Faulty kinase purged by tuberculosis?

Abstract

Tuberculosis Rare mutations in genes involved in interferon-γ–dependent immunity underpin human genetic susceptibility to severe mycobacterial diseases, including primary tuberculosis. Boisson-Dupuis et al. investigated whether two common missense variants of the TYK2 Janus kinase that have impaired catalytic activity conferred an increased risk of tuberculosis. Individuals homozygous for the P1104A (proline to alanine substitution at residue 1104) variant of TYK2 are markedly predisposed to developing primary tuberculosis, defining a common monogenic etiology for the “white plague.” The current frequency of the P1104A allele in European populations is significantly decreased compared with its frequency in ancient European DNA samples. These findings suggest that negative selection against the TYK2 P1104A allele by endemic tuberculosis in Europe may have contributed to a slow genetic purge of this susceptibility allele during recent millennia. Sci. Immunol. 3 , eaau8714 (2018).