Looking at gene products in postmortem brain provides a more detailed picture of autism biology

Genes are the code that allows our bodies to make RNAs, which then goes on to produce proteins. But this code is complex. For example, individual genes can code for different protein products, or isoforms, through a process called RNA alternative splicing. This process plays an important role in brain development, yet its role in neurodevelopmental conditions is unclear. Understanding how alternative splicing regulates brain development and contribute to risk for neurodevelopmental conditions require examining how proteins are made and how they function in the brain at different times during development.

In a recent study,1 Kevin Chau and Lilia Iakoucheva at the University of California, San Diego and their colleagues investigated these processes by looking at RNA-sequencing data from postmortem brain tissue from the PsychENCODE (PEC) Capstone Collection. The researchers first examined all of the RNAs made (transcribed) from each gene to create a detailed “isoform transcriptome,” and found that genes in the human brain code on average for 4 different protein isoforms—variants of the same protein that are created by a single gene through the process of alternative splicing. They also showed that different isoforms tended to be made at distinct times during human brain development, especially during mid/late fetal and neonatal development.

Importantly, the changes they saw looking at isoforms that were differentially expressed across development were larger than the changes they saw in the activity of single genes across development. This suggests that examining changes at the level of isoforms can provide a fuller picture about typical (and atypical) brain development, than examining changes at the level of individual genes.

To better understand the role of isoforms in autism susceptibility, the researchers then looked at isoforms in the postmortem brains carrying loss-of-function mutations that had been previously linked to autism2, comparing 12,111 mutations associated with autism and 3,588 changes unrelated to the condition. This work showed that the prenatal human brain was more likely to have isoforms carrying autism-linked mutations than mutations not linked to autism.

The researchers then used a variety of computational techniques to explore distinct patterns of expression and interactions across groups of isoforms at distinct stages of human brain development. Such comparisons pointed to changes in splicing and in synaptic brain connectivity in isoforms carrying autism-linked mutations. Direct examination of a few specific genes and their isoforms also supported the idea that autism-linked mutations are more likely to affect gene isoforms that play a role in earlier aspects of brain development.

Combined, this research provides a rich dataset that can help to unravel the complexity of how autism-linked gene mutations relate to the expression of specific gene products, or protein isoforms. It also points to the importance of considering isoform expression in addition to genome level expression in future studies, to better understand the mechanisms that regulate brain development and the mechanisms that underlie autism susceptibility.


  1. Chau K.K. et al. Cell Rep. 36, 109631 (2021) PubMed
  2. Satterstrom F.K. et al. Cell 180, 568-584 (2020) PubMed