@article {Dubovik256073, author = {Tania Dubovik and Elina Starosvetsky and Benjamin LeRoy and Rachelly Normand and Yasmin Admon and Ayelet Alpert and Yishai Ofran and Max G{\textquoteright}Sell and Shai S. Shen-Orr}, title = {Architecture of a multi-cellular polygenic network governing immune homeostasis}, elocation-id = {256073}, year = {2018}, doi = {10.1101/256073}, publisher = {Cold Spring Harbor Laboratory}, abstract = {Complex physiological functionality is often the outcome of multiple interacting cell-types, yet mechanistically how a large number of trait-associated genes yield a single multi-cellular network governing the phenotype has not been well defined. Individuals{\textquoteright} immune-cellular profiles at homeostasis show high heritability and inter-individual variation with functional and clinical implications. We profiled immune cellular variation by mass-cytometry in 55 genetically diverse mouse strains. We identify 788 genes associated with cellular homeostasis, supporting a polygenic model where 52\% of genes correspond to core homeostatic functions whose genetic variants suffice to predict phenotype. Trait genes form a multi-cellular network architecture showing increased functional complexity over evolutionary timescales for shared regulation to all cells, specialized cell-specific programs, and between-cell synchronization. Contrasting to human studies suggests the regulatory network expands with environmental exposure history. Our findings shed light on the origin of immune-cellular variation and regulatory architectures that may generalize to other environmentally sensitive systems.}, URL = {https://www.biorxiv.org/content/early/2018/09/23/256073}, eprint = {https://www.biorxiv.org/content/early/2018/09/23/256073.full.pdf}, journal = {bioRxiv} }