Gene expression in the rodent brain is associated with its regional connectivity

Abstract

The putative link between gene expression of brain regions and their neural connectivity patterns is a fundamental question in neuroscience. Here this question is addressed in the first large scale study of a prototypical mammalian rodent brain, using a combination of rat brain regional connectivity data with gene expression of the mouse brain. Remarkably, even though this study uses data from two different rodent species (due to the data limitations), we still find that the connectivity of the majority of brain regions is highly predictable from their gene expression levels-the outgoing (incoming) connectivity is successfully predicted for 73% (56%) of brain regions, with an overall fairly marked accuracy level of 0.79 (0.83). Many genes are found to play a part in predicting both the incoming and outgoing connectivity (241 out of the 500 top selected genes, p-value<1e-5). Reassuringly, the genes previously known from the literature to be involved in axon guidance do carry significant information about regional brain connectivity. Surveying the genes known to be associated with the pathogenesis of several brain disorders, we find that those associated with schizophrenia, autism and attention deficit disorder are the most highly enriched in the connectivity-related genes identified here. Finally, we find that the profile of functional annotation groups that are associated with regional connectivity in the rodent is significantly correlated with the annotation profile of genes previously found to determine neural connectivity in C. elegans (Pearson correlation of 0.24, p<1e-6 for the outgoing connections and 0.27, p<1e-5 for the incoming). Overall, the association between connectivity and gene expression in a specific extant rodent species' brain is likely to be even stronger than found here, given the limitations of current data.

Figure 1. Brain regions for which prediction ability is significantly above chance.

(a) The hierarchy of the brain regions in the Allen Brain Atlas is shown in the inner circle as circles with abbreviates. Colors are used to distinguish between subtrees. (b) Regions in the rodent brain for which prediction was significant at the p = 0.05 level for outgoing connectivity are marked green in the circle next to the outermost one. Those with insignificant prediction results are marked yellow. Note that only regions with at least 5 outgoing connections are marked by either color. (c) Similarly, for incoming connectivity in the outermost circle.

Figure 2. Frequency histogram of gene selection across regions.

The number of times each of the 20,936 genes was selected as connectivity-predictive by the per-region zero-norm experiments. Graphs are shown for the Outgoing connections experiment, for the Incoming one, and compared to the frequency obtained with a random shuffle.

Figure 3. The correlation between variability in gene expression and predictability of connectivity.

All genes were ranked by their region to region variability and put into equally sized bins. The intersection of each bin with the list of 500 efferent connectivity genes and the list of 500 afferent connectivity genes is shown (highest variance bin on the right, the x-axis depicts the amount of variability). As can be seen, the genes with the highest variability are not excessively frequent within the lists of most informative connectivity genes.