Publications by authors named "Alexander Herbig"

47 Publications

Comparison of target enrichment strategies for ancient pathogen DNA.

Biotechniques 2020 12 2;69(6):455-459. Epub 2020 Nov 2.

Institute for Archaeological Sciences, Archaeo- & Palaeogenetics, University of Tübingen, 72070 Tübingen, Germany.

In ancient DNA research, the degraded nature of the samples generally results in poor yields of highly fragmented DNA; targeted DNA enrichment is thus required to maximize research outcomes. The three commonly used methods - array-based hybridization capture and in-solution capture using either RNA or DNA baits - have different characteristics that may influence the capture efficiency, specificity and reproducibility. Here we compare their performance in enriching pathogen DNA of and from 11 ancient and 19 modern samples. We find that in-solution approaches are the most effective method in ancient and modern samples of both pathogens and that RNA baits usually perform better than DNA baits.
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http://dx.doi.org/10.2144/btn-2020-0100DOI Listing
December 2020

2000-year-old pathogen genomes reconstructed from metagenomic analysis of Egyptian mummified individuals.

BMC Biol 2020 08 28;18(1):108. Epub 2020 Aug 28.

Institute of Evolutionary Medicine, University of Zurich, Winterthurerstrasse 190, 8057, Zurich, Switzerland.

Background: Recent advances in sequencing have facilitated large-scale analyses of the metagenomic composition of different samples, including the environmental microbiome of air, water, and soil, as well as the microbiome of living humans and other animals. Analyses of the microbiome of ancient human samples may provide insights into human health and disease, as well as pathogen evolution, but the field is still in its very early stages and considered highly challenging.

Results: The metagenomic and pathogen content of Egyptian mummified individuals from different time periods was investigated via genetic analysis of the microbial composition of various tissues. The analysis of the dental calculus' microbiome identified Red Complex bacteria, which are correlated with periodontal diseases. From bone and soft tissue, genomes of two ancient pathogens, a 2200-year-old Mycobacterium leprae strain and a 2000-year-old human hepatitis B virus, were successfully reconstructed.

Conclusions: The results show the reliability of metagenomic studies on Egyptian mummified individuals and the potential to use them as a source for the extraction of ancient pathogen DNA.
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http://dx.doi.org/10.1186/s12915-020-00839-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456089PMC
August 2020

A seventeenth-century Mycobacterium tuberculosis genome supports a Neolithic emergence of the Mycobacterium tuberculosis complex.

Genome Biol 2020 08 10;21(1):201. Epub 2020 Aug 10.

Department of Archaeogenetics, Max Planck Institute for the Science of Human History, 07745, Jena, Germany.

Background: Although tuberculosis accounts for the highest mortality from a bacterial infection on a global scale, questions persist regarding its origin. One hypothesis based on modern Mycobacterium tuberculosis complex (MTBC) genomes suggests their most recent common ancestor followed human migrations out of Africa approximately 70,000 years before present. However, studies using ancient genomes as calibration points have yielded much younger dates of less than 6000 years. Here, we aim to address this discrepancy through the analysis of the highest-coverage and highest-quality ancient MTBC genome available to date, reconstructed from a calcified lung nodule of Bishop Peder Winstrup of Lund (b. 1605-d. 1679).

Results: A metagenomic approach for taxonomic classification of whole DNA content permitted the identification of abundant DNA belonging to the human host and the MTBC, with few non-TB bacterial taxa comprising the background. Genomic enrichment enabled the reconstruction of a 141-fold coverage M. tuberculosis genome. In utilizing this high-quality, high-coverage seventeenth-century genome as a calibration point for dating the MTBC, we employed multiple Bayesian tree models, including birth-death models, which allowed us to model pathogen population dynamics and data sampling strategies more realistically than those based on the coalescent.

Conclusions: The results of our metagenomic analysis demonstrate the unique preservation environment calcified nodules provide for DNA. Importantly, we estimate a most recent common ancestor date for the MTBC of between 2190 and 4501 before present and for Lineage 4 of between 929 and 2084 before present using multiple models, confirming a Neolithic emergence for the MTBC.
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http://dx.doi.org/10.1186/s13059-020-02112-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7418204PMC
August 2020

A treponemal genome from an historic plague victim supports a recent emergence of yaws and its presence in 15 century Europe.

Sci Rep 2020 06 11;10(1):9499. Epub 2020 Jun 11.

Max Planck Institute for the Science of Human History, Jena, Germany.

Developments in techniques for identification of pathogen DNA in archaeological samples can expand our resolution of disease detection. Our application of a non-targeted molecular screening tool for the parallel detection of pathogens in historical plague victims from post-medieval Lithuania revealed the presence of more than one active disease in one individual. In addition to Yersinia pestis, we detected and genomically characterized a septic infection of Treponema pallidum pertenue, a subtype of the treponemal disease family recognised as the cause of the tropical disease yaws. Our finding in northern Europe of a disease that is currently restricted to equatorial regions is interpreted within an historical framework of intercontinental trade and potential disease movements. Through this we offer an alternative hypothesis for the history and evolution of the treponemal diseases, and posit that yaws be considered an important contributor to the sudden epidemic of late 15 century Europe that is widely ascribed to syphilis.
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http://dx.doi.org/10.1038/s41598-020-66012-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7290034PMC
June 2020

Origin and Health Status of First-Generation Africans from Early Colonial Mexico.

