Periodic Reporting for period 1 - PATHOGEN (Paleogenomic Analysis of Tuberculosis epidemiological Histories Over Geo-cultural and Ecological Networks in South America)
Reporting period: 2023-05-01 to 2025-04-30
Tuberculosis (TB) remains the leading cause of death by a single infectious agent globally, despite extensive efforts to combat the disease. Its persistence is partly due to limited knowledge of the evolutionary history of the causative pathogen, the Mycobacterium tuberculosis complex (MTBC). Understanding how this pathogen emerged, spread, and adapted over time is essential for informing modern TB control strategies. However, the current understanding of MTBC evolution is mostly based on modern pathogen strains, as there are only a few ancient genomes available, primarily from Europe and the Andean region of South America. This lack of diverse ancient genomes restricts insights into the geographic and temporal development of TB strains.
The PATHOGEN project addresses these gaps by investigating the evolutionary history of TB in South America, focusing on “how, when, and where” MTBC emerged, evolved, and spread. Recent advances in ancient DNA (aDNA) technology have enabled the reconstruction of MTBC genomes from ancient and historical samples, revealing strains previously unknown to infect humans. However, only nine ancient or historic MTBC genomes are publicly available, with only three from the Americas. These three represent an animal strain of MTBC (M. pinnipedii) and are geographically limited to the Andean region. Meanwhile, archaeological findings show widespread evidence of TB in skeletal remains across South America, including Argentina. This abundance of skeletal evidence but paucity of genomic data leaves significant gaps in our understanding of MTBC’s emergence, diversity, and spread.
PATHOGEN aims to fill these gaps by analyzing aDNA from skeletal remains from archaeological contexts in Argentina’s Southern Cone, a culturally rich yet understudied region. By reconstructing MTBC genomes from a broad temporal and geographic range, the project seeks to uncover patterns of MTBC evolution and the molecular and biocultural factors that contributed to its success as a pathogen. This research is driven by the need to understand MTBC's evolutionary history, persistence, and spread, with important implications for current TB research and public health.
The project aims to (1) estimate the breadth of MTBC diversity and its geographic distribution in South America, (2) investigate whether MTBC emerged from single or multiple zoonotic events in this region, (3) identify evolutionary mutations associated with virulence and host-pathogen interactions, and (4) explore socio-environmental contexts that facilitated the pathogen's spread and persistence in this region. The research is divided into two main objectives: 1) investigating precolonial MTBC emergence, evolution, and diversity across different Indigenous communities in South America, and 2) examine TB epidemics in the postcolonial period, including the impact of colonial encounters on disease dynamics.
PATHOGEN addresses the broader socio-cultural impact of TB on South American societies, particularly Indigenous communities. The project integrates social sciences with genomics, archaeology, and historical records to examine how factors like migration, social disruption, and environmental change influenced MTBC evolution and dissemination. This interdisciplinary approach seeks to understand social forces influencing MTBC spread and persistence by examining the socio-cultural contexts of TB, with a particular focus on the impact of colonialism on Indigenous health and disease susceptibility.
PATHOGEN is expected to yield valuable insights into the evolutionary dynamics of MTBC, providing a clearer understanding of TB’s historical trajectory. The project will generate important datasets for global MTBC evolution studies, enabling researchers to identify genetic adaptations that may influence pathogenicity and resistance. This project has the potential to serve as a model for interdisciplinary research in paleogenomics, offering historical perspectives that can help inform present-day TB control strategies and improve public health outcomes.
The PATHOGEN project addresses these gaps by investigating the evolutionary history of TB in South America, focusing on “how, when, and where” MTBC emerged, evolved, and spread. Recent advances in ancient DNA (aDNA) technology have enabled the reconstruction of MTBC genomes from ancient and historical samples, revealing strains previously unknown to infect humans. However, only nine ancient or historic MTBC genomes are publicly available, with only three from the Americas. These three represent an animal strain of MTBC (M. pinnipedii) and are geographically limited to the Andean region. Meanwhile, archaeological findings show widespread evidence of TB in skeletal remains across South America, including Argentina. This abundance of skeletal evidence but paucity of genomic data leaves significant gaps in our understanding of MTBC’s emergence, diversity, and spread.
