Edited by Edward G. Jones, University of California, Davis, CA, and approved September 21, 2010 (received for review March 31, 2010)
Considerable progress has been made in understanding variations in gene sequence and expression level associated with phenotype, yet how genetic diversity translates into complex phenotypic differences remains poorly understood. Here, we examine the relationship between genetic background and spatial patterns of gene expression across seven strains of mice, providing the most extensive cellular-resolution comparative analysis of gene expression in the mammalian brain to date. Using comprehensive brainwide anatomic coverage (more than 200 brain regions), we applied in situ hybridization to analyze the spatial expression patterns of 49 genes encoding well-known pharmaceutical drug targets. Remarkably, over 50% of the genes examined showed interstrain expression variation. In addition, the variability was nonuniformly distributed across strain and neuroanatomic region, suggesting certain organizing principles. First, the degree of expression variance among strains mirrors genealogic relationships. Second, expression pattern differences were concentrated in higher-order brain regions such as the cortex and hippocampus. Divergence in gene expression patterns across the brain could contribute significantly to variations in behavior and responses to neuroactive drugs in laboratory mouse strains and may help to explain individual differences in human responsiveness to neuroactive drugs.
Author contributions: J.A.M., J.S.T., E.S.L., J.G.H., and A.R.J. designed research; J.A.M., J.J.R., D.B., A.F.B., E.J.B., C.C., T.D., S.R.F., J.G., K.J.G., J.M.K., T.L., G.J.O., S.E.P., O.C.P., M.R., S.S., K.A.S., and J.W. performed research; J.A.M., J.J.R., J.J.B., K.J.G., S.D.P., C.S., B.M.S., and M.J.H. analyzed data; and J.A.M., C.C.O., E.S.L., M.J.H., and A.R.J. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1003732107/-/DCSupplemental.
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