25 Years of TB Genomes Reveal How Migration Reshapes Hamburg’s Tuberculosis Landscape

Tuberculosis remains one of humanity’s oldest infectious foes, yet its behavior in modern low-incidence countries is increasingly shaped by a new force: the movement of people across borders. In a study published in Genome Medicine, researchers led by Nicole Ullrich, Viola Dreyer and Stefan Niemann of the Research Center Borstel, together with collaborators from Hamburg’s public health services, have assembled one of the most comprehensive long-term genomic portraits of Mycobacterium tuberculosis complex populations ever compiled in a European city. By sequencing 3,131 bacterial strains collected from tuberculosis patients in Hamburg over a quarter of a century, from 1997 to 2021, the team was able to trace how migration has transformed the genetic makeup of the city’s tuberculosis reservoir and, crucially, whether that transformation changed the way the disease actually spreads.

The scale of the dataset is what gives the study its power. Whole genome sequencing was performed on nearly every culture-confirmed tuberculosis case in Hamburg across 25 years, allowing the researchers to compare the full genetic blueprints of bacterial strains rather than relying on older, lower-resolution fingerprinting methods. The team analyzed population structure and transmission dynamics in relation to patients’ self-reported geographical origins, combining genomic data with demographic and epidemiological information gathered through mandatory public health surveillance under Germany’s infectious diseases law. This integration of pathogen genetics with host demographics is precisely what earlier molecular epidemiological studies lacked, and it allowed the investigators to distinguish between bacteria that had merely been imported with their hosts and bacteria that were genuinely transmitting from person to person within the city.

The first major finding concerns lineage diversity. The Mycobacterium tuberculosis complex comprises several major lineages with distinct geographic footprints: Lineage 2 and Lineage 4 are highly transmissible, globally distributed generalists, while Lineages 1, 3 and 5 through 9 are geographically restricted specialists adapted to particular regions. In Hamburg, the researchers detected strains from lineages L1 through L6 as well as Mycobacterium bovis, the cattle-adapted member of the complex. Lineage 4 dominated throughout, accounting for 74.6 percent of all strains, or 2,337 isolates. But the composition of the bacterial population shifted markedly over time. In the first five years of the study, L4 strains made up 83.5 percent of isolates; in the final five years, that share had fallen to 63.0 percent. Over the same period, strains of Lineage 3, a specialist lineage classically associated with the Horn of Africa and South Asia, rose from 4.8 percent to 18.1 percent of the population.

That shift might seem to suggest that newly arrived lineages were outcompeting established ones, or that changing bacterial properties were driving the epidemiology. The genomic evidence says otherwise. When the researchers examined transmission clusters, groups of patients infected with nearly identical strains that indicate recent person-to-person spread, they found that the changing lineage distribution correlated with the increasing number of foreign-born patients rather than with enhanced transmission of any particular lineage. In other words, the diversification of Hamburg’s tuberculosis population was a demographic phenomenon, not a microbiological one. New strains arrived with new residents, but they did not, for the most part, go on to spread widely within the local population.

The cluster analysis drives this point home. Of the 269 transmission clusters identified across the 25-year period, 81 percent, or 218, were composed of Lineage 4 strains. This dominance was far out of proportion even to L4’s overall prevalence, indicating that sustained local transmission in Hamburg remained overwhelmingly the province of long-established bacterial lineages. Strains of specialist lineages such as L3, despite becoming numerically more common as imports increased, contributed relatively little to ongoing chains of transmission. The bacteria that thrive in Hamburg are, in an evolutionary sense, the bacteria that were already there.

Delving deeper into Lineage 4 revealed another layer of complexity: heterogeneity in transmission potential among its sublineages. Not all L4 strains are equal. The researchers found that sublineages L4.1.2.1, L4.8 and L4.3 were each detected in patients born in more than 15 different world regions, with more than 57 percent of those cases occurring in people from Europe. This pattern supports what evolutionary biologists call the generalist-specialist hypothesis at a finer resolution than ever before. Certain sublineages behave as globally successful generalists, capable of infecting and transmitting among host populations of vastly different genetic backgrounds and geographic origins, while others remain confined to specific regions. The importance of this sublineage-level resolution is a methodological lesson for the field: analyses that stop at the major-lineage level would miss the heterogeneity in transmissibility that the Hamburg data expose.

The technical machinery behind these conclusions deserves attention. Whole genome sequencing of more than 3,000 isolates allowed the team to apply a five-allele distance threshold, a conservative criterion under which strains sharing nearly identical core genomes are considered part of the same recent transmission chain. Core genome multilocus sequence typing and single nucleotide polymorphism analyses provided complementary views of population structure, and maximum likelihood phylogenetic methods placed the Hamburg strains within the global diversity of the tuberculosis complex. By combining these genomic tools with the patients’ self-reported regions and countries of birth, grouped according to United Nations statistical divisions, the researchers could ask, for any given cluster, whether it represented a single introduction with limited onward spread or sustained transmission across the community.

The public health implications are significant. In low-incidence settings, the central strategic question is whether each tuberculosis case is an isolated importation or part of an active local transmission network, because the two scenarios demand different responses. Imported cases call for ensuring that arriving populations have access to screening and care, while clustered cases call for contact investigation and outbreak response. The Hamburg study shows that genomic surveillance can make this distinction reliably at scale, and that the answer may not follow intuition. A rising share of foreign-born cases and a diversifying bacterial population did not translate into altered transmission dynamics; the city’s transmission landscape remained anchored in its established L4 sublineages. Policymakers worried that migration inherently fuels tuberculosis spread can point to this evidence that pathogen characteristics and local adaptation matter as much as host demographics.

The study also underscores the interplay between pathogen evolution and human population structure. Successful transmission, the authors conclude, is mediated by locally adapted sublineages, and the predominance of L4.1.2.1 and L4.8 among patients from a wide range of countries demonstrates that these sublineages have achieved a breadth of host adaptation that specialist lineages lack. Migration substantially increased the genetic diversity of the bacterial population in Hamburg but did not fundamentally alter how tuberculosis transmits there. As genomic sequencing becomes cheaper and more routine, the Hamburg experience offers a template for other low-incidence cities: maintain long-term, systematic sequencing integrated with demographic data, analyze at sublineage resolution, and interpret lineage shifts in light of migration patterns before attributing them to changes in bacterial fitness. Twenty-five years of genomes have turned a single German city into a natural laboratory for understanding how one of the world’s deadliest pathogens responds to the movement of its human hosts, and the answer, reassuringly, is that established local strains still hold the ground.

Subject of Research: Molecular epidemiology of Mycobacterium tuberculosis complex transmission and lineage diversity in relation to migration in Hamburg, Germany, over 25 years

Article Title: Migration and tuberculosis transmission in Hamburg, Germany: insights from 25 years of molecular epidemiology

Article References: Ullrich, N., Diel, R., Meywald-Walter, K., Schwarzbach, C., Gröschel, M. I., Kuhns, M., Friesen, I., Niemann, S., & Dreyer, V. (2026). Migration and tuberculosis transmission in Hamburg, Germany: insights from 25 years of molecular epidemiology. Genome Medicine. https://doi.org/10.1186/s13073-026-01750-7

Image Credits: AI Generated

DOI: 10.1186/s13073-026-01750-7

Keywords: tuberculosis, Mycobacterium tuberculosis complex, whole genome sequencing, molecular epidemiology, migration, lineage 4, transmission clusters, generalist-specialist hypothesis, genomic surveillance, Hamburg, low-incidence settings, sublineages