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Interactions between immune cell types facilitate the evolution of immune traits

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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 evolution. The immune system belongs to the fastest evolving components in mammals3, yet the sources of variation in immune traits remain largely unknown4,5. Here, we show that an important 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 many associated genes are involved in homeostatic balance through cell-intrinsic functions of proliferation, migration and cell death. However, we also found genes associated with the frequency of a particular cell type, which are expressed in a different cell type, exerting their effect in what we term cyto-trans. Vertebrate evolutionary record shows that genes associated in cyto-trans have faced weaker negative selection, thus increasing the robustness and hence evolvability2,7,8 of the immune system. This phenomenon is similarly observable in human blood. Our findings suggest that interactions between different components of the immune system provide a phenotypic space where mutations can produce variation without much detriment, underscoring the role of modularity in the evolution of complex systems9.

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Correspondence to Shai S. Shen-Orr.

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Dubovik, T., Lukačišin, M., Starosvetsky, E. et al. Interactions between immune cell types facilitate the evolution of immune traits. Nature (2024).

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