Curr Biol 2020 Jun 30;30(11):2078-2091.e11. Epub 2020 Apr 30.

Department of Archaeogenetics (DAG), Max-Planck Institute for the Science of Human History (MPI-SHH), Kahlaische Str. 10, 07745 Jena, Germany. Electronic address:

The forced relocation of several thousand Africans during Mexico's historic period has so far been documented mostly through archival sources, which provide only sparse detail on their origins and lived experience. Here, we employ a bioarchaeological approach to explore the life history of three 16 century Africans from a mass burial at the San José de los Naturales Royal Hospital in Mexico City. Our approach draws together ancient genomic data, osteological analysis, strontium isotope data from tooth enamel, δC and δN isotope data from dentine, and ethnohistorical information to reveal unprecedented detail on their origins and health. Analyses of skeletal features, radiogenic isotopes, and genetic data from uniparental, genome-wide, and human leukocyte antigen (HLA) markers are consistent with a Sub-Saharan African origin for all three individuals. Complete genomes of Treponema pallidum sub. pertenue (causative agent of yaws) and hepatitis B virus (HBV) recovered from these individuals provide insight into their health as related to infectious disease. Phylogenetic analysis of both pathogens reveals their close relationship to strains circulating in current West African populations, lending support to their origins in this region. The further relationship between the treponemal genome retrieved and a treponemal genome previously typed in an individual from Colonial Mexico highlights the role of the transatlantic slave trade in the introduction and dissemination of pathogens into the New World. Putting together all lines of evidence, we were able to create a biological portrait of three individuals whose life stories have long been silenced by disreputable historical events.
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http://dx.doi.org/10.1016/j.cub.2020.04.002DOI Listing
June 2020

CoproID predicts the source of coprolites and paleofeces using microbiome composition and host DNA content.

PeerJ 2020 17;8:e9001. Epub 2020 Apr 17.

Department of Archaeogenetics, Max Planck Institute for the Science of Human History, Jena, Germany.

Shotgun metagenomics applied to archaeological feces (paleofeces) can bring new insights into the composition and functions of human and animal gut microbiota from the past. However, paleofeces often undergo physical distortions in archaeological sediments, making their source species difficult to identify on the basis of fecal morphology or microscopic features alone. Here we present a reproducible and scalable pipeline using both host and microbial DNA to infer the host source of fecal material. We apply this pipeline to newly sequenced archaeological specimens and show that we are able to distinguish morphologically similar human and canine paleofeces, as well as non-fecal sediments, from a range of archaeological contexts.
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http://dx.doi.org/10.7717/peerj.9001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7169968PMC
April 2020

Emergence of human-adapted Salmonella enterica is linked to the Neolithization process.

Nat Ecol Evol 2020 03 24;4(3):324-333. Epub 2020 Feb 24.

Department of Archaeogenetics, Max Planck Institute for the Science of Human History, Jena, Germany.

It has been hypothesized that the Neolithic transition towards an agricultural and pastoralist economy facilitated the emergence of human-adapted pathogens. Here, we recovered eight Salmonella enterica subsp. enterica genomes from human skeletons of transitional foragers, pastoralists and agropastoralists in western Eurasia that were up to 6,500 yr old. Despite the high genetic diversity of S. enterica, all ancient bacterial genomes clustered in a single previously uncharacterized branch that contains S. enterica adapted to multiple mammalian species. All ancient bacterial genomes from prehistoric (agro-)pastoralists fall within a part of this branch that also includes the human-specific S. enterica Paratyphi C, illustrating the evolution of a human pathogen over a period of 5,000 yr. Bacterial genomic comparisons suggest that the earlier ancient strains were not host specific, differed in pathogenic potential and experienced convergent pseudogenization that accompanied their downstream host adaptation. These observations support the concept that the emergence of human-adapted S. enterica is linked to human cultural transformations.
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http://dx.doi.org/10.1038/s41559-020-1106-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7186082PMC
March 2020

Advances in the molecular detection of tuberculosis in pre-contact Andean South America.

Int J Paleopathol 2020 06 20;29:128-140. Epub 2020 Jan 20.

