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bioRxiv · 10.1101/256073

Immune cellular homeostasis in early life is determined by genetic variants of cellular production and turnover

Dubovik, T.·Starosvetsky, E.·LeRoy, B.·Normand, R.·Admon, Y.·Alpert, A.·Ofran, Y.·G'Sell, M.·Shen-Orr, S. S.
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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 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.

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Dubovik, T., Starosvetsky, E., LeRoy, B., Normand, R., Admon, Y., Alpert, A., Ofran, Y., G'Sell, M., Shen-Orr, S. S.. 2018-01-29. Immune cellular homeostasis in early life is determined by genetic variants of cellular production and turnover. https://doi.org/10.1101/256073

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