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Ancient DNA provides insights into how tuberculosis shaped the immune system

A new study, using ancient DNA, has revealed how tuberculosis has affected populations over the past 2,000 years and impacted the human genome.


Tuberculosis (TB), usually caused by Mycobacterium tuberculosis, is considered to be the deadliest infection of the common era. Over the last 2,000 years, it has caused over one billion deaths and is still responsible for more than 1.5 million deaths annually. Until the turn of the 21st century, the genetic basis of TB susceptibility remained elusive. It was only in 2018 that the first common, monogenic predisposition to TB was found. Researchers found that homozygotes for the TYK2 P1104A polymorphism (rs34536443) were at higher risk of developing clinical forms of TB.

Pathogen-imposed selective pressures have been critical during human evolution. Population genetic studies have found distinct selection signatures among host defence genes. This has emphasised the important immunological mechanisms and supported the role of microbes in human genome diversity.

Historical burden

To investigate the historical burden of TB in humans, researchers sought to reconstruct the evolutionary history of the P1104A variant. They specifically examined the frequency trajectory of this variant over the last 10,000 years of European history. They screened a collection of 1,013 genomes that expand from the Mesolithic period to the Middle Ages.

Their results, published in AJHG, indicated that the P1104A variant originated in the common ancestors of West Eurasians ∼30,000 years ago. Further analysis revealed that the frequency of the variant drastically declined about 2,000 years ago, around the same time present-day forms of M. tuberculosis strains became prevalent. This drop in frequency indicates strong negative selection, with a relative fitness reduction on homozygotes of 20%.

Overall, these results provide genetic evidence that TB has imposed a heavy burden on European health over the last two millennia. This evolutionary approach also represents a promising strategy to investigate the genetic sources of present-day disparities in susceptibility to infection.

Image credit: By Image Team –

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Ancient DNA / Immune System / Tuberculosis