positivity rate was 8.3% (3.3%-14.3% by site). Our phylogenetic analysis revealed that the Danish Y. pestis sequences were interspersed with those from other European countries, rather than forming a single cluster, indicative of the generation, spread, and replacement of bacterial variants through communities rather than their long-term local persistence. These results provide an epidemiological link between Y. pestis and the unknown pestilence that afflicted medieval and early modern Europe. They also demonstrate how population-scale genomic evidence can be used to test hypotheses on disease mortality and epidemiology and help pave the way for the next generation of historical disease research.