The Impact of Tuberculosis on our Human Genome

By Chloe Teng

Infectious diseases have long been a threat to the health of global populations, but no single infectious agent has rivalled the deadliness of tuberculosis (TB). Caused by the bacteria Mycobacterium tuberculosis, it reached epidemic proportions in European and North American regions in the 18th century, resulting in a mortality rate as high as 900 deaths per 100,000 inhabitants per year (Barberis et al., 2017). Although TB is curable and preventable, it remains present in all countries worldwide. In 2019, a total of 1.4 million people died due to TB (WHO, 2020), and its death toll has now accumulated to a total of over 1 billion people over the last 2000 years (Science, 2021). However, how TB rose to such deadly proportions over time has largely remained a mystery.

To better understand the factors behind how TB presented itself as a disease of such high mortality and infectious rates throughout history, population genetics was utilised by researchers to analyse ancient human genomes (Kerner et al., 2021). Variants of the tyrosine kinase 2 (TYK2) gene, namely P1104A, were of particular interest as TYK2 had previously been discovered to increase the risk of developing clinical forms of TB when the patient is homozygous for this variant. The evolutionary trajectory of the P1104A variant was thus used to determine the history of human exposure to TB, where the variant was found to have originated more than 30,000 years ago in common ancestors of Western Eurasians. The variant frequency was then shown to decrease significantly approximately 2000 years ago (Kerner et al., 2021), which was attributable to strong negative selection correlated to the beginning of the tuberculosis epidemic in Europe (Cell Press, 2021). 

This decrease in frequency had been drastic. During the Bronze Age, 10% of Europeans possessed the P1104A mutation. However, its frequency gradually declined to 2.9% as the modern TB variant emerged and has remained at this frequency since within current European populations. Seeing as individuals with homozygous variants of the gene were at greater risk of developing severe forms of the disease upon encountering the TB pathogen, researchers proposed that natural selection had therefore acted to eliminate the P1104A gene variant to the low levels as seen today. Approximately one-fifth of the population with homozygous copies of the variant had been estimated to have died of TB and were as such unable to pass on the P1104A variant to their offspring (Kerner et al., 2021).

With one of the United Nations Sustainable Development Goals being that of ending the TB epidemic by 2030 (WHO, 2020), there is a need to identify the levels and regions by which the P1104A variant remains within the global population. In areas where TB is endemic such as India and China, the variant appears rare in these populations. UK Biobank data, however, shows that around 1 in 600 British individuals are homozygous for the variant, and thus at high risk of mortality if afflicted with TB (Gibbons, 2021). This presents a new area that needs to be targeted in the fight against the disease, as well as increasingly prevalent challenges such as the rise of multidrug-resistant TB cases (The Lancet, 2017). Using this population genetics approach to map out the changes in our genome due to pathogens could prove useful in identifying genetic groups at greatest risk to help reduce infectious disease burdens in the future.

Ultimately, the current study provides a novel framework that analyses the genetic evolution of infectious diseases to improve our understanding of the coevolution of the human immune system with pathogens. By reconstructing the forgotten history of certain epidemics, immune gene variants with the greatest increase in frequency can be inferenced to be of greater benefit than those that have decreased due to the selective pressure of the specific disease. Along with other immunological studies, research as such can greatly aid our understanding of the implications of distinct genetic variants for different infectious diseases and provide new evidence into why varying susceptibilities to infection exists within modern populations.


  1. Barberis, I., Bragazzi, N.L., Galluzzo, L., Martini, M. (2017) The history of tuberculosis: from the first historical records to the isolation of Koch’s bacillus. Journal of Preventative Medicine and Hygiene. 58(1), 9-12. Available from: PMID:28515626
  2. Cell Press. (2021) Ancient DNA reveals clues about how tuberculosis shaped the human immune system. Available from: [Accessed 14th March 2021]
  3. Kerner, G., Laval, G., Patin, E., Abel, L., Casanova, J-L., Quintana-Murci, L. (2021) Human ancient DNA analyses reveal the high burden of tuberculosis in Europeans over the last 2,000 years. The American Journal of Human Genetics. 108(3), 517-524. Available from: doi:10.1016/j.ajhg.2021.02.009.
  4. The Lancet. (2017) Global rise of multidrug resistant tuberculosis threatens to derail decades of progress. Available from: [Accessed 15th March 2021]
  5. Gibbons, A. (2021) How tuberculosis reshaped our immune systems. Available from: [Accessed 15th March 2021]
  6. World Health Organisation. (2020) Tuberculosis. Available from: [Accessed 13th March 2021]

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