Department of Archaeogenetics, Max Planck Institute for the Science of Human History, Kahlaische Str 10, 07745 Jena, Germany. Electronic address:

Andean paleopathological research has significantly enhanced knowledge about the geographical distribution and evolution of tuberculosis (TB) in pre-Columbian South America. In this paper, we review the history and progress of research on ancient tuberculosis (TB) in the Andean region, focusing on the strengths and limitations of current approaches for the molecular detection of ancient pathogens, with special attention to TB. As a case study, we describe a molecular screening approach for the detection of ancient Mycobacterium tuberculosis in individuals from Late Intermediate Period (1000-1400 CE) contexts at the site of Huari, Peru. We evaluate 34 commingled human vertebrae and combine morphological assessments of pathology with high throughput sequencing and a non-selective approach to ancient pathogen DNA screening. Our method enabled the simultaneous detection of ancient M. tuberculosis DNA and an evaluation of the environmental microbial composition of each sample. Our results show that despite the dominance of environmental DNA, molecular signatures of M. tuberculosis were identified in eight vertebrae, six of which had no observable skeletal pathology classically associated tuberculosis infection. This screening approach will assist in the identification of candidate samples for downstream genomic analyses. The method permits higher resolution disease identification in cases where pathology may be absent, or where the archaeological context may necessitate a broad differential diagnosis based on morphology alone.
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http://dx.doi.org/10.1016/j.ijpp.2019.12.006DOI Listing
June 2020

HOPS: automated detection and authentication of pathogen DNA in archaeological remains.

Genome Biol 2019 12 16;20(1):280. Epub 2019 Dec 16.

Max Planck Institute for the Science of Human History, Jena, Germany.

High-throughput DNA sequencing enables large-scale metagenomic analyses of complex biological systems. Such analyses are not restricted to present-day samples and can also be applied to molecular data from archaeological remains. Investigations of ancient microbes can provide valuable information on past bacterial commensals and pathogens, but their molecular detection remains a challenge. Here, we present HOPS (Heuristic Operations for Pathogen Screening), an automated bacterial screening pipeline for ancient DNA sequences that provides detailed information on species identification and authenticity. HOPS is a versatile tool for high-throughput screening of DNA from archaeological material to identify candidates for genome-level analyses.
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http://dx.doi.org/10.1186/s13059-019-1903-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6913047PMC
December 2019

Phylogeography of the second plague pandemic revealed through analysis of historical Yersinia pestis genomes.

Nat Commun 2019 10 2;10(1):4470. Epub 2019 Oct 2.

Max Planck Institute for the Science of Human History, 07745, Jena, Germany.

The second plague pandemic, caused by Yersinia pestis, devastated Europe and the nearby regions between the 14 and 18 centuries AD. Here we analyse human remains from ten European archaeological sites spanning this period and reconstruct 34 ancient Y. pestis genomes. Our data support an initial entry of the bacterium through eastern Europe, the absence of genetic diversity during the Black Death, and low within-outbreak diversity thereafter. Analysis of post-Black Death genomes shows the diversification of a Y. pestis lineage into multiple genetically distinct clades that may have given rise to more than one disease reservoir in, or close to, Europe. In addition, we show the loss of a genomic region that includes virulence-related genes in strains associated with late stages of the pandemic. The deletion was also identified in genomes connected with the first plague pandemic (541-750 AD), suggesting a comparable evolutionary trajectory of Y. pestis during both events.
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http://dx.doi.org/10.1038/s41467-019-12154-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6775055PMC
October 2019

Paleomicrobiology: Diagnosis and Evolution of Ancient Pathogens.

Annu Rev Microbiol 2019 09 5;73:639-666. Epub 2019 Jul 5.

Department of Archaeogenetics, Max Planck Institute for the Science of Human History, 07745 Jena, Germany; email:

The last century has witnessed progress in the study of ancient infectious disease from purely medical descriptions of past ailments to dynamic interpretations of past population health that draw upon multiple perspectives. The recent adoption of high-throughput DNA sequencing has led to an expanded understanding of pathogen presence, evolution, and ecology across the globe. This genomic revolution has led to the identification of disease-causing microbes in both expected and unexpected contexts, while also providing for the genomic characterization of ancient pathogens previously believed to be unattainable by available methods. In this review we explore the development of DNA-based ancient pathogen research, the specialized methods and tools that have emerged to authenticate and explore infectious disease of the past, and the unique challenges that persist in molecular paleopathology. We offer guidelines to mitigate the impact of these challenges, which will allow for more reliable interpretations of data in this rapidly evolving field of investigation.
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http://dx.doi.org/10.1146/annurev-micro-090817-062436DOI Listing
September 2019

Ancient genomes from across Western Europe reveal early diversification during the First Pandemic (541-750).

Proc Natl Acad Sci U S A 2019 06 4;116(25):12363-12372. Epub 2019 Jun 4.

Department of Archaeogenetics, Max Planck Institute for the Science of Human History, 07745 Jena, Germany;

The first historically documented pandemic caused by began as the Justinianic Plague in 541 within the Roman Empire and continued as the so-called First Pandemic until 750. Although paleogenomic studies have previously identified the causative agent as , little is known about the bacterium's spread, diversity, and genetic history over the course of the pandemic. To elucidate the microevolution of the bacterium during this time period, we screened human remains from 21 sites in Austria, Britain, Germany, France, and Spain for DNA and reconstructed eight genomes. We present a methodological approach assessing single-nucleotide polymorphisms (SNPs) in ancient bacterial genomes, facilitating qualitative analyses of low coverage genomes from a metagenomic background. Phylogenetic analysis on the eight reconstructed genomes reveals the existence of previously undocumented diversity during the sixth to eighth centuries, and provides evidence for the presence of multiple distinct strains in Europe. We offer genetic evidence for the presence of the Justinianic Plague in the British Isles, previously only hypothesized from ambiguous documentary accounts, as well as the parallel occurrence of multiple derived strains in central and southern France, Spain, and southern Germany. Four of the reported strains form a polytomy similar to others seen across the phylogeny, associated with the Second and Third Pandemics. We identified a deletion of a 45-kb genomic region in the most recent First Pandemic strains affecting two virulence factors, intriguingly overlapping with a deletion found in 17th- to 18th-century genomes of the Second Pandemic.
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http://dx.doi.org/10.1073/pnas.1820447116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6589673PMC
June 2019

Ancient pathogen genomics as an emerging tool for infectious disease research.

