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Autism Study Reveals Gene Expression Changes in Specific Brain Cell Types

NEW YORK (GenomeWeb) – Specific cell types in the brain appear to have altered gene expression in individuals with autism spectrum disorder (ASD), according to new research from investigators at the University of California at San Francisco, UC Santa Cruz, and elsewhere.

In a paper published online today in Science, the team did single-nucleus RNA sequencing on almost 104,600 individual cells from post-mortem cortical brain tissue samples collected from dozens of individuals with or without ASD. None of ASD-affected individuals included in the study had been diagnosed with an intellectual disability during their lifetimes, though just over half of them had a history of epileptic seizures.

When the researchers clustered the nuclei based on their transcriptome features, focusing in particular on ASD-specific cell types and features, they saw signs of synaptic signaling differences in the upper-layer excitatory neurons as well as microglia expression differences.

"Our results show that specific sets of genes in upper-layer projection neurons and microglia correlate with the clinical severity of ASD," senior and co-corresponding author Arnold Kriegstein, a regeneration medicine, stem cell, and neurology researcher at UCSF, and his colleagues wrote, noting that genes with ASD-specific expression shifts "represent high-priority therapeutic targets for ASD."

The shared genes and pathways highlighted by past gene expression analyses of bulk neocortex samples in ASD appear to belie the clinical and genetic heterogeneity that has been described in the disease, the team explained.

In an effort to narrow in on specific brain cell types with altered expression in ASD — including ASD cases with varying clinical features — the researchers used snRNA-seq with the 10x Genomics platform to profile 104,559 individual nuclei in 41 post-mortem prefrontal cortex or anterior cingulate cortex samples.

In the process, they generated transcriptome data for more than 52,000 cortical cell nuclei from individuals with 15 ASD and 52,556 nuclei representing brain samples from 16 unaffected control individuals.

The team uncovered 17 cell types in the available cortical brain cell samples — from excitatory neurons to astrocytes — before looking at how well the data lined up with bulk RNA-seq data. From there, the investigators searched for ASD-related expression changes in specific brain cell types, along with transcriptome changes that occurred in ASD-affected individuals without sporadic epilepsy symptoms.

In some, for example, the researchers saw ASD-related expression shifts in nuclei from both neuron and non-neuron cell types, including lower-than-usual expression of some genes in excitatory neurons in ASD and a rise in the expression of genes in astrocyte and microglia cells.

When they looked at how well the differentially expressed genes in the samples lined up with genes implicated in past ASD association studies, meanwhile, the investigators identified a few dozen overlapping genes. Those included genes expressed in specific excitatory neurons and inter-neurons, and genes from pathways involved in processes such as neuronal migration, synaptic transmission, and other brain processes.

From there, the group went on to explore cell-specific expression ties to ASD severity, sporadic epilepsy, development, and more, uncovering upper-layer projection neurons and microglia shifts that appeared to impact the severity of the disease, along with clues to regulatory alterations that might influence brain development in an ASD-related manner. 

"Future studies involving larger patient cohorts, including whole-exome sequencing and improved single-cell technologies, will allow for more precise identification of ASD-driven molecular changes and their association with deleterious genetic variants," the authors concluded, noting that the transcriptome data generated for the study are available through an interactive UCSC web browser.