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 unknown^4,5. 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 evolvability^2,7,8 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.

自然选择进化的一个重要先决条件是个体之间影响适应性的性状变异¹ 。系统产生可选择变异的能力，称为进化性² ，因此极大地影响进化速率。免疫系统属于哺乳动物中进化最快的组成部分³ ，但免疫特征变异的来源仍然很大程度上未知^4,5 。在这里，我们表明，免疫系统进化性的一个重要决定因素是其组织成由不同免疫细胞类型代表的相互作用的模块。通过分析来自 Collaborative Cross ⁶的 54 种遗传多样性小鼠品系的骨髓中的免疫细胞变异，我们发现免疫细胞频率的变异是多基因的，并且许多相关基因通过增殖、迁移和迁移等细胞内在功能参与稳态平衡。细胞死亡。然而，我们还发现了与特定细胞类型的频率相关的基因，这些基因在不同的细胞类型中表达，在我们所说的细胞反式中发挥作用。脊椎动物的进化记录表明，与细胞反式相关的基因面临较弱的负选择，从而增加了免疫系统的鲁棒性和进化性^2,7,8 。这种现象在人类血液中也同样可以观察到。我们的研究结果表明，免疫系统不同组成部分之间的相互作用提供了一个表型空间，突变可以在其中产生变异而不会造成太大损害，这强调了模块化在复杂系统进化中的作用⁹ 。