Interactions between immune cell types facilitate the evolution of immune traits

Abstract

Abstract An essential prerequisite for evolution by natural selection is variation among individuals in traits that affect fitness1. The ability of a system to produce selectable variation, known as evolvability2, thus greatly affects the rate of its evolution. The immune system belongs to the fastest evolving components of mammalian genomes3, yet the sources of useful variation in immune traits remain largely unknown4,5. Here, we show that a key determinant of the immune system’s evolvability is its organisation into interacting modules represented by different immune cell types. By profiling immune cell variation in bone marrow of 54 genetically diverse mouse strains from the Collaborative Cross6, we found that variation in immune cell frequencies is polygenic and that associated genes are largely involved in quantitative homeostasis through cell-intrinsic functions of proliferation, migration and cell death. However, we also found that many genes influencing the frequency of a particular cell type are not expressed in that specific cell type, but rather in a different immune cell type. Vertebrate evolutionary record shows that genes implicated in this non-cell-intrinsic variation have faced fewer purifying constraints, indicating that they have acted as key determinants in the recent evolvability of immune traits. Our findings suggest that interactions between different components of the immune system provide a phenotypic space where mutations can produce selectable variation without much detriment, offering a solution to the robustness-evolvability conundrum2,7,8 in the context of the immune system.