Divergent and nonuniform gene expression patterns in mouse brain

Abstract

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. T here are numerous and complex mechanisms by which genetic variation within or across species contributes to phenotypic diversity (1-3). The most appreciated and easily testable of these involve sequence modifications that alter the amino acid coding regions of genes and measurably affect protein function. Quantitative differences in transcript abundance, due to gene dosage or regulatory mutations have also been associated with phenotype (4-6). However, outside the realm of developmental biology and recent studies of copy number variation (7,8), the spatial distribution of gene expression within defined tissues and cell types remains relatively unexplored as a means by which genetic differences confer phenotypic differences.To investigate the relationship between spatial gene expression patterns and genetic background, we conducted a large-scale, systematic, brainwide survey of gene expression (9)

Allen Brain Atlas: an integrated spatio-temporal portal for exploring the central nervous system

“…A companion database, available at http://www.ivygap.org, developed by project partners at the Ben and Catherine Ivy Center for Advanced Brain Tumor Treatment, provides additional clinical and genomic data. The Mouse Diversity Study characterizes gene expression across genetic backgrounds and sex, expanding beyond the adult male C57BL/6J reference brain comprising the Allen Mouse Brain Atlas to include seven strains of male mice and female C57BL/6J mice at three stages of estrus (11). This Mouse Diversity Study allows for simultaneous navigation and comparison of different mouse brains at high resolution, providing users with a data set to probe for possible differences in gene regulation.…”

Dynamic expression of tyrosine hydroxylase mRNA and protein in neurons of the striatum and amygdala of mice, and experimental evidence of their multiple embryonic origin

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Neuronal Migration Defect of the Developing Cerebellar Vermis in Substrains of C57BL/6 Mice: Cytoarchitecture and Prevalence of Molecular Layer Heterotopia

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