RNA sequencing suggests alternate RNA versions of genes may shape autism

in Commentary, Publications January 11, 2022 1,246 Views

From Spectrum by Giorgia Guglielmi

Playing alternates: More than half of the genes expressed in the human cortex, including some linked to autism, have more than one transcript isoform.

Researchers have uncovered thousands of new alternate RNA versions, or isoforms, of brain-expressed genes, including some involved in autism, according to a new study.

Several of the RNA isoforms are expressed at different levels during brain development, a separate analysis shows. Isoforms affected by autism-linked ‘loss-of-function’ mutations — which destroy a protein or disrupt its activity — tend to be expressed before birth and are typically involved in essential neuronal processes….

“This tells us that what’s going on in the cell is determined by isoforms, not by genes,” says Lilia Iakoucheva, associate professor of psychiatry at the University of California, San Diego, who led the first study. “It’s a no-brainer that we should be looking at the isoform-level data rather than gene-level data.”

…The BrainSpan data Iakoucheva’s study used was obtained with a sequencing technology that reads a few hundred base pairs at a time. Assembling long isoforms from such short reads can be challenging, and some isoforms may not be assembled correctly, she cautions.

Newer methods can sequence an entire transcript in one go, says Jonathan Mill, professor of epigenetics at the University of Exeter in the United Kingdom, who led the second study.

“That means you can see the structure of that transcript and work out whether there are quirks in the sequence that could be interesting from a functional perspective,” he says.

Mill and his team used such ‘long-read’ sequencing approaches to characterize RNA isoforms in samples of fetal and adult human cortex — the brain’s outer layer. They identified transcripts mapping to nearly 13,000 genes expressed in this brain region.

More than half of the genes, including some involved in some forms of autism, have more than one transcript isoform, the team found.

Source – Spectrum

Leung SK, Jeffries AR, Castanho I, Jordan BT, Moore K, Davies JP, Dempster EL, Bray NJ, O’Neill P, Tseng E, Ahmed Z, Collier DA, Jeffery ED, Prabhakar S, Schalkwyk L, Jops C, Gandal MJ, Sheynkman GM, Hannon E, Mill J. (2021) Full-length transcript sequencing of human and mouse cerebral cortex identifies widespread isoform diversity and alternative splicing. Cell Rep 37(7):110022. [article]

Chau KK, Zhang P, Urresti J, Amar M, Pramod AB, Chen J, Thomas A, Corominas R, Lin GN, Iakoucheva LM. (2021) Full-length isoform transcriptome of the developing human brain provides further insights into autism. Cell Rep 36(9):109631. [article]