Journal: eLife

Article Title: Transcriptional cartography integrates multiscale biology of the human cortex

doi: 10.7554/eLife.86933

Figure Lengend Snippet: ( a ) Overview of weighted gene co-expression network analysis (WGCNA) pipeline applied to the full dense expression map (DEM) dataset. Starting top left: the pairwise DEM spatial correlation matrix is used to generate a topological overlap matrix between genes (middle top), which is then clustered. Of the 23 WGCNA-defined modules, 7 were significantly enriched for non-cortical genes and removed, leaving 16 modules. Each module is defined by a set of spatially co-expressed genes, for which the principal component of expression can be computed and mapped at each cortical point (eigenmap). M6 is shown as an example projected onto an inflated left hemisphere (M6 z-scored expression and M6 expression change), and the bulk transcriptional distinctiveness (TD) terrain view from (M6 expression). ( b ) The extremes of WGCNA eigenmaps highlight different peaks in the cortical terrain: the main TD terrain colored by TD value (center, from ), surrounded by TD terrain projections of selected WGCNA eigenmaps. ( c ) WGCNA modules (eigenmaps and gradient maps, rows) are enriched for multiscale aspects of cortical organization (columns). Cell color intensity indicates pairwise statistical significance (p<0.05), while black outlines show significance after correction for multiple comparisons across modules. Columns capture key levels of cortical organization at different spatial scales (arranged from macro- to microscale) and developmental epochs: spatial alignment between module eigenmaps and in vivo MRI maps of cortical folding orientation, cortical thickness and T1/T2 ratio, fMRI resting-state functional networks; enrichment for module gene sets for independent annotations marking: cortical layers ( ; ); cell types ( ; ; ; ; ; ; ; ; ); subcellular compartments ; synapse-related genes ; protein–protein interactions between gene products ; temporal epochs of peak expression (‘fetal’: 8–24 21 post conception weeks [PCW]/’‘perinatal’' 24 PCW–6 mo/‘postnatal’ > 6 mo); transient layers of the mid-fetal human cortex at 21 PCW (subpial granular zone [SG], marginal zone [MZ], cortical plate [CP], subplate [SP], intermediate zone [IZ], subventricular zone [SZ], and ventricular zone [VZ]); and fetal cell types at 17–18 PCW . ( d ) Independent validation of multiscale enrichments for selected modules M2 and M12. M2 significantly overlaps the Neurosynth topic associated with the terms motor, cortex, and hand. Two high-ranking M2 genes, MOG and TF, exhibit clear layer VI peaks on in situ hybridization (ISH) and GO enrichment analysis myelin-related annotations. M12, overlapping the limbic network most closely overlapped the Neurosynth topic associated with social reasoning. Two high-ranking M22 genes GABRA2 and GRIN2B showed layer II ISH peaks and GO enrichment analysis revealed synaptic annotations. ( e ) Network visualization of pairwise overlaps between annotational gene sets used in (c), including WGCNA module gene sets (inset expression eigenmaps).

Article Snippet: Cellular compartment gene lists were taken from the COMPARTMENTS database , which identifies subcellular localisation of marker genes based on integrated information from the Human Protein Atlas, literature mining, and GO annotations.

Techniques: Expressing, In Vivo, Functional Assay, Protein-Protein interactions, Biomarker Discovery, In Situ Hybridization