Linking gene expression data to biomedical imaging data

Project Description

“Imaging Genetics: Linking Gene
Expression Data to Medical Images”

 

Motivation:

Understanding the brain’s anatomical structure is of critical importance across areas of study in neuroscience. There is a significant uncertainty about how to define regions within the brain, because classical neuroanatomic labeling is based mainly on morphological properties of cells in those regions. Nevertheless, it’s clear that spatial expression of particular genes in the brain plays an important role in dissecting the brain into different functional regions.

Functions
of different brain regions are the product of unique combinations of expressed gene products; therefore, the availability of large scale genome-wide data offers the possibility to reveal the functional organization of the brain.

Allen Brain Atlas (ABA):

The Allen Brain Atlas (ABA) [1] is a pioneered large-scale integration of genomic and anatomic data, resulting in a genome-wide map of the adult mouse brain revealing locations of gene expression. The ABA has made it possible to examine gene expression patterns in the adult mouse brain at an unprecedented scale and level of resolution.

ABA is a 3D digital atlas containing the expression patterns of ~20,000 genes in the male, 8-week old (adult) C57BL/6J mouse brain. The gene expression data was produced using automated in situ hybridization (ISH), a process which marks where a gene is expressed in thin tissue sections. Standard procedures were developed to isolate, cut, fix and pre-treat brain tissue to preserve as much macro and cellular morphology as possible. The fresh frozen brains are sectioned in two different orientations, sagittal and coronal. Sections are 25 µm thick with a uniform inter-slice spacing of 200 µm, allowing for uniform sampling every 200 µm across the entire brain for each gene.

The high resolution (1.07 µm/pixel) primary data from each experiment (images resulting from scanning each section) were reconstructed in 3D and registered to the Nissl stain-based reference atlas (Allen Reference Atlas; ARA). For each gene, the data were aggregated into isotropic voxels defined by a uniform 200 µm grid in the reference space. Expression of each gene within each 200 µm voxel was summarized by a measure of smoothed gene expression (the average intensity of pixels in the ISH image intersecting that voxel). Resulting data consists of a spatially aligned 67 X 41 X 58 volume for each gene.

 

Figure 1: Data from the Allen Brain Atlas, showing the expression of Prkcd (gene) reconstructed using the Brain Explorer software; source [2].

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The Project:

The goal of this project is to link the gene expression data, available through ABA, to anatomical and functional information available through magnetic resonance imaging (MRI) of the mouse brain. Our intent is to investigate the correlation between the classical neuroanatomical structures and the gene expression patterns across the brain.

We will work on developing a genetic signature for each brain region and determine whether the molecular organization of the brain can be reconciled with classical neuroanatomical parcellations at a particular spatial scale. The localization and density of gene expressions encoding certain neural functions in a specific brain region, reveals the role that the region plays in that neural function.

Similarities between gene expression patterns at different brain regions/structures could reveal information about the functions of these genes. For example, if two genes are co-expressed in the brain and one of them is of a well-known neural function, the other gene should be reported for examination for involvement in the same function. With the gene expression data (ABA) registered to the MRI data, it would be easy to visualize where those correlations or similarities are localized within the brain.

People involved:

Ahmed Mahfouz, MSc.

Dr. Emile A. Hendriks

Dr. ir. Boudewijn Lelieveldt

Prof. dr. ir. Marcel Reinders

Dr. Louise van der Weerd (LUMC)

References:

[1]   Ed S. Lein et al., “Genome-wide Atlas of Gene Expression in the Adult Mouse Brain”, Nature 445, 186 – 176,
2007

[2]     C. Lau et al., “Exploration and visualization of gene expression with neuroanatomy in the adult mouse brain”, BMC Bioinformatics, 9, 153, 2007