BrainScope: interactive visual exploration of the spatial and temporal human brain transcriptome

Abstract Spatial and temporal brain transcriptomics has recently emerged as an invaluable data source for molecular neuroscience. The complexity of such data poses considerable challenges for analysis and visualization. We present BrainScope: a web portal for fast, interactive visual exploration of the Allen Atlases of the adult and developing human brain transcriptome. Through a novel methodology to explore high-dimensional data (dual t-SNE), BrainScope enables the linked, all-in-one visualization of genes and samples across the whole brain and genome, and across developmental stages. We show that densities in t-SNE scatter plots of the spatial samples coincide with anatomical regions, and that densities in t-SNE scatter plots of the genes represent gene co-expression modules that are significantly enriched for biological functions. We also show that the topography of the gene t-SNE maps reflect brain region-specific gene functions, enabling hypothesis and data driven research. We demonstrate the discovery potential of BrainScope through three examples: (i) analysis of cell type specific gene sets, (ii) analysis of a set of stable gene co-expression modules across the adult human donors and (iii) analysis of the evolution of co-expression of oligodendrocyte specific genes over developmental stages. BrainScope is publicly accessible at www.brainscope.nl.

[1]  Raymond K. Auerbach,et al.  An Integrated Encyclopedia of DNA Elements in the Human Genome , 2012, Nature.

[2]  Allan R. Jones,et al.  Comprehensive transcriptional map of primate brain development , 2016, Nature.

[3]  Shuiwang Ji.  Computational genetic neuroanatomy of the developing mouse brain: dimensionality reduction, visualization, and clustering , 2013, BMC Bioinformatics.

[4]  J. Kleinman,et al.  Spatiotemporal transcriptome of the human brain , 2011, Nature.

[5]  Allan R. Jones,et al.  An anatomic gene expression atlas of the adult mouse brain , 2009, Nature Neuroscience.

[6]  M. Mearin,et al.  Mass Cytometry of the Human Mucosal Immune System Identifies Tissue- and Disease-Associated Immune Subsets. , 2016, Immunity.

[7]  Mark M. Davis,et al.  Automatic Classification of Cellular Expression by Nonlinear Stochastic Embedding (ACCENSE) , 2013, Proceedings of the National Academy of Sciences.

[8]  Michael J. Purcaro,et al.  The PsychENCODE project , 2015, Nature Neuroscience.

[9]  Data production leads,et al.  An integrated encyclopedia of DNA elements in the human genome , 2012 .

[10]  G. Kreutzberg,et al.  Microglia: Intrinsic immuneffector cell of the brain , 1995, Brain Research Reviews.

[11]  Allan R. Jones,et al.  An anatomically comprehensive atlas of the adult human brain transcriptome , 2012, Nature.

[12]  Allan R. Jones,et al.  Transcriptional Architecture of the Primate Neocortex , 2012, Neuron.

[13]  G. Bates,et al.  A common gene expression signature in Huntington’s disease patient brain regions , 2014, BMC Medical Genomics.

[14]  Juan Carlos Fernández,et al.  Multiobjective evolutionary algorithms to identify highly autocorrelated areas: the case of spatial distribution in financially compromised farms , 2014, Ann. Oper. Res..

[15]  Ying Dai,et al.  Principal component analysis based methods in bioinformatics studies , 2011, Briefings Bioinform..

[16]  Elmar Eisemann,et al.  Approximated and User Steerable tSNE for Progressive Visual Analytics , 2015, IEEE Transactions on Visualization and Computer Graphics.

[17]  Evan Z. Macosko,et al.  Highly Parallel Genome-wide Expression Profiling of Individual Cells Using Nanoliter Droplets , 2015, Cell.

[18]  Ellen T. Gelfand,et al.  The Genotype-Tissue Expression (GTEx) project , 2013, Nature Genetics.

[19]  S. Nelson,et al.  Cell-type–based model explaining coexpression patterns of genes in the brain , 2011, Proceedings of the National Academy of Sciences.

[20]  Allan R. Jones,et al.  A High-Resolution Spatiotemporal Atlas of Gene Expression of the Developing Mouse Brain , 2014, Neuron.

[21]  S. Grant,et al.  Characterization of the proteome, diseases and evolution of the human postsynaptic density , 2011, Nature Neuroscience.

[22]  Ahmed Mahfouz,et al.  Visualizing the spatial gene expression organization in the brain through non-linear similarity embeddings. , 2015, Methods.

[23]  Geoffrey E. Hinton,et al.  Visualizing Data using t-SNE , 2008 .

[24]  Alan N. Simmons,et al.  Whole Brain Expression of Bipolar Disorder Associated Genes: Structural and Genetic Analyses , 2014, PloS one.

[25]  Washington Seattle.  An integrated encyclopedia of DNA elements in the human genome , 2016 .

[26]  Allan R. Jones,et al.  Canonical Genetic Signatures of the Adult Human Brain , 2015, Nature Neuroscience.

[27]  Allan R. Jones,et al.  Transcriptional Landscape of the Prenatal Human Brain , 2014, Nature.

[28]  Jing Chen,et al.  ToppGene Suite for gene list enrichment analysis and candidate gene prioritization , 2009, Nucleic Acids Res..

[29]  Avi Ma'ayan,et al.  Enrichr: interactive and collaborative HTML5 gene list enrichment analysis tool , 2013, BMC Bioinformatics.

[30]  Allan R. Jones,et al.  Genome-wide atlas of gene expression in the adult mouse brain , 2007, Nature.

[31]  ENCODEConsortium,et al.  An Integrated Encyclopedia of DNA Elements in the Human Genome , 2012, Nature.

[32]  Michael Poidinger,et al.  Mapping the Diversity of Follicular Helper T Cells in Human Blood and Tonsils Using High-Dimensional Mass Cytometry Analysis. , 2015, Cell reports.

[33]  Jengnan Tzeng,et al.  Multidimensional scaling for large genomic data sets , 2008, BMC Bioinformatics.

[34]  John Morris,et al.  Multi-scale correlation structure of gene expression in the brain , 2011, Neural Networks.

[35]  A. Singleton,et al.  Genetic variability in the regulation of gene expression in ten regions of the human brain , 2014, Nature Neuroscience.

[36]  S. Horvath,et al.  Transcriptomic Analysis of Autistic Brain Reveals Convergent Molecular Pathology , 2011, Nature.

[37]  Lydia Ng,et al.  Allen Brain Atlas: an integrated spatio-temporal portal for exploring the central nervous system , 2012, Nucleic Acids Res..

[38]  Pietro Liò,et al.  The BioMart community portal: an innovative alternative to large, centralized data repositories , 2015, Nucleic Acids Res..

[39]  T. Maniatis,et al.  An RNA-Sequencing Transcriptome and Splicing Database of Glia, Neurons, and Vascular Cells of the Cerebral Cortex , 2014, The Journal of Neuroscience.

[40]  S. Horvath,et al.  A General Framework for Weighted Gene Co-Expression Network Analysis , 2005, Statistical applications in genetics and molecular biology.