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Study of Gene Function Based on Spatial Co-Expression in a High-Resolution Mouse Brain Atlas

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Study of Gene Function Based on Spatial Co-Expression in a High-Resolution Mouse Brain Atlas

Zheng Liu et al. BMC Syst Biol.

Abstract

Background: The Allen Brain Atlas (ABA) project systematically profiles three-dimensional high-resolution gene expression in postnatal mouse brains for thousands of genes. By unveiling gene behaviors at both the cellular and molecular levels, ABA is becoming a unique and comprehensive neuroscience data source for decoding enigmatic biological processes in the brain. Given the unprecedented volume and complexity of the in situ hybridization image data, data mining in this area is extremely challenging. Currently, the ABA database mainly serves as an online reference for visual inspection of individual genes; the underlying rich information of this large data set is yet to be explored by novel computational tools. In this proof-of-concept study, we studied the hypothesis that genes sharing similar three-dimensional expression profiles in the mouse brain are likely to share similar biological functions.

Results: In order to address the pattern comparison challenge when analyzing the ABA database, we developed a robust image filtering method, dubbed histogram-row-column (HRC) algorithm. We demonstrated how the HRC algorithm offers the sensitivity of identifying a manageable number of gene pairs based on automatic pattern searching from an original large brain image collection. This tool enables us to quickly identify genes of similar in situ hybridization patterns in a semi-automatic fashion and consequently allows us to discover several gene expression patterns with expression neighborhoods containing genes of similar functional categories.

Conclusion: Given a query brain image, HRC is a fully automated algorithm that is able to quickly mine vast number of brain images and identify a manageable subset of genes that potentially shares similar spatial co-distribution patterns for further visual inspection. A three-dimensional in situ hybridization pattern, if statistically significant, could serve as a fingerprint of certain gene function. Databases such as ABA provide valuable data source for characterizing brain-related gene functions when armed with powerful image querying tools like HRC.

Figures

Figure 1
Figure 1
The performance of three algorithms benchmarked by a 60-gene test set. The performance improvement of the adjusted pixel-wise method versus the naïve pixel-wise method and the HRC algorithm versus the adjusted pixel-wise method are statistically significant (see also Table 1).
Figure 2
Figure 2
Spatial gene expression patterns of various adenylyl cyclase isoforms. Adcy5 is predominantly expressed in mouse striatum, while Adcy2, Adcy8, and Adcy9 show substantially different expression patterns. Brain images were obtained from the ABA, GenePaint.org, and GENSAT databases. The striatum region in ABA-6875 and ABA-2775 is outlined by a blue box.
Figure 3
Figure 3
Genes involved in the neuronal cAMP signaling pathway share a similar striatum-enriched hybridization profile to Adcy5. Brain images were obtained from the ABA, GenePaint.org, and GENSAT databases. The striatum region is outlined in ABA-2175.
Figure 4
Figure 4
Spatial gene expression of the Arpp21 gene variants suggests only the isoform represented by RefSeq NM_028755 may be involved in the striatal cAMP signaling pathway. The striatum region is outlined by a red box. Brain images were obtained from the ABA database and the tissue gene expression data were obtained from GNF SymAtlas.
Figure 5
Figure 5
Gene expression of Slc6a3, Slc18a2, and Ddc. All three genes are enriched in the brain substantia nigra region as indicated by the arrow. Brain images were obtained from the ABA database and the tissue gene expression data were obtained from GNF SymAtlas.
Figure 6
Figure 6
Gene expression of Avp, Hcrt, and Pmch. While little difference in expression among these genes is shown in the GNF mouse tissue atlas, the ABA images offer a better resolution and suggest Avp may play a different biological role than Hcrt and Pmch. The black boxes outline the brain hypothalamus region. Avp expression is concentrated in a specific hypothalamus region called periventricular region, while expressions of Hcrt and Pmch are largely concentrated in a different hypothalamus region called lateral hypothalamic area. Brain images were obtained from the ABA database and the tissue gene expression data were obtained from GNF SymAtlas.
Figure 7
Figure 7
The mask images of slide 2175 of Adcy5, slide 2050 of Pde1b, and slide 2275 of Ddc. Adcy5 and Pde1b show similar expression profiles, while Ddc is expressed differently. The pixel intensity histogram, row vector, and column vector (H, R, and C, respectively) for the three genes are shown. Green represents Adcy5, red is for Pde1b, and blue is for Ddc.

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    1. The Allen Brain Atlas Project

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