Variation and Genetic Control of Gene Expression in Primary Immunocytes across Inbred Mouse Strains
Mostafavi S., Ortiz-Lopez A., Bogue MA., Hattori K., Pop C., Koller D., Mathis D., Benoist C., Blair DA., Dustin ML., Shinton SA., Hardy RR., Shay T., Regev A., Cohen N., Brennan P., Brenner M., Kim F., Rao TN., Wagers A., Heng T., Ericson J., Rothamel K., Ortiz-Lopez A., Mathis D., Benoist C., Kreslavsky T., Fletcher A., Elpek K., Bellemare-Pelletier A., Malhotra D., Turley S., Miller J., Brown B., Merad M., Gautier EL., Jakubzick C., Randolph GJ., Monach P., Best AJ., Knell J., Goldrath A., Jojic V., Koller D., Laidlaw D., Collins J., Gazit R., Rossi DJ., Malhotra N., Sylvia K., Kang J., Bezman NA., Sun JC., Min-Oo G., Kim CC., Lanier LL.
Abstract To determine the breadth and underpinning of changes in immunocyte gene expression due to genetic variation in mice, we performed, as part of the Immunological Genome Project, gene expression profiling for CD4+ T cells and neutrophils purified from 39 inbred strains of the Mouse Phenome Database. Considering both cell types, a large number of transcripts showed significant variation across the inbred strains, with 22% of the transcriptome varying by 2-fold or more. These included 119 loci with apparent complete loss of function, where the corresponding transcript was not expressed in some of the strains, representing a useful resource of “natural knockouts.” We identified 1222 cis-expression quantitative trait loci (cis-eQTL) that control some of this variation. Most (60%) cis-eQTLs were shared between T cells and neutrophils, but a significant portion uniquely impacted one of the cell types, suggesting cell type–specific regulatory mechanisms. Using a conditional regression algorithm, we predicted regulatory interactions between transcription factors and potential targets, and we demonstrated that these predictions overlap with regulatory interactions inferred from transcriptional changes during immunocyte differentiation. Finally, comparison of these and parallel data from CD4+ T cells of healthy humans demonstrated intriguing similarities in variability of a gene’s expression: the most variable genes tended to be the same in both species, and there was an overlap in genes subject to strong cis-acting genetic variants. We speculate that this “conservation of variation” reflects a differential constraint on intraspecies variation in expression levels of different genes, either through lower pressure for some genes, or by favoring variability for others.