BrainImageR: spatiotemporal gene set analysis referencing the human brain

Abstract

Motivation: Neuronal analyses such as transcriptomics, epigenetics and genome-wide association studies must be assessed in the context of the human brain to generate biologically meaningful inferences. It is often difficult to access primary human brain tissue; therefore, approximations are made using alternative sources such as peripheral tissues or in vitro-derived neurons. Gene sets from these studies are then assessed for their association with the post-mortem human brain. However, most analyses of post-mortem datasets are achieved by building new computational tools each time in-house, which can cause discrepancies from study to study. The field is in need of a user-friendly tool to examine spatiotemporal expression with respect to the postmortem brain. Such a tool will be of use in the molecular interrogation of neurological and psychiatric disorders, with direct advantages for the disease-modeling and human genetics communities.

Results: We have developed brainImageR, an R package that calculates both the spatial and temporal association of a dataset with post-mortem human brain. BrainImageR identifies anatomical regions enriched for candidate gene set expression. It further predicts the developmental time point of the sample, a task that has become increasingly important in the field of in vitro neuronal modeling. These functionalities of brainImageR enable a quick and efficient characterization of a given dataset across normal human brain development.

Availability and implementation: BrainImageR is released under the Creative Commons CC BY-SA 4.0 license and can be accessed directly at brainimager.salk.edu or the R code can be downloaded through github at https://github.com/saralinker/brainImageR.

Fig. 1.

SGSE with brainImageR. (A) BrainImageR identifies gene set enrichment with respect to postmortem expression data from the ABA. (B–C) Enrichment per region, x-axis: background gene set, y-axis: query gene set for the ventral thalamus of the developing brain (B) and the hippocampus of the adult brain (C). Red dots indicate enrichment scores with a bootstrapped P_adj < 0.05. Reference images for the developing (D) and adult (E) brain. The top number is used as input into brainImageR to plot the enrichment data. The bottom number is the section for the respective image in the ABA and can be used to look up additional information about each section. (F and G) SGSE for values in (B) and (C), respectively. (H) Predicted age in pcw from iPSC-neural progenitors (iPS-NPC), single-cell RNA-seq from post-mortem 16–18 pcw neurons (sc-N), 2D iPSC-neurons (iPS-N) and single-cell RNA-seq from 3D organoid neurons (scOr-N). (I) Predicted age in pcw from human post-mortem prefrontal cortex