PT  - JOURNAL ARTICLE
AU  - Tania Dubovik
AU  - Elina Starosvetsky
AU  - Benjamin LeRoy
AU  - Rachelly Normand
AU  - Yasmin Admon
AU  - Ayelet Alpert
AU  - Yishai Ofran
AU  - Max G’Sell
AU  - Shai S. Shen-Orr
TI  - Architecture of a multi-cellular polygenic network governing immune homeostasis
AID  - 10.1101/256073
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 256073
4099  - http://biorxiv.org/content/early/2018/09/23/256073.short
4100  - http://biorxiv.org/content/early/2018/09/23/256073.full
AB  - 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’ 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.