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Defect in non-coding DNA can impair language

The human genome is made up of approximately 3 billion letters of DNA. Each 'letter' can also become reorganized, and therefore be a variant of the norm. Some variants are harmless but others can be detrimental. It's a mammoth task to find out which variant causes a particular disorder.


Researchers often choose to search only 1 to 2% of the genome, which is the complete set of genetic material making up an entire body, in order to identify which gene variant affects which protein. While there has been some success in diagnosis of a few neurodevelopmental disorders, most are largely unexplained. Clearly, looking deeper in the genome is needed.


"The remaining 98% of the genome offers a lot of untapped potential to find what can cause disordersparts of the genome known as 'non-coding'. But, that doesn't mean these parts aren't important as they perform vital jobs. For example, controllng when, where and how much protein is made. If this process gets messed up, it could have severe consequences, such as seen in neurodevelopmental disorders [NDDs]."

Paolo Devanna PhD, Neurogenetics of Vocal Communication Group, Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands, and co-author of the study.


Devanna and his colleagues decided to look at a portion of the gene known as the 3'UTRome. Although a 'non-coding' part of a gene, if misorganized the 3'UTRome affects regulation of how much protein is made. To test their idea, they examined the DNA of children with severe language problems and identified genetic variants in the 3'UTRome. The work appears in the March 14, 2017 issue of Molecular Biology


"Language disorders are a very complex neuro-developmental disorder. Finding their genetic causes has been particularly challenging. We have only a small number of candidate genes thus far."

Sonja Vernes PhD, Neurogenetics of Vocal Communication Group, Max Planck Institute for Psycholinguistics; Donders Institute for Brain, Cognition and Behaviour, both located in Nijmegen, The Netherlands; and leader of the research.


Researchers tested the impact of each 3'UTRome variant as it affects the expression of genes associated with languages impairment and found one of the variants has a significant effect on the expression of ARHGEF39 a protein coding gene.


"If a cell carries this single letter change in the 3'UTRome, they express more ARHGEF39. Having too much of a protein at important points in development could affect how neurons and neuronal circuits develop and function.This could in turn affect how children develop language."

Paolo Devanna PhD


Given their success, researchers went on to explore the 3'UTRome portion of DNA in other neurodevelopmental disorders. So far, they have identified 25 gene changes in DNA of individuals with autism, schizophrenia and bipolar disorder, that may be expressing higher protein levels in a similar way.


"We are tapping into a new and promising source of genetic variation. Our study shows that identification and testing of non-coding variants will foster our understanding of genetic causes of NDD disorders, crucial in the long term for design of new and effective therapeutics."

Sonja Vernes PhD


Neurodevelopmental disorders (NDDs) like schizophrenia, autism and bipolar disorders encompass a wide range of disabilities associated with 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.

Abstract
Understanding the genetic factors underlying neurodevelopmental and neuropsychiatric disorders is a major challenge given their prevalence and potential severity for quality of life. While large-scale genomic screens have made major advances in this area, for many disorders the genetic underpinnings are complex and poorly understood. To date the field has focused predominantly on protein coding variation, but given the importance of tightly controlled gene expression for normal brain development and disorder, variation that affects non-coding regulatory regions of the genome is likely to play an important role in these phenotypes. Herein we show the importance of 3 prime untranslated region (3'UTR) non-coding regulatory variants across neurodevelopmental and neuropsychiatric disorders. We devised a pipeline for identifying and functionally validating putatively pathogenic variants from next generation sequencing (NGS) data. We applied this pipeline to a cohort of children with severe specific language impairment (SLI) and identified a functional, SLI-associated variant affecting gene regulation in cells and post-mortem human brain. This variant and the affected gene (ARHGEF39) represent new putative risk factors for SLI. Furthermore, we identified 3′UTR regulatory variants across autism, schizophrenia and bipolar disorder NGS cohorts demonstrating their impact on neurodevelopmental and neuropsychiatric disorders. Our findings show the importance of investigating non-coding regulatory variants when determining risk factors contributing to neurodevelopmental and neuropsychiatric disorders. In the future, integration of such regulatory variation with protein coding changes will be essential for uncovering the genetic causes of complex neurological disorders and the fundamental mechanisms underlying health and disease.

Related articles
The place and function of non-coding DNA in the evolution of variability.

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Mar 23, 2017   Fetal Timeline   Maternal Timeline   News   News Archive   



Examining a 'non-coding' portion of genes known as 3'UTRome, researchers found
a single letter variant in this portion of a gene causes an increase in how much of a

protein is produced. Examining the DNA of children with severe language problems,
they also identified the same genetic variant on 3'UTRome in their genes.
Image Credit: Public Domain

 


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