Abstract
SummaryTuberculosis (TB), usually caused by Mycobacterium tuberculosis bacteria, is the first cause of death from an infectious disease at the worldwide scale, yet the mode and tempo of TB pressure on humans remain unknown. The recent discovery that homozygotes for the P1104A polymorphism of TYK2 are at higher risk to develop clinical forms of TB provided the first evidence of a common, monogenic predisposition to TB, offering a unique opportunity to inform on human co-evolution with a deadly pathogen. Here, we investigate the history of human exposure to TB by determining the evolutionary trajectory of the TYK2 P1104A variant in Europe, where TB is considered to be the deadliest documented infectious disease. Leveraging a large dataset of 1,013 ancient human genomes and using an approximate Bayesian computation approach, we find that the P1104A variant originated in the common ancestors of West Eurasians ∼30,000 years ago. Furthermore, we show that, following large-scale population movements of Anatolian Neolithic farmers and Eurasian steppe herders into Europe, P1104A has markedly fluctuated in frequency over the last 10,000 years of European history, with a dramatic decrease in frequency after the Bronze Age. Our analyses indicate that such a frequency drop is attributable to strong negative selection starting ∼2,000 years ago, with a relative fitness reduction on homozygotes of 20%, among the highest in the human genome. Together, our results provide genetic evidence that TB has imposed a heavy burden on European health over the last two millennia.
Highlights
The P1104A variant, which we found to be the result of a single mutational event (Figure S1), appeared for the first time in our dataset during the early Neolithic $8,500 ya in the Anatolian peninsula, and spread to Central Europe where it remained at frequencies lower than 3% until $5,000 ya (Figures 1A–1C)
We estimated the origin of the tyrosine kinase 2 (TYK2) P1104A mutation, based on its frequency in K 1⁄4 12 populations sampled at different epochs, including European ancient DNA (aDNA) data (Paleolithic, Mesolithic, Early Neolithic, Late Neolithic, Bronze Age, Iron Age, and Middle Ages; supplemental material and methods) and present-day Europeans, Middle Easterners, Central Asians, Sub-Saharan Africans (0%), and East Asians (0%) (Figure 2A; Table S3)
Our results provide robust evidence that TYK2 P1104A appeared during the Upper Paleolithic in West Eurasia, largely predating the estimated emergence of TB in Europe.[18,19,31]
Summary
We estimated the origin of the TYK2 P1104A mutation, based on its frequency in K 1⁄4 12 populations sampled at different epochs, including European aDNA data (Paleolithic, Mesolithic, Early Neolithic, Late Neolithic, Bronze Age, Iron Age, and Middle Ages; supplemental material and methods) and present-day Europeans, Middle Easterners, Central Asians (from 1% to 4%), Sub-Saharan Africans (0%), and East Asians (0%) (Figure 2A; Table S3).
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