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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 agro-pastoralists in western Eurasia that were up to 6,500 years 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 five thousand years. 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.

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 15th century Europe that is widely ascribed to syphilis.

The mechanisms behind carbon dioxide (CO2) dependency in non-autotrophic bacterial isolates are unclear. Here we show that the Staphylococcus aureus mpsAB operon, known to play a role in membrane potential generation, is crucial for growth at atmospheric CO2 levels. The genes mpsAB can complement an Escherichia coli carbonic anhydrase (CA) mutant, and CA from E. coli can complement the S. aureus delta-mpsABC mutant. In comparison with the wild type, S. aureus mps mutants produce less hemolytic toxin and are less virulent in animal models of infection. Homologs of mpsA and mpsB are widespread among bacteria and are often found adjacent to each other on the genome. We propose that MpsAB represents a dissolved inorganic carbon transporter, or bicarbonate concentrating system, possibly acting as a sodium bicarbonate cotransporter.

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.

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 16th 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, δ13C and δ15N 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.

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., Yersinia pestis has caused infections (plague) in humans since the Early Bronze Age (5000 years ago). Here, Spyrou et al. reconstruct Y. pestis genomes from Late Bronze Age individuals, and find genomic evidence compatible with flea-mediated transmission causing bubonic plague.

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., Author summary Among the worldwide prevalent treponemal diseases syphilis is a global threat that is currently re-emerging. The origins of syphilis and other treponemal diseases are as yet unresolved and are subject to an intensive scholarly debate. Until now, assumptions on its origins and evolutionary history could only be drawn from osteological analyses of past cases and genetic analysis of contemporary T. pallidum genomes; contributions from ancient DNA are very rare and have so far failed to provide genome-level data. The ancient T. pallidum genomes presented here allow us, for the first time, to perform genome-wide comparative analyses and to assess a connection between osteological manifestations of past treponemal cases and specific T. pallidum species. Our study demonstrates the possibility of retrieving ancient T. pallidum genomes from archeological material and thereby establishes a new method that could greatly contribute to uncover the mystery regarding the origins of treponemal diseases.

Pyrazinamide (PZA) is an important first-line anti-tuberculosis drug, resistance to which occurs primarily due to mutations in pncA (Rv2043c) that encodes the pyrazinamidase enzyme responsible for conversion of pro-drug PZA into its active form. Previous studies have reported numerous resistance-conferring mutations distributed across the entire length of pncA without any hotspot regions. As different lineages of Mycobacterium tuberculosis display a strong geographic association, we sought to understand whether the genetic background influenced the distribution of mutations in pncA. We analyzed the whole genome sequence data of 1,480 clinical isolates representing four major M. tuberculosis lineages to identify the distribution of mutations in the complete operon (Rv2044c-pncA-Rv2042c) and its upstream promoter region. We observed a non-overlapping pattern of mutations among various lineages and identified a lineage 3-specific frame-shift deletion in gene Rv2044c upstream of pncA that disrupted the stop codon and led to its fusion with pncA. This resulted in the addition of a novel domain of unknown function (DUF2784) to the pyrazinamidase enzyme. The variant molecule was computationally modelled and physico-chemical parameters determined to ascertain stability. Although the functional impact of this mutation remains unknown, its lineage specific nature highlights the importance of genetic background and warrants further study.

Pyrazinamide (PZA) is an important first-line anti-tuberculosis drug, resistance to which occurs primarily due to mutations in pncA (Rv2043c) that encodes the pyrazinamidase enzyme responsible for conversion of pro-drug PZA into its active form. Previous studies have reported numerous resistance-conferring mutations distributed across the entire length of pncA without any hotspot regions. As different lineages of Mycobacterium tuberculosis display a strong geographic association, we sought to understand whether the genetic background influenced the distribution of mutations in pncA. We analyzed the whole genome sequence data of 1,480 clinical isolates representing four major M. tuberculosis lineages to identify the distribution of mutations in the complete operon (Rv2044c-pncA-Rv2042c) and its upstream promoter region. We observed a non-overlapping pattern of mutations among various lineages and identified a lineage 3-specific frame-shift deletion in gene Rv2044c upstream of pncA that disrupted the stop codon and led to its fusion with pncA. This resulted in the addition of a novel domain of unknown function (DUF2784) to the pyrazinamidase enzyme. The variant molecule was computationally modelled and physico-chemical parameters determined to ascertain stability. Although the functional impact of this mutation remains unknown, its lineage specific nature highlights the importance of genetic background and warrants further study.

A wide variety of genome sequencing platforms have emerged in the recent past. High-throughput platforms like Illumina and 454 are essentially adaptations of the shotgun approach generating millions of fragmented single or paired sequencing reads. To reconstruct whole genomes, the reads have to be assembled into contigs, which often require further downstream processing. The contigs can be directly ordered according to a reference, scaffolded based on paired read information, or assembled using a combination of the two approaches. While the reference-based approach appears to mask strain-specific information, scaffolding based on paired-end information suffers when repetitive elements longer than the size of the sequencing reads are present in the genome. Sequencing technologies that produce long reads can solve the problems associated with repetitive elements but are not necessarily easily available to researchers. The most common high-throughput technology currently used is the Illumina short read platform. To improve upon the shortcomings associated with the construction of draft genomes with Illumina paired-end sequencing, we developed Contig-Layout-Authenticator (CLA). The CLA pipeline can scaffold reference-sorted contigs based on paired reads, resulting in better assembled genomes. Moreover, CLA also hints at probable misassemblies and contaminations, for the users to cross-check before constructing the consensus draft. The CLA pipeline was designed and trained extensively on various bacterial genome datasets for the ordering and scaffolding of large repetitive contigs. The tool has been validated and compared favorably with other widely-used scaffolding and ordering tools using both simulated and real sequence datasets. CLA is a user friendly tool that requires a single command line input to generate ordered scaffolds.