Nat Rev Genet 2019 06;20(6):323-340

Department of Archaeogenetics, Max Planck Institute for the Science of Human History, Jena, Germany.

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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http://dx.doi.org/10.1038/s41576-019-0119-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7097038PMC
June 2019

Selection of Appropriate Metagenome Taxonomic Classifiers for Ancient Microbiome Research.

mSystems 2018 Jul-Aug;3(4). Epub 2018 Jul 17.

Department of Archaeogenetics, Max Planck Institute for the Science of Human History, Jena, Germany.

Metagenomics enables the study of complex microbial communities from myriad sources, including the remains of oral and gut microbiota preserved in archaeological dental calculus and paleofeces, respectively. While accurate taxonomic assignment is essential to this process, DNA damage characteristic of ancient samples (e.g., reduction in fragment size and cytosine deamination) may reduce the accuracy of read taxonomic assignment. Using a set of -generated metagenomic data sets, we investigated how the addition of ancient DNA (aDNA) damage patterns influences microbial taxonomic assignment by five widely used profilers: QIIME/UCLUST, MetaPhlAn2, MIDAS, CLARK-S, and MALT. -generated data sets were designed to mimic dental plaque, consisting of 40, 100, and 200 microbial species/strains, both with and without simulated aDNA damage patterns. Following taxonomic assignment, the profiles were evaluated for species presence/absence, relative abundance, alpha diversity, beta diversity, and specific taxonomic assignment biases. Unifrac metrics indicated that both MIDAS and MetaPhlAn2 reconstructed the most accurate community structure. QIIME/UCLUST, CLARK-S, and MALT had the highest number of inaccurate taxonomic assignments; false-positive rates were highest by CLARK-S and QIIME/UCLUST. Filtering out species present at <0.1% abundance greatly increased the accuracy of CLARK-S and MALT. All programs except CLARK-S failed to detect some species from the input file that were in their databases. The addition of ancient DNA damage resulted in minimal differences in species detection and relative abundance between simulated ancient and modern data sets for most programs. Overall, taxonomic profiling biases are program specific rather than damage dependent, and the choice of taxonomic classification program should be tailored to specific research questions. Ancient biomolecules from oral and gut microbiome samples have been shown to be preserved in the archaeological record. Studying ancient microbiome communities using metagenomic techniques offers a unique opportunity to reconstruct the evolutionary trajectories of microbial communities through time. DNA accumulates specific damage over time, which could potentially affect taxonomic classification and our ability to accurately reconstruct community assemblages. It is therefore necessary to assess whether ancient DNA (aDNA) damage patterns affect metagenomic taxonomic profiling. Here, we assessed biases in community structure, diversity, species detection, and relative abundance estimates by five popular metagenomic taxonomic classification programs using -generated data sets with and without aDNA damage. Damage patterns had minimal impact on the taxonomic profiles produced by each program, while false-positive rates and biases were intrinsic to each program. Therefore, the most appropriate classification program is one that minimizes the biases related to the questions being addressed.
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http://dx.doi.org/10.1128/mSystems.00080-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6050634PMC
July 2018

Historic Treponema pallidum genomes from Colonial Mexico retrieved from archaeological remains.

PLoS Negl Trop Dis 2018 06 21;12(6):e0006447. Epub 2018 Jun 21.

Institute for Archaeological Sciences, University of Tübingen, Tübingen, Germany.

Treponema pallidum infections occur worldwide causing, among other diseases, syphilis and yaws. In particular sexually transmitted syphilis is regarded as a re-emerging infectious disease with millions of new infections annually. Here we present three historic T. pallidum genomes (two from T. pallidum ssp. pallidum and one from T. pallidum ssp. pertenue) that have been reconstructed from skeletons recovered from the Convent of Santa Isabel in Mexico City, operational between the 17th and 19th century. Our analyses indicate that different T. pallidum subspecies caused similar diagnostic presentations that are normally associated with syphilis in infants, and potential evidence of a congenital infection of T. pallidum ssp. pertenue, the causative agent of yaws. This first reconstruction of T. pallidum genomes from archaeological material opens the possibility of studying its evolutionary history at a resolution previously assumed to be out of reach.
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http://dx.doi.org/10.1371/journal.pntd.0006447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6013024PMC
June 2018

Analysis of 3800-year-old Yersinia pestis genomes suggests Bronze Age origin for bubonic plague.

