Autism: Link to increased genetic change in regions of genome instability

These microscopic images were taken as part of research to explore rearrangements of DNA in one of the "hotspots" of the human genome, where deletions and duplications occur at higher rates. 

Credit: Betsy Hirsch/University of Minnesota and Scott Selleck /Penn State University

Children with autism have increased levels of genetic change in regions of the genome prone to DNA rearrangements, so called "hotspots," according to a research discovery to be published in the print edition of the journal Human Molecular Genetics.

The research indicates that these genetic changes come in the form of an excess of duplicated DNA segments in hotspot regions and may affect the chances that a child will develop