PATHOGEN aims to fill these gaps by analyzing aDNA from skeletal remains from archaeological contexts in Argentina’s Southern Cone, a culturally rich yet understudied region. By reconstructing MTBC genomes from a broad temporal and geographic range, the project seeks to uncover patterns of MTBC evolution and the molecular and biocultural factors that contributed to its success as a pathogen. This research is driven by the need to understand MTBC's evolutionary history, persistence, and spread, with important implications for current TB research and public health.
The project aims to (1) estimate the breadth of MTBC diversity and its geographic distribution in South America, (2) investigate whether MTBC emerged from single or multiple zoonotic events in this region, (3) identify evolutionary mutations associated with virulence and host-pathogen interactions, and (4) explore socio-environmental contexts that facilitated the pathogen's spread and persistence in this region. The research is divided into two main objectives: 1) investigating precolonial MTBC emergence, evolution, and diversity across different Indigenous communities in South America, and 2) examine TB epidemics in the postcolonial period, including the impact of colonial encounters on disease dynamics.
PATHOGEN addresses the broader socio-cultural impact of TB on South American societies, particularly Indigenous communities. The project integrates social sciences with genomics, archaeology, and historical records to examine how factors like migration, social disruption, and environmental change influenced MTBC evolution and dissemination. This interdisciplinary approach seeks to understand social forces influencing MTBC spread and persistence by examining the socio-cultural contexts of TB, with a particular focus on the impact of colonialism on Indigenous health and disease susceptibility.
PATHOGEN is expected to yield valuable insights into the evolutionary dynamics of MTBC, providing a clearer understanding of TB’s historical trajectory. The project will generate important datasets for global MTBC evolution studies, enabling researchers to identify genetic adaptations that may influence pathogenicity and resistance. This project has the potential to serve as a model for interdisciplinary research in paleogenomics, offering historical perspectives that can help inform present-day TB control strategies and improve public health outcomes.
As part of the PATHOGEN project, we have successfully extracted DNA, sequenced and screened sequencing data of approximately 720 individuals from various archaeological contexts. Our screening process identified the presence of Mycobacterium tuberculosis complex (MTBC) DNA in 22 individuals. We selected 12 of these individuals for in-solution hybridization capture to enhance the recovery of MTBC DNA. This approach led to the successful reconstruction of a high-coverage, high-quality MTBC genome from a unique archaeological context in Argentina, which stands as the oldest and highest quality ancient MTBC genome to date (based on published data).
In addition, we developed novel methods for authenticating ancient MTBC DNA through customized phylogenetic analysis, enabling us to confirm three of the 22 additional cases with high confidence. Among these cases was a remarkable find that extends the known existence of MTBC in this region by 700 years, offering unprecedented insights into the pathogen’s deep history in South America.
In addition, we developed novel methods for authenticating ancient MTBC DNA through customized phylogenetic analysis, enabling us to confirm three of the 22 additional cases with high confidence. Among these cases was a remarkable find that extends the known existence of MTBC in this region by 700 years, offering unprecedented insights into the pathogen’s deep history in South America.
This project has broadly expanded the known geographic and temporal presence of MTBC as a human pathogen, challenging previous models of MTBC introduction to South America. PATHOGEN has now provided the highest quality and oldest genomic data of MTBC from archaeological contexts, offering a 66-fold coverage ancient genome. This project has demonstrated the presence of MTBC infecting human populations from socio-cultural contexts that do not reflect the conditions known to harbor TB, challenging previous assumptions of disease dynamics for TB. Furthermore, this work has led to the development of a reliable and valuable method of authenticating ancient MTBC DNA from metagenomic data. Leading to the detection and authentication of MTBC DNA from a hunter-gatherer dating to 1705 BP, resulting in the oldest genetically confirmed case of TB. These findings provide unprecedented insight to TB evolutionary history and change the current assumptions driven by ancient DNA. The data generated here along with the computational method will be highly valuable to the field of paleogenomics and modern mycobacterial research.