Nat Commun 2018 06 8;9(1):2234. Epub 2018 Jun 8.

Max Planck Institute for the Science of Human History, Kahlaische Str. 10, 07745, Jena, Germany.

The origin of Yersinia pestis and the early stages of its evolution are fundamental subjects of investigation given its high virulence and mortality that resulted from past pandemics. Although the earliest evidence of Y. pestis infections in humans has been identified in Late Neolithic/Bronze Age Eurasia (LNBA 5000-3500y BP), these strains lack key genetic components required for flea adaptation, thus making their mode of transmission and disease presentation in humans unclear. Here, we reconstruct ancient Y. pestis genomes from individuals associated with the Late Bronze Age period (~3800 BP) in the Samara region of modern-day Russia. We show clear distinctions between our new strains and the LNBA lineage, and suggest that the full ability for flea-mediated transmission causing bubonic plague evolved more than 1000 years earlier than previously suggested. Finally, we propose that several Y. pestis lineages were established during the Bronze Age, some of which persist to the present day.
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http://dx.doi.org/10.1038/s41467-018-04550-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5993720PMC
June 2018

Ancient genomes reveal a high diversity of Mycobacterium leprae in medieval Europe.

PLoS Pathog 2018 05 10;14(5):e1006997. Epub 2018 May 10.

Institute for Archaeological Sciences, University of Tübingen, Tübingen, Germany.

Studying ancient DNA allows us to retrace the evolutionary history of human pathogens, such as Mycobacterium leprae, the main causative agent of leprosy. Leprosy is one of the oldest recorded and most stigmatizing diseases in human history. The disease was prevalent in Europe until the 16th century and is still endemic in many countries with over 200,000 new cases reported annually. Previous worldwide studies on modern and European medieval M. leprae genomes revealed that they cluster into several distinct branches of which two were present in medieval Northwestern Europe. In this study, we analyzed 10 new medieval M. leprae genomes including the so far oldest M. leprae genome from one of the earliest known cases of leprosy in the United Kingdom-a skeleton from the Great Chesterford cemetery with a calibrated age of 415-545 C.E. This dataset provides a genetic time transect of M. leprae diversity in Europe over the past 1500 years. We find M. leprae strains from four distinct branches to be present in the Early Medieval Period, and strains from three different branches were detected within a single cemetery from the High Medieval Period. Altogether these findings suggest a higher genetic diversity of M. leprae strains in medieval Europe at various time points than previously assumed. The resulting more complex picture of the past phylogeography of leprosy in Europe impacts current phylogeographical models of M. leprae dissemination. It suggests alternative models for the past spread of leprosy such as a wide spread prevalence of strains from different branches in Eurasia already in Antiquity or maybe even an origin in Western Eurasia. Furthermore, these results highlight how studying ancient M. leprae strains improves understanding the history of leprosy worldwide.
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http://dx.doi.org/10.1371/journal.ppat.1006997DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5944922PMC
May 2018

Neolithic and medieval virus genomes reveal complex evolution of hepatitis B.

Elife 2018 05 10;7. Epub 2018 May 10.

Max Planck Institute for the Science of Human History, Jena, Germany.

The hepatitis B virus (HBV) is one of the most widespread human pathogens known today, yet its origin and evolutionary history are still unclear and controversial. Here, we report the analysis of three ancient HBV genomes recovered from human skeletons found at three different archaeological sites in Germany. We reconstructed two Neolithic and one medieval HBV genome by assembly from shotgun DNA sequencing data. Additionally, we observed HBV-specific peptides using paleo-proteomics. Our results demonstrated that HBV has circulated in the European population for at least 7000 years. The Neolithic HBV genomes show a high genomic similarity to each other. In a phylogenetic network, they do not group with any human-associated HBV genome and are most closely related to those infecting African non-human primates. The ancient viruses appear to represent distinct lineages that have no close relatives today and possibly went extinct. Our results reveal the great potential of ancient DNA from human skeletons in order to study the long-time evolution of blood borne viruses.
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http://dx.doi.org/10.7554/eLife.36666DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6008052PMC
May 2018

Salmonella enterica genomes from victims of a major sixteenth-century epidemic in Mexico.

Nat Ecol Evol 2018 03 15;2(3):520-528. Epub 2018 Jan 15.

Max Planck Institute for the Science of Human History, Jena, Germany.

Indigenous populations of the Americas experienced high mortality rates during the early contact period as a result of infectious diseases, many of which were introduced by Europeans. Most of the pathogenic agents that caused these outbreaks remain unknown. Through the introduction of a new metagenomic analysis tool called MALT, applied here to search for traces of ancient pathogen DNA, we were able to identify Salmonella enterica in individuals buried in an early contact era epidemic cemetery at Teposcolula-Yucundaa, Oaxaca in southern Mexico. This cemetery is linked, based on historical and archaeological evidence, to the 1545-1550 CE epidemic that affected large parts of Mexico. Locally, this epidemic was known as 'cocoliztli', the pathogenic cause of which has been debated for more than a century. Here, we present genome-wide data from ten individuals for Salmonella enterica subsp. enterica serovar Paratyphi C, a bacterial cause of enteric fever. We propose that S. Paratyphi C be considered a strong candidate for the epidemic population decline during the 1545 cocoliztli outbreak at Teposcolula-Yucundaa.
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http://dx.doi.org/10.1038/s41559-017-0446-6DOI Listing
March 2018

Central European Woolly Mammoth Population Dynamics: Insights from Late Pleistocene Mitochondrial Genomes.

