Twenty years of tuberculosis-driven selection shaped the evolution of the meerkat major histocompatibility complex

Pathogen-mediated balancing selection (PMBS) drives host evolution across the tree of life. Distinguishing between the three main mechanisms underlying PMBS, that is, rare-allele advantage, fluctuating selection and heterozygote advantage, remains difficult, limiting our understanding of frequency-dependent adaptations by hosts and counter-adaptation by pathogens. Here we leverage immune genetic and disease surveillance data from over 1,500 wild meerkats (Suricata suricatta) to track how selection by the tuberculosis (TB)-causing Mycobacterium suricattae shaped the evolution of the meerkats' major histocompatibility complex (MHC) over two decades. Compared with neutral genetic markers, we detect more rapid differentiation and recycling of alleles at the MHC-DRB loci, suggesting that TB imposes strong PMBS on wild meerkats. In addition, we show that meerkats carrying the MHC allele Susu-DRB*13 were initially more likely to develop clinical signs of TB, with the effect reversing over the course of the study, followed by an increase in the frequency of Susu-DRB*13. Meerkats carrying Susu-DRB*13 also showed slower progression to TB signs and longer survival once signs of TB manifested. Lifetime reproductive success reflected the resilience effect conferred by Susu-DRB*13. Based on several lines of evidence, we propose that rare-allele advantage or fluctuating selection, rather than heterozygote advantage, drive our observation in this longitudinally sampled wild mammal population.