Abstract
Evolutionary genetics has long struggled with understanding how functional genes under selection remain polymorphic in natural populations. Taking as a starting point that natural selection is ultimately a manifestation of ecological processes, we spotlight an underemphasized and potentially ubiquitous ecological effect that may have fundamental effects on the maintenance of genetic variation. Negative frequency dependency is a well‐established emergent property of density dependence in ecology, because the relative profitability of different modes of exploiting or utilizing limiting resources tends to be inversely proportional to their frequency in a population. We suggest that this may often generate negative frequency‐dependent selection (NFDS) on major effect loci that affect rate‐dependent physiological processes, such as metabolic rate, that are phenotypically manifested as polymorphism in pace‐of‐life syndromes. When such a locus under NFDS shows stable intermediate frequency polymorphism, this should generate epistatic selection potentially involving large numbers of loci with more minor effects on life‐history (LH) traits. When alternative alleles at such loci show sign epistasis with a major effect locus, this associative NFDS will promote the maintenance of polygenic variation in LH genes. We provide examples of the kind of major effect loci that could be involved and suggest empirical avenues that may better inform us on the importance and reach of this process.