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. 2010 Nov 2;107(44):19049-54.
doi: 10.1073/pnas.1003732107. Epub 2010 Oct 18.

Divergent and nonuniform gene expression patterns in mouse brain

John A Morris  1 , Joshua J Royall, Darren Bertagnolli, Andrew F Boe, Josh J Burnell, Emi J Byrnes, Cathy Copeland, Tsega Desta, Shanna R Fischer, Jeff Goldy, Katie J Glattfelder, Jolene M Kidney, Tracy Lemon, Geralyn J Orta, Sheana E Parry, Sayan D Pathak, Owen C Pearson, Melissa Reding, Sheila Shapouri, Kimberly A Smith, Chad Soden, Beth M Solan, John Weller, Joseph S Takahashi, Caroline C Overly, Ed S Lein, Michael J Hawrylycz, John G Hohmann, Allan R Jones
Affiliations

Divergent and nonuniform gene expression patterns in mouse brain

John A Morris et al. Proc Natl Acad Sci U S A. .

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.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Strain differences in gene expression within members of the dopamine family. Each panel shows a comparison between the C57 reference strain and a strain that differed in expression pattern for a particular gene. The low magnification images at the Left of each panel provide anatomical context and show similar expression patterns in other brain areas. The Center column shows the expression pattern difference at high magnification, denoted by arrows. The column on the Right shows the nearest corresponding Nissl section for each strain. (A) The CAST strain shows lower density of Drd1a in the parabrachial (PB) nucleus. (B) The SPRET strain shows greater density of Drd1a expression in the anterodorsal (AD) nucleus of the thalamus. (C) The DBA strain shows greater density of Drd2 expression in the entorhinal area, lateral part (ENTl). (D) The DBA strain shows lower density of Drd2 expression in the lateral dorsal nucleus (LD) of the thalamus. (E) The CAST strain shows greater density of Maob expression in the lateral septal nucleus (LS). (F) The PWD strain shows greater density of Maob expression in the lateral amygdalar (LA) nucleus. (G) The CAST strain shows lower density of Th expression in the caudate-putamen (CP). (H) The PWD strain shows higher density of Th expression in the reticular nucleus (RT) of the thalamus. [Scale bars, (low magnification) 1,000 μm; (high magnification) 500 μm.] Drd1a, dopamine receptor 1a; Drd2, dopamine receptor 2; Th, tyrosine hydroxylase; Maob, monoamine oxidase b.
Fig. 2.
Fig. 2.
Strain differences in gene expression within the hippocampal formation. Each panel shows a comparison between the C57 reference strain and a strain that differed in expression pattern for a particular gene. The Left column of each panel shows the difference in gene expression pattern, denoted by arrows, and the Right column shows the nearest corresponding Nissl section for each strain. (A) The SPRET strain shows greater density of Htr1a expression in the subiculum (Sub) and in cornu ammonis field 3, pyramidal layer (CA3). (B) The WSB strain shows greater density of Adra2a expression in the dentate gyrus, polymorph layer (DG). (C) The DBA strain shows greater density of Drd1a expression in the cornu ammonis field 2, pyramidal layer (CA2). (D) The CAST strain shows greater density of Egfr expression in the dentate gyrus, subgranular zone. (E) The DBA strain shows greater density of Htr1b expression in the dentate gyrus, subgranular zone. (F) The PWD strain shows greater density of Htr1b expression in the postsubiculum. [Scale bars, 500 μm; C (high magnification), 100 μm.] Htr1a, 5-hydroxytryptamine receptor 1A; Adra2a, adrenergic receptor, type 2a; Drd1a, dopamine receptor 1a, Egfr, epidermal growth factor receptor; Htr1b, 5hydroxytryptamine receptor 1B.
Fig. 3.
Fig. 3.
Drug target gene expression pattern differences across brain structures and strains. (A) Organized by unsupervised two-way hierarchical clustering, the matrix depicts the incidence between the genes that varied in expression pattern (Left column) and the brain structures (Right column) where they differed, in each strain (column headings), relative to the C57 reference strain. Relative expression differences were qualitatively binned as either decreased (green cells) or increased (red cells), with black cells indicating no difference. Two major groupings were returned, composed of the classic laboratory strains (129 and DBA) with M. m. domesticus subspecies (WSB), and that of subspecies M. m. castaneus (CAST), M. m. musculus (PWD) with the outgroup species M. spretus (SPRET). (B) Total number of differences across brain structures ranked across major brain divisions. The number of brain structures contained within each division are listed in parentheses. Gene and structure abbreviations are defined in Datasets S1 and S2. (C) Total strain differences in expression organized by rank order. Total differences also showed the 129 strain most similar to the C57, and SPRET the most different from the C57 reference strain.
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