Cross-Species Analysis of Gene Expression and Function in Prefrontal Cortex, Hippocampus and Striatum

Mouse has been extensively used as a tool for investigating the onset and development of human neurological disorders. As a first step to construct a transgenic mouse model of human brain lesions, it is of fundamental importance to clarify the similarity and divergence of genetic background between non-diseased human and mouse brain tissues.

We systematically compared, based on large scale integrated microarray data, the transcriptomes of three anatomically distinct brain regions; prefrontal cortex (PFC), hippocampus (HIP) and striatum (STR), across human and mouse. The widely used DAVID web server was used to decipher the biological functions of the highly expressed genes that were identified using a previously reported approach. Venn analysis was used to depict the overlapping ratios of the notably enriched biological process (BP) terms (one-tailed Fisher's exact test and Benjamini correction; adjusted p < 0.01) between two brain tissues. GOSemSim, an R package, was selected to perform GO semantic similarity analysis. Next, we adjusted signal intensities of orthologous genes by the total signals in all samples within species, and used one minus Pearson's correlation coefficient to assess the expression distance. Hierarchical clustering and principal component analysis (PCA) were selected for expression pattern analysis. Lineage specific expressed orthologous genes were identified by comparison of the most extreme sub-datasets across species and further verified using reverse transcription PCR (RT-PCR) and quantitative real-time PCR (qRT-PCR).

We found that the number of the significantly enriched BP terms of the highly expressed genes in human brain regions is larger than that in mouse corresponding brain regions. The mainly involved BP terms in human brain tissues associated with protein-membrane targeting and selenium metabolism are species-specific. The overlapping ratios of all the significantly enriched BP terms between any two brain tissues across species are lower than that within species, but the pairwise semantic similarities are very high between any two brain tissues from either human or mouse. Hierarchical clustering analysis shows the biological functions of the highly expressed genes in brain tissues are more consistent within species than interspecies; whereas it shows the expression patterns of orthologous genes are evidently conserved between human and mouse equivalent brain tissues. In addition, we identified four orthologous genes (COX5B, WIF1, SLC4A10 and PLA2G7) that are species-specific, which have been widely studied and confirmed to be closely linked with neuro- physiological and pathological functions.

Our study highlights the similarities and divergences in gene function and expression between human and mouse corresponding brain regions, including PFC, HIP and STR.