An atlas of the protein-coding genes in the human, pig, and mouse brain

Mapping the mammalian brain The diverse physiology of the brain is reflected in its complex organization at regional, cellular, and subcellular levels. Sjöstedt et al. combined data—both newly acquired and from other large-scale brain mapping projects—from transcriptomics, single-cell genomics, in situ hybridization, and antibody-based protein profiling to map the molecular profiles in human, pig, and mouse brain. The analysis is consistent with a conserved basic brain architecture during mammalian evolution, but it does show differences in regional gene expression profiles. Science, this issue p. eaay5947 The Brain Atlas compares the expression of protein-coding genes in the mammalian brain. INTRODUCTION The brain is the most complex organ of the mammalian body, boasting a diverse physiology combined with intricate cellular organization. In an effort to expand our basic understanding of the neurobiology of the brain and its diseases, we performed a comprehensive molecular dissection of the main regions of the human, pig, and mouse brain using transcriptomics and antibody-based mapping. With this approach, we have identified regional expression profiles and observed similarities and differences in expression levels between these three mammalian species. RATIONALE There is a need for a comprehensive overview of genes expressed in the mammalian brain categorized by organ, brain region, and species specificity. To address this need, a brain-centered knowledge resource of RNA and protein expression in the brain of three mammalian species has been created and used for cell topological analysis, systems modeling, and data integration. The regional expression of all protein-coding genes is reported, and this classification is integrated with results from the analysis of tissues and organs of the whole human body. All generated data, including high-resolution images and metadata, have been made publicly available in an open-access Human Protein Atlas (HPA) Brain Atlas. RESULTS The global analysis suggests similar regional organization and expression patterns in the three mammalian species, consistent with the view that basic brain architecture is preserved during mammalian evolution. However, there is considerable variability between species for many neurotransmitter receptors, in particular between human and mouse. This calls for caution when using the mouse as a model system for the human brain, for example, in attempts to develop therapeutic strategies. For some of the brain regions, such as the cerebellum and hypothalamus, the human global expression profile is closer to that of the pig than it is to that of the mouse, suggesting that the pig might be considered a preferred animal model to study many brain processes. We show that many “signature genes” identified previously for specific brain cell types (such as astrocytes, microglia, oligodendrocytes, and neurons) are expressed at even higher levels in peripheral organs. In fact, our results support a view of shared functions between many genes in microglia and immune cells, and a large number of genes previously identified as signature genes for astrocytes are shown to be shared with liver or skeletal muscle. The cerebellum stands out as having a distinct molecular signature with many regionally enriched genes. Several genes suggested to be involved in neuropsychiatric diseases are selectively expressed in the cerebellum. CONCLUSION The integration of data from several sources has allowed us to combine data from transcriptomics, single-cell genomics, in situ hybridization, and antibody-based protein profiling. This integrative approach for mapping the molecular profiles in the human, pig, and mouse brain has generated a detailed multilevel genome-wide view on the protein-coding genes of the mammalian brain, where we compared tissue specificity across the whole body, as classified in the HPA (www.proteinatlas.org). The open-access HPA Brain Atlas resource offers the opportunity to explore individual genes and classes of genes and their expression profiles in the various parts of the mammalian brain. Genome-wide transcriptomics analysis of anatomically dissected regions in mammalian brains uncovers regional and species-specific expression. Multiple regions of the human, pig, and mouse brain were dissected and analyzed. A uniform manifold approximation and projection (UMAP) analysis (middle) shows the global expression patterns of 1710 samples in the human brain, with the cerebellum as the outlier. The HPA Brain Atlas (right) shows the expression of individual genes, for example, synaptosomal-associated protein 25 (SNAP25), in the different brain regions in the three mammalian species. The brain, with its diverse physiology and intricate cellular organization, is the most complex organ of the mammalian body. To expand our basic understanding of the neurobiology of the brain and its diseases, we performed a comprehensive molecular dissection of 10 major brain regions and multiple subregions using a variety of transcriptomics methods and antibody-based mapping. This analysis was carried out in the human, pig, and mouse brain to allow the identification of regional expression profiles, as well as to study similarities and differences in expression levels between the three species. The resulting data have been made available in an open-access Brain Atlas resource, part of the Human Protein Atlas, to allow exploration and comparison of the expression of individual protein-coding genes in various parts of the mammalian brain.