Sci Rep 2017 12 18;7(1):17714. Epub 2017 Dec 18.

Institute for Archaeological Science, University of Tübingen, Rümelinstraße 23, 72070, Tübingen, Germany.

The population dynamics of the Pleistocene woolly mammoth (Mammuthus primigenius) has been the subject of intensive palaeogenetic research. Although a large number of mitochondrial genomes across Eurasia have been reconstructed, the available data remains geographically sparse and mostly focused on eastern Eurasia. Thus, population dynamics in other regions have not been extensively investigated. Here, we use a multi-method approach utilising proteomic, stable isotope and genetic techniques to identify and generate twenty woolly mammoth mitochondrial genomes, and associated dietary stable isotopic data, from highly fragmentary Late Pleistocene material from central Europe. We begin to address region-specific questions regarding central European woolly mammoth populations, highlighting parallels with a previous replacement event in eastern Eurasia ten thousand years earlier. A high number of shared derived mutations between woolly mammoth mitochondrial clades are identified, questioning previous phylogenetic analysis and thus emphasizing the need for nuclear DNA studies to explicate the increasingly complex genetic history of the woolly mammoth.
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http://dx.doi.org/10.1038/s41598-017-17723-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5735091PMC
December 2017

AureoWiki ̵ The repository of the Staphylococcus aureus research and annotation community.

Int J Med Microbiol 2018 Aug 24;308(6):558-568. Epub 2017 Nov 24.

Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany. Electronic address:

In light of continuously accumulating data and knowledge on major human pathogens, comprehensive and up-to-date sources of easily accessible information are urgently required. The AureoWiki database (http://aureowiki.med.uni-greifswald.de) provides detailed information on the genes and proteins of clinically and experimentally relevant S. aureus strains, currently covering NCTC 8325, COL, Newman, USA300_FPR3757, and N315. By implementing a pan-genome approach, AureoWiki facilitates the transfer of knowledge gained in studies with different S. aureus strains, thus supporting functional annotation and better understanding of this organism. All data related to a given gene or gene product is compiled on a strain-specific gene page. The gene pages contain sequence-based information complemented by data on, for example, protein function and localization, transcriptional regulation, and gene expression. The information provided is connected via links to other databases and published literature. Importantly, orthologous genes of the individual strains, which are linked by a pan-genome gene identifier and a unified gene name, are presented side by side using strain-specific tabs. The respective pan-genome gene page contains an orthologue table for 32 S. aureus strains, a multiple-strain genome viewer, a protein sequence alignment as well as other comparative information. The data collected in AureoWiki is also accessible through various download options in order to support bioinformatics applications. In addition, based on two large-scale gene expression data sets, AureoWiki provides graphical representations of condition-dependent mRNA levels and protein profiles under various laboratory and infection-related conditions.
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http://dx.doi.org/10.1016/j.ijmm.2017.11.011DOI Listing
August 2018

The Stone Age Plague and Its Persistence in Eurasia.

Curr Biol 2017 Dec 22;27(23):3683-3691.e8. Epub 2017 Nov 22.

Max Planck Institute for the Science of Human History, Jena, Germany; Institute for Archaeological Sciences, Archaeo- and Palaeogenetics, University of Tübingen, Tübingen, Germany. Electronic address:

Yersinia pestis, the etiologic agent of plague, is a bacterium associated with wild rodents and their fleas. Historically it was responsible for three pandemics: the Plague of Justinian in the 6 century AD, which persisted until the 8 century [1]; the renowned Black Death of the 14 century [2, 3], with recurrent outbreaks until the 18 century [4]; and the most recent 19 century pandemic, in which Y. pestis spread worldwide [5] and became endemic in several regions [6]. The discovery of molecular signatures of Y. pestis in prehistoric Eurasian individuals and two genomes from Southern Siberia suggest that Y. pestis caused some form of disease in humans prior to the first historically documented pandemic [7]. Here, we present six new European Y. pestis genomes spanning the Late Neolithic to the Bronze Age (LNBA; 4,800 to 3,700 calibrated years before present). This time period is characterized by major transformative cultural and social changes that led to cross-European networks of contact and exchange [8, 9]. We show that all known LNBA strains form a single putatively extinct clade in the Y. pestis phylogeny. Interpreting our data within the context of recent ancient human genomic evidence that suggests an increase in human mobility during the LNBA, we propose a possible scenario for the early spread of Y. pestis: the pathogen may have entered Europe from Central Eurasia following an expansion of people from the steppe, persisted within Europe until the mid-Bronze Age, and moved back toward Central Eurasia in parallel with human populations.
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http://dx.doi.org/10.1016/j.cub.2017.10.025DOI Listing
December 2017

Mining Metagenomic Data Sets for Ancient DNA: Recommended Protocols for Authentication.

