Spatio-temporal transcriptome of the human brain

Abstract

SummaryHere we report the generation and analysis of genome-wide exon-level transcriptome data from 16 brain regions comprising the cerebellar cortex, mediodorsal nucleus of the thalamus, striatum, amygdala, hippocampus, and 11 areas of the neocortex. The dataset was generated from 1,340 tissue samples collected from one or both hemispheres of 57 postmortem human brains, spanning from embryonic development to late adulthood and representing males and females of multiple ethnicities. We also performed genotyping of 2.5 million SNPs and assessed copy number variations for all donors. Approximately 86% of protein-coding genes were found to be expressed using stringent criteria, and over 90% of these were differentially regulated at the whole transcript or exon level across regions and/or time. The majority of these spatiotemporal differences occurred before birth, followed by an increase in the similarity among regional transcriptomes during postnatal lifespan. Genes were organized into functionally distinct co-expression networks, and sex differences were present in gene expression and exon usage. Finally, we demonstrate how these results can be used to profile trajectories of genes associated with neurodevelopmental processes, cell types, neurotransmitter systems, autism, and schizophrenia, as well as to discover associations between SNPs and spatiotemporal gene expression. This study provides a comprehensive, publicly available dataset on the spatiotemporal human brain transcriptome and new insights into the transcriptional foundations of human neurodevelopment.

Genome‐wide significant schizophrenia risk variation on chromosome 10q24 is associated with altered cis‐regulation of BORCS7, AS3MT, and NT5C2 in the human brain

“…Microarray data indicate that AS3MT and NT5C2 are both expressed at a higher level in the prenatal human brain compared to that of the adult [Kang et al, 2011; Birnbaum et al, 2015]. We find that heterozygosity for rs11191419 is associated with particularly pronounced allelic expression imbalance of AS3MT in the fetal brain, with an average 40% increase in expression of the AS3MT allele that is generally carried on the same chromosome as the risk allele.…”

Gene expression‐based drug repurposing to target aging

“…We analysed data from seven, published, microarray‐based studies of age‐related changes in RNA expression (Barnes et al, 2011; Berchtold et al, 2008; Colantuoni et al, 2011; Kang et al, 2011; Lu et al, 2004; Maycox et al, 2009; Somel et al, 2010, 2011 ). The data came from 22 different brain regions, and the ages of the donors ranged from 20 to 106 years (Figure 1a and Supporting Information Figure S1a).…”

“…Gene annotations for the probe‐sets are obtained from the Ensembl database using the “biomaRt” library (Durinck, Spellman, Birney, & Huber, 2009) in r . Because the annotations for the probe‐sets used in Kang et al (2011) and Colantuoni et al (2011) are not available in Ensembl, we used the GPL files deposited in GEO. If Ensembl gene IDs are not provided in the GPL files, Entrez gene IDs were extracted and converted to Ensembl Gene IDs using the “biomaRt” package.…”

DNA methylation changes in plasticity genes accompany the formation and maintenance of memory

“…More recent papers studied several brain regions across development. For example, Kang et al (2011) created a network using data from six brain structures across pre-and post-natal development and found modules related to different spatiotemporal profiles 4 , while Voineagu et al (2011) studied changes in expression modules in the autistic brain 7 . In our initial assessment of the first two brains in the Allen Human Brain Atlas 3 , we identified groups of genes related both to major cell types (i.e., astrocytes, choroid plexus, etc.…”