LAUSR

Abstract Balancing selection is a classic mechanism for maintaining variability in immune genes involved in host–pathogen interactions. However, it remains unclear how widespread the mechanism is across immune genes other than the major histocompatibility complex (MHC). Although occasional reports suggest that balancing selection (heterozygote advantage, negative frequency-dependent selection, and fluctuating selection) may act on other immune genes, the current understanding of the phenomenon in non-MHC immune genes is far from solid. In this review, we focus on Toll-like receptors (TLRs), innate immune genes directly involved in pathogen recognition and immune response activation, as there is a growing body of research testing the assumptions of balancing selection in these genes. After reviewing infection- and fitness-based evidence, along with evidence based on population allelic frequencies and heterozygosity levels, we conclude that balancing selection maintains variation in TLRs, though it tends to occur under specific conditions in certain evolutionary lineages rather than being universal and ubiquitous. Our review also identifies key gaps in current knowledge and proposes promising areas for future research. Improving our understanding of host–pathogen interactions and balancing selection in innate immune genes are increasingly important, particularly regarding threats from emerging zoonotic diseases.