Trends Genet 2017 08 5;33(8):508-520. Epub 2017 Jul 5.

Max Planck Institute for the Science of Human History, Jena, Germany. Electronic address:

While a comparatively young area of research, investigations relying on ancient DNA data have been highly valuable in revealing snapshots of genetic variation in both the recent and the not-so-recent past. Born out of a tradition of single-locus PCR-based approaches that often target individual species, stringent criteria for both data acquisition and analysis were introduced early to establish high standards of data quality. Today, the immense volume of data made available through next-generation sequencing has significantly increased the analytical resolution offered by processing ancient tissues and permits parallel analyses of host and microbial communities. The adoption of this new approach to data acquisition, however, requires an accompanying update on methods of DNA authentication, especially given that ancient molecules are expected to exist in low proportions in archaeological material, where an environmental signal is likely to dominate. In this review, we provide a summary of recent data authentication approaches that have been successfully used to distinguish between endogenous and nonendogenous DNA sequences in metagenomic data sets. While our discussion mostly centers on the detection of ancient human and ancient bacterial pathogen DNA, their applicability is far wider.
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http://dx.doi.org/10.1016/j.tig.2017.05.005DOI Listing
August 2017

dRNA-seq transcriptional profiling of the FK506 biosynthetic gene cluster in Streptomyces tsukubaensis NRRL18488 and general analysis of the transcriptome.

RNA Biol 2017 11 31;14(11):1617-1626. Epub 2017 Jul 31.

a Pharmaceutical Institute, Department of Pharmaceutical Biology , University of Tübingen , Tübingen , Germany.

FK506 (tacrolimus) is a valuable immunosuppressant produced by several Streptomyces strains. In the genome of the wild type producer Streptomyces tsukubaensis NRRL18488, FK506 biosynthesis is encoded by a gene cluster that spans 83.5 (kb). A whole transcriptome differential shotgun sequencing (dRNA-seq) of S. tsukubaensis was performed to analyze transcription at 2 different time points; before and during active FK506 production. In total, 8,914 transcription start sites were identified in either condition, which enabled precise determination of the 5'-UTR length of the corresponding transcripts as well as the identification of 2 consensus sequence motifs in the promoter regions. The transcription start sites of all gene operons within the FK506 cluster were identified, including 3 examples of leaderless RNA transcripts. These data provide detailed insight into the transcription of the FK506 biosynthetic gene cluster to support future regulatory studies, genetic manipulation, and industrial production.
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http://dx.doi.org/10.1080/15476286.2017.1341020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5785230PMC
November 2017

A Robust Framework for Microbial Archaeology.

Annu Rev Genomics Hum Genet 2017 08 26;18:321-356. Epub 2017 Apr 26.

Department of Archaeogenetics, Max Planck Institute for the Science of Human History, Jena 07745, Germany; email:

Microbial archaeology is flourishing in the era of high-throughput sequencing, revealing the agents behind devastating historical plagues, identifying the cryptic movements of pathogens in prehistory, and reconstructing the ancestral microbiota of humans. Here, we introduce the fundamental concepts and theoretical framework of the discipline, then discuss applied methodologies for pathogen identification and microbiome characterization from archaeological samples. We give special attention to the process of identifying, validating, and authenticating ancient microbes using high-throughput DNA sequencing data. Finally, we outline standards and precautions to guide future research in the field.
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http://dx.doi.org/10.1146/annurev-genom-091416-035526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5581243PMC
August 2017

Origin of modern syphilis and emergence of a pandemic Treponema pallidum cluster.

Nat Microbiol 2016 Dec 5;2:16245. Epub 2016 Dec 5.

Institute for Evolutionary Biology and Environmental Studies, University of Zurich, 8057 Zurich, Switzerland.

The abrupt onslaught of the syphilis pandemic that started in the late fifteenth century established this devastating infectious disease as one of the most feared in human history. Surprisingly, despite the availability of effective antibiotic treatment since the mid-twentieth century, this bacterial infection, which is caused by Treponema pallidum subsp. pallidum (TPA), has been re-emerging globally in the last few decades with an estimated 10.6 million cases in 2008 (ref. 2). Although resistance to penicillin has not yet been identified, an increasing number of strains fail to respond to the second-line antibiotic azithromycin. Little is known about the genetic patterns in current infections or the evolutionary origins of the disease due to the low quantities of treponemal DNA in clinical samples and difficulties in cultivating the pathogen. Here, we used DNA capture and whole-genome sequencing to successfully interrogate genome-wide variation from syphilis patient specimens, combined with laboratory samples of TPA and two other subspecies. Phylogenetic comparisons based on the sequenced genomes indicate that the TPA strains examined share a common ancestor after the fifteenth century, within the early modern era. Moreover, most contemporary strains are azithromycin-resistant and are members of a globally dominant cluster, named here as SS14-Ω. The cluster diversified from a common ancestor in the mid-twentieth century subsequent to the discovery of antibiotics. Its recent phylogenetic divergence and global presence point to the emergence of a pandemic strain cluster.
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http://dx.doi.org/10.1038/nmicrobiol.2016.245DOI Listing
December 2016

Effect of X-ray irradiation on ancient DNA in sub-fossil bones - Guidelines for safe X-ray imaging.

