Defect in non-coding DNA could cause brain disorders like severe language impairment

Tuesday, 21 March 2017

BMS Research Group

Genetic variation in the non-coding DNA may contribute to language impairments in children and other neurodevelopmental disorders including schizophrenia, autism and bipolar disorder, an international team of scientists has found.

Work by researchers from Oxford Brookes University and Max Planck Institute for Psycholinguistics and Radboud University both in The Netherlands, has been published today (14 March) in the Molecular Psychiatry journal.

The human genome is made up of three billion letters of DNA and at each position it is possible to have different letters, called variants. Some variants are harmless but others can be detrimental, making it a mammoth talk to find out which variants cause a disorder. 

Researchers often choose to search only the 1-2% of the genome that carries the information to make proteins. While this has been successful for a few disorders, most neurodevelopmental disorders are still largely unexplained, making it clear that looking elsewhere in the genome is necessary. 

Developmental language disorders are very common in the population and run in families, but yet we have little idea of the genetic variants that contribute to such disorders.

This project was particularly interesting as it allowed us to look at regions that are usually ignored in genetic sequencing studies. The findings represent a proof of principle and will help us to understand how gene regulation may contribute to speech and language disorders.

Dianne Newbury, Senior Lecturer in Medical Genetics and Genomics, Oxford Brookes University

“The remaining 98% of the genome offers a lot of untapped potential to find changes that can cause disorders,” Co-author of the study Paolo Devanna from Max Planck Institute for Psycholinguistics explains.

“These parts of the genome are known as ‘non-coding’, but that doesn’t mean that they are not important. They have very vital jobs to do, for example, to control when, where and how much protein in made. 

“So if this process gets messed up, it could have severe consequences, like neurodevelopmental disorders.”

For this reason, Paolo and his colleagues decided to look at the so called 3’UTRome – part of the non-coding genome that regulates how much protein is made. 

Searching for causes of language impairment

To test this approach, the researchers worked with Dianne Newbury at Oxford Brookes University to look at the DNA of children with severe language problems. The samples used for part of the SLI Consortium project in which Dianne is a lead researcher. 

Her research group is based in the Biomedical Science Department in the Faculty of Health and Life Sciences at Oxford Brookes, she said:

“Developmental language disorders are very common in the population and run in families, but yet we have little idea of the genetic variants that contribute to such disorders.

“This project was particularly interesting as it allowed us to look at regions that are usually ignored in genetic sequencing studies. The findings represent a proof of principle and will help us to understand how gene regulation may contribute to speech and language disorders.”

The researchers tested the impact of each 3’UTRome variant on the expression of the candidate genes for languages impairment. One of the variants has a significant effect on the expression of a gene known as ARHGEF39. 

“If a cell carries this single letter change in the 3’UTRome, they express more ARHGEF39. We were very excited by this finding because this is the first time we have found a variant associated with specific language impairment that we can show has a clear biological effect.” continued Paolo.

Given this success, the researchers went on to explore the 3’UTRome in other neurodevelopmental disorders. They identified 25 further genetic changes in the DNA of individuals with autism, schizophrenia and bipolar disorder that are thought to control protein levels in the same way. 

Neurodevelopmental disorders (NDDs) like schizophrenia, autism and bipolar disorders encompass a wide range of disabilities associated with the functioning of the brain. Severe NDDs are currently known to affect approximately 5% of the population, making understanding their causes and in turn, their possible treatments an important area of study.