An expanded microexon map links rare genetic variants to autism
A peer-reviewed study identified previously unannotated short segments involved in RNA processing and modelled the sequences governing their inclusion. Rare genetic variants had larger predicted effects on this process and were associated with autism. Experiments in human-derived neurons supported selected examples, while most individual effects remain predictions rather than established clinical outcomes.
Science··Midday
Short RNA segments gain a larger map
A peer-reviewed Nature study expanded the map of microexons and identified genetic variants associated with autism that are predicted to alter their processing. Microexons are very short segments, 3–27 nucleotides long, that can be included when ribonucleic acid, or RNA, is processed. Human tissue and single-nucleus data revealed 1,514 previously unannotated microexons; 292 differed in inclusion between neural and other tissues. Mouse data added 1,115 newly identified examples.[1], [2]
Rare variants have larger predicted effects
The team used machine learning to identify sequence features surrounding microexons that help predict their inclusion. Genetic analyses compared autistic individuals with unaffected siblings and included a broader within-family test of 25,132 people from 7,391 families. Rare and ultrarare variants had larger predicted splicing effects than common variants. A final set of 72 candidate variants occurred in 2.5 per cent of autistic individuals and was absent from their unaffected siblings.[1]
Selected variants alter processing in neurons
Experiments using short gene fragments in human-derived neurons supported altered processing for selected variants. Implicated genes converged on synaptic function, intracellular transport and protein degradation. Many individual effects remain computational predictions, and variants predicted to affect microexons also occur in unaffected people. These experiments examine part of the genetic burden associated with autism; their cellular reporters do not reproduce a person’s entire nervous system, behaviour or clinical outcome.[1]