Sci Rep 2016 09 12;6:32969. Epub 2016 Sep 12.

Department of Archaeogenetics, Max Planck Institute for the Science of Human History, Jena, Germany.

Sub-fossilised remains may still contain highly degraded ancient DNA (aDNA) useful for palaeogenetic investigations. Whether X-ray computed [micro-] tomography ([μ]CT) imaging of these fossils may further damage aDNA remains debated. Although the effect of X-ray on DNA in living organisms is well documented, its impact on aDNA molecules is unexplored. Here we investigate the effects of synchrotron X-ray irradiation on aDNA from Pleistocene bones. A clear correlation appears between decreasing aDNA quantities and accumulating X-ray dose-levels above 2000 Gray (Gy). We further find that strong X-ray irradiation reduces the amount of nucleotide misincorporations at the aDNA molecule ends. No representative effect can be detected for doses below 200 Gy. Dosimetry shows that conventional μCT usually does not reach the risky dose level, while classical synchrotron imaging can degrade aDNA significantly. Optimised synchrotron protocols and simple rules introduced here are sufficient to ensure that fossils can be scanned without impairing future aDNA studies.
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http://dx.doi.org/10.1038/srep32969DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5018823PMC
September 2016

A High-Coverage Yersinia pestis Genome from a Sixth-Century Justinianic Plague Victim.

Mol Biol Evol 2016 11 30;33(11):2911-2923. Epub 2016 Aug 30.

Max Planck Institute for the Science of Human History, Jena, Germany.

The Justinianic Plague, which started in the sixth century and lasted to the mid eighth century, is thought to be the first of three historically documented plague pandemics causing massive casualties. Historical accounts and molecular data suggest the bacterium Yersinia pestis as its etiological agent. Here we present a new high-coverage (17.9-fold) Y. pestis genome obtained from a sixth-century skeleton recovered from a southern German burial site close to Munich. The reconstructed genome enabled the detection of 30 unique substitutions as well as structural differences that have not been previously described. We report indels affecting a lacl family transcription regulator gene as well as nonsynonymous substitutions in the nrdE, fadJ, and pcp genes, that have been suggested as plague virulence determinants or have been shown to be upregulated in different models of plague infection. In addition, we identify 19 false positive substitutions in a previously published lower-coverage Y. pestis genome from another archaeological site of the same time period and geographical region that is otherwise genetically identical to the high-coverage genome sequence reported here, suggesting low-genetic diversity of the plague during the sixth century in rural southern Germany.
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http://dx.doi.org/10.1093/molbev/msw170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5062324PMC
November 2016

Historical Y. pestis Genomes Reveal the European Black Death as the Source of Ancient and Modern Plague Pandemics.

Cell Host Microbe 2016 Jun;19(6):874-81

Max Planck Institute for the Science of Human History, Jena 07743, Germany; Department of Archeological Sciences, University of Tuebingen, Tuebingen 72070, Germany. Electronic address:

Ancient DNA analysis has revealed an involvement of the bacterial pathogen Yersinia pestis in several historical pandemics, including the second plague pandemic (Europe, mid-14(th) century Black Death until the mid-18(th) century AD). Here we present reconstructed Y. pestis genomes from plague victims of the Black Death and two subsequent historical outbreaks spanning Europe and its vicinity, namely Barcelona, Spain (1300-1420 cal AD), Bolgar City, Russia (1362-1400 AD), and Ellwangen, Germany (1485-1627 cal AD). Our results provide support for (1) a single entry of Y. pestis in Europe during the Black Death, (2) a wave of plague that traveled toward Asia to later become the source population for contemporary worldwide epidemics, and (3) the presence of an historical European plague focus involved in post-Black Death outbreaks that is now likely extinct.
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http://dx.doi.org/10.1016/j.chom.2016.05.012DOI Listing
June 2016

EAGER: efficient ancient genome reconstruction.

Genome Biol 2016 Mar 31;17:60. Epub 2016 Mar 31.

Center for Bioinformatics (ZBIT), Integrative Transcriptomics, Eberhard-Karls-Universität, Sand 14, Tübingen, 72076, Germany.

Background: The automated reconstruction of genome sequences in ancient genome analysis is a multifaceted process.

Results: Here we introduce EAGER, a time-efficient pipeline, which greatly simplifies the analysis of large-scale genomic data sets. EAGER provides features to preprocess, map, authenticate, and assess the quality of ancient DNA samples. Additionally, EAGER comprises tools to genotype samples to discover, filter, and analyze variants.

Conclusions: EAGER encompasses both state-of-the-art tools for each step as well as new complementary tools tailored for ancient DNA data within a single integrated solution in an easily accessible format.
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http://dx.doi.org/10.1186/s13059-016-0918-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4815194PMC
March 2016