Complex role of genes in autism revealed
At the University of Washington in Seattle, Dr. Brian O'Roak studies genetic origins of intellectual, social and psychiatry disabilities in children. Credit: Clare McLean
University of Washington researchers announced their findings from a major study looking into the genetic basis of autism spectrum disorders (ASD) with an approach piloted at the UW. Their results are reported in the April 4 advanced online edition of the journal Nature.
The researchers have been studying ASD in children who have no family history of this or related impairments so called "sporadic autism" and also why autism varies in its symptoms and severity. By focusing on "sporadic autism," the researchers sought to evaluate a specific genetic model for ASD risk, namely the appearance of new mutations (termed de novo) in children with ASD that were not found in either parent.
By uncovering new gene mutations that disrupt the function of proteins, the researchers have discovered a pathway related to modifying chromatin the tightly coiled spools of DNA in the cell and to regulating genes in the brain and nervous system. Various changes in this pathway contribute to children developing autism in different ways. Mutations in this pathway also may contribute to a variety of childhood intellectual, social, and psychiatric disabilities, with implications beyond autism.
To identify these new mutations, the researchers used the latest sequencing technologies and analytical methods to determine the sequence of the protein-coding portion of the human genome, called the "exome," in family trios (father, mother, and child). This approach was piloted this past year at the University of Washington with an initial set of 20 autism families. The pilot demonstrated the technical feasibility and potential impact of this approach.
For the current study, the researchers expanded the project to include 677 individuals from 209 families with a single child with autism. They also sequenced the exomes of 50 unaffected brothers and sisters. In the newly reported results, 248 de novo mutations were validated, and 120 of these were classified as severe. These were predicted to produce, for example, proteins that were truncated or malfunctioning. The researchers then narrowed in on 60 top candidates most likely to contribute to autism risk, based on the nature of the mutation, functional evidence, or previous studies.
"It is important to point out that in each generation there is on average one new coding mutation per child and not all of these will cause developmental problems. However, in the case of children with autism, what we are finding are disruptions in many genes that are known to directly interact and also look similar to genes previous associated with autism," said Dr. Brian J. O'Roak, a senior fellow in the Department of Genome Sciences working with senior authors Drs. Jay Shendure and Evan Eichler. In fact, researchers found that 49 of the genes mutated had products known to directly interact by forming a highly interconnected network.
Interestingly, many of the proteins in this pathway are important in terms of remodeling chromatin changing the way DNA is packaged in the cell and controlling the expression and function of other genes and proteins. These protein pathways are thought to be critical in brain cell formation, brain cell connections, and nerve-cell signaling.
Having this large data set also allowed the researchers to evaluate the parental source of these new mutations, that is, whether they came from the sperm of the father or egg of the mother. Their analysis revealed that the new mutations were overwhelming paternal in origin (in a ratio of 4:1). Their results confirmed a prediction population geneticist J.B.S. Haldane made in in 1935. Moreover, the new mutations occurred at a rate that correlated with the age of the father. These findings, they said, support other studies that show older fathers have a slightly increased risk of having a child with an autism spectrum disorder.
What is also very clear from this study and two additional studies appearing concurrently in the same issue of Nature is that autism risk mutations are scattered across many genes. One of the other studies was led by Mount Sinai Medical Center in New York, the second by Yale University in New Haven.
In the UW study, recurrent protein-altering mutations were discovered in only two genes, NTNG1, and CHD8. The data suggest that, at the molecular level, there are many different forms of autism and that the term "autism spectrum disorder" is better thought of as an umbrella disorder with many root causes. The authors predict that although no single gene will account for more than 1 percent of autism, collectively all of these rare mutations will account for much of the genetic basis of the disease.
While this level of complexity is a major challenge for the field, the authors are already working on a solution using next-generation sequencing approaches. To tackle this challenge, the researchers implemented a new cost-effective screening technology that allowed them to screen more than 2,500 inviduals for mutations in six genes in only a month. In so doing they found strong evidence for the involvement of a glutamate receptor gene GRIN2B for a subset of cases with autism. This same approach will allow the authors to screen all of the newly discovered genes to rapidly test which ones are truly disease-causing.
Among the other genes they discovered with de novo mutations in children with autism, several have been previously implicated in intellectual disability and developmental delay. This indicates, the authors said, that the divisions clinicians made between these various types of diseases in children may not readily translate into differences at the molecular level. The researchers added that it is still uncertain whether there are subsets of people with autism who share a common or strongly related causative mechanism in their underlying molecular biology, or how large those groups might be.
More information: Neale et al. Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature DOI: 10.1038/nature11011
Journal reference: Nature
Provided by University of Washington
- Further support for a role of synaptic proteins in autism spectrum disorders Feb 09, 2012 | not rated yet | 0
- Hopkins researchers release genome data on autism Oct 23, 2007 | not rated yet | 0
- Autism Speaks and BGI to complete whole genome sequencing on 10,000 with autism Oct 13, 2011 | not rated yet | 0
- X marks the spot -- TBL1X gene involved in autism spectrum disorder Nov 04, 2011 | not rated yet | 0
- Toward a long-sought saliva test for autism Jan 12, 2009 | not rated yet | 0
- Motion perception revisited: High Phi effect challenges established motion perception assumptions Apr 23, 2013 | 3 / 5 (2) | 2
- Anything you can do I can do better: Neuromolecular foundations of the superiority illusion (Update) Apr 02, 2013 | 4.5 / 5 (11) | 5
- The visual system as economist: Neural resource allocation in visual adaptation Mar 30, 2013 | 5 / 5 (2) | 9
- Separate lives: Neuronal and organismal lifespans decoupled Mar 27, 2013 | 4.9 / 5 (8) | 0
- Sizing things up: The evolutionary neurobiology of scale invariance Feb 28, 2013 | 4.8 / 5 (10) | 14
Does a charged particle rotate when traveling through a static Bf?
1 hour ago I have been looking at mass spectrometers, in particular the interactions between the Bf ind of a charged particle in motion in a static Bf of the...
Find a link between physics and assignment problems
3 hours ago Hi ! I've been working about assignments problems and how to solve them. I will have to do a presentation about it in few weeks. However, I'll...
Light as a source of electricity
3 hours ago Hello Dear Fellows! We all know that light is an electromagnetic wave and also we know that an antenna receives EM waves and...
A question about the energy stored in a capacitor.
3 hours ago If we imagine a simple circuit with a battery and a capacitor with negligible internal resistance, the capacitor is charged up to a point where the...
Electric field-Charge inside a metallic shell
5 hours ago I am having few doubts while studying electric field which i am putting here Suppose there is a spherical metallic shell with point charge q1 at...
Change in momentum when a body is thrown up and falls back down.
12 hours ago Say, a body of mass 'm' is thrown at a certain angle with the vertical with certain initial velocity 'u'. The initial momentum of this object is mu....
- More from Physics Forums - Classical Physics
More news stories
Research by Victoria University PhD education graduand Larah van der Meer highlights the importance of understanding the communication preferences of children with developmental disabilities such as autism.
Autism spectrum disorders May 14, 2013 | 3.3 / 5 (3) | 1
At times, Andy Shih still finds himself overwhelmed by the groundswell of interest in autism applications he's seen in the three years since Apple Inc. released the first iPad.
Autism spectrum disorders May 09, 2013 | 2 / 5 (1) | 0
Children with autism see simple movement twice as quickly as other children their age, and this hypersensitivity to motion may provide clues to a fundamental cause of the developmental disorder, according ...
Autism spectrum disorders May 08, 2013 | not rated yet | 0 |
(AP)—Autism scientists are seeking more brain samples for research.
Autism spectrum disorders May 02, 2013 | 5 / 5 (1) | 0
Researchers at the University of Wisconsin have identified a potential new risk factor for obstructive sleep apnea: asthma. Using data from the National Institutes of Health (Heart, Lung, and Blood Institute)-funded Wisconsin ...
2 hours ago | not rated yet | 0 |
A new study looking at sleep-disordered breathing (SDB) and markers for Alzheimer's disease (AD) risk in cerebrospinal fluid (CSF) and neuroimaging adds to the growing body of research linking the two.
2 hours ago | not rated yet | 0 |
The hunt for an HIV vaccine has gobbled up $8 billion in the past decade, and the failure of the most recent efficacy trial has delivered yet another setback to 26 years of efforts.
7 hours ago | not rated yet | 0
In their quest to learn more about the variability of cells between and within tissues, biomedical scientists have devised tools capable of simultaneously measuring dozens of characteristics of individual ...
3 hours ago | 5 / 5 (1) | 0 |
Scientists at Johns Hopkins have turned their view of osteoarthritis (OA) inside out. Literally. Instead of seeing the painful degenerative disease as a problem primarily of the cartilage that cushions joints, ...
3 hours ago | 5 / 5 (1) | 0 |
Gourmands and foodies everywhere have long recognized ginger as a great way to add a little peppery zing to both sweet and savory dishes; now, a study from researchers at Columbia University shows purified components of the ...
2 hours ago | not rated yet | 0