ABSTRACT
Neuroanatomically precise, genome-wide maps of transcript distributions are critical resources to complement genomic sequence data and to correlate functional and genetic brain architecture. Here we describe the generation and analysis of a transcriptional atlas of the adult human brain, comprising extensive histological analysis and comprehensive microarray profiling of â¼900 neuroanatomically precise subdivisions in two individuals. Transcriptional regulation varies enormously by anatomical location, with different regions and their constituent cell types displaying robust molecular signatures that are highly conserved between individuals. Analysis of differential gene expression and gene co-expression relationships demonstrates that brain-wide variation strongly reflects the distributions of major cell classes such as neurons, oligodendrocytes, astrocytes and microglia. Local neighbourhood relationships between fine anatomical subdivisions are associated with discrete neuronal subtypes and genes involved with synaptic transmission. The neocortex displays a relatively homogeneous transcriptional pattern, but with distinct features associated selectively with primary sensorimotor cortices and with enriched frontal lobe expression. Notably, the spatial topography of the neocortex is strongly reflected in its molecular topography-the closer two cortical regions, the more similar their transcriptomes. This freely accessible online data resource forms a high-resolution transcriptional baseline for neurogenetic studies of normal and abnormal human brain function.
Subject(s)
Anatomy, Artistic , Atlases as Topic , Brain/anatomy & histology , Brain/metabolism , Gene Expression Profiling , Transcriptome/genetics , Adult , Animals , Brain/cytology , Calbindins , Databases, Genetic , Dopamine/metabolism , Health , Hippocampus/cytology , Hippocampus/metabolism , Humans , In Situ Hybridization , Internet , Macaca mulatta/anatomy & histology , Macaca mulatta/genetics , Male , Mice , Neocortex/anatomy & histology , Neocortex/cytology , Neocortex/metabolism , Oligonucleotide Array Sequence Analysis , Post-Synaptic Density/genetics , RNA, Messenger/analysis , RNA, Messenger/genetics , S100 Calcium Binding Protein G/genetics , Species SpecificityABSTRACT
The mammalian brain is best understood as a multi-scale hierarchical neural system, in the sense that connection and function occur on multiple scales from micro to macro. Modern genomic-scale expression profiling can provide insight into methodologies that elucidate this architecture. We present a methodology for understanding the relationship of gene expression and neuroanatomy based on correlation between gene expression profiles across tissue samples. A resulting tool, NeuroBlast, can identify networks of genes co-expressed within or across neuroanatomic structures. The method applies to any data modality that can be mapped with sufficient spatial resolution, and provides a computation technique to elucidate neuroanatomy via patterns of gene expression on spatial and temporal scales. In addition, from the perspective of spatial location, we discuss a complementary technique that identifies gene classes that contribute to defining anatomic patterns.
