Evolutionary complexity of primate immune system uncovered by the extensive phylogenomic sampling

Abstract The immune system mediates the complex interaction between pathogenic microorganisms and their hosts. Despite its significance, the evolutionary mechanisms underlying immune system complexity in primates remain largely elusive. In this study, we investigated the evolution of the primate immune system by generating the first comprehensive catalog of immune-related genes through extensive phylogenomic sampling. Our analyses uncovered substantial genetic diversity in the evolution of the primate immune system, in the form of modules that vary in their sequences and functional capabilities. We identified a novel module (Type 3c) that has experienced long-term coevolution between primates and lentiviruses over a long evolutionary timescale. Furthermore, we found that social system complexity, rather than diet or group size, may potentially shape the immune system evolution of primates. We further uncovered the evolutionary histories of key immune-associated genes, including IFNAR2 and C5AR1, which are implicated in SARS-CoV-2 infection. More importantly, we revealed a divergence in the selective pressures on immune-associated genes between experimental primates and humans. This finding provides a critical caveat, suggesting that the extreme caution is warranted when using these primates as models for human diseases such as HIV-1, Hepatitis C, and Influenza A. In summary, this work uncovers key evolutionary mechanisms that have fundamentally shaped the complexity of immune systems across primates.