Toronto scientists discover largely overlooked `microexons? serve important role in neurological disorders


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A key to fighting autism and other neurological disorders may rest in segments of genes so small they mostly went unnoticed, scientists at the University of Toronto have found.

While the genetic coding that makes up the human genome consists of about three billion letters, the segments found by Toronto scientists have as few as three and were only found using a sophisticated computer program created for the research.

But while the segments called microexons are tiny, their impact may be large, especially in a disorder such as autism, that manifest genetically in so many ways that, to fight it, scientists must look for root causes.

“The challenge here is in identifying common pathways,” said Ben Blencowe of the Donnelly Centre for Cellular and Biomolecular Research at the University of Toronto.

His research was published Thursday in the biomedical research journal Cell.

Microexons are spliced into gene messengers called mRNAs to generate proteins the nervous system needs to function well.

Blencowe and colleagues, led by post-doctoral fellow Manuel Irimia, created a tool to detect more splicing combinations within a cell, including those involving microexons.

“Microexons perform a type of microsurgery on proteins to alter their function,” said Irimia, who will set up his own lab at the Centre for Genomic Regulation in Barcelona, Spain.

Even though microexons make small changes to proteins, the effects of those changes can be dramatic.

In people with autism, many neuronal microexons are weakly spliced, in part because of reduced production of a protein called nSR100 that the scientists suspect may be a factor in autism.


New method able to predict diseases, traits

In the decade since the genome was sequenced in 2003, scientists and doctors have struggled to answer an all-consuming question: Which DNA mutations cause disease?

A new computational technique developed at the University of Toronto may be able to tell us.

A team led by Brendan Frey has developed the first method for ranking genetic mutations, revealing how likely any given alteration is to cause disease. Their work was published Thursday in the journal Science.

“A huge amount of effort has been invested into searching for mutations in the genome that cause disease, without a rational approach to understanding why they cause disease,” said Frey, who holds positions with the Donnelly Centre for Cellular and Biomolecular Research and the departments of molecular genetics and computer science at the U of T.

Genetic research has focused on mutations but these alone don’t explain disease. Frey’s team instead focused on how genetic instructions are spliced together. Their method correctly predicted 94% of the genetic culprits behind well-studied diseases such as spinal muscular atrophy and colorectal cancer, then accurately predicted mutations never seen before.

They then tackled autism, a condition with complex genetic under­pinnings. “With autism there are only a few dozen genes definitely known to be involved and these account for a small proportion of individuals with this condition,” Frey said.

Autism is just the beginning: Frey said he believes this method can be applied to many diseases, and even non-disease traits that differ between individuals.

About autism:

  • Neurological disorder that causes a wide range of developmental disability, from mild to severe.
  • One in every 68 children is born with autism and about 515,000 Canadians live with the disorder.
  • Genetic factors associated with those with autism are varied and complex.

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