Abstract
The advent of animal husbandry and hunting increased human exposure to zoonotic pathogens. To understand how a zoonotic disease may have influenced human evolution, we study changes in human expression of anthrax toxin receptor 2 (ANTXR2), which encodes a cell surface protein necessary for Bacillus anthracis virulence toxins to cause anthrax disease. In immune cells, ANTXR2 is 8-fold down-regulated in all available human samples compared to non-human primates, indicating regulatory changes early in the evolution of modern humans. We also observe multiple genetic signatures consistent with recent positive selection driving a European-specific decrease in ANTXR2 expression in multiple tissues affected by anthrax toxins. Our observations fit a model in which humans adapted to anthrax disease following early ecological changes associated with hunting and scavenging, as well as a second period of adaptation after the rise of modern agriculture.
Highlights
The advent of animal husbandry and hunting increased human exposure to zoonotic pathogens
We focused our analysis on the anthrax toxin receptor 2 (ANTXR2) gene, which encodes a ubiquitously expressed transmembrane receptor that aids in the cellular entry of toxins secreted by the B. anthracis bacterium[25,26,27] (Fig. 1a)
Expanding our analysis of RNA-seq data from CD4 + T cells to 91 humans confirmed the loss of ANTXR2 expression in all of the available human data[28] (Fig. 1d and Supplementary Fig. 4)
Summary
The advent of animal husbandry and hunting increased human exposure to zoonotic pathogens. Our observations fit a model in which humans adapted to anthrax disease following early ecological changes associated with hunting and scavenging, as well as a second period of adaptation after the rise of modern agriculture. Anthrax disease has been associated with the rise of animal husbandry[18,19,20], the putative African origin of anthrax diseaseassociated Bacillus species may have provided opportunities for early humans to encounter B. anthracis, or the ancestral B. cereus, while hunting or scavenging ruminant game species well before the advent of modern farming. Our results are consistent with at least two stages of human adaptation to anthrax disease—first to early ecological changes associated with hunting and scavenging, followed by the second period of adaptation after the rise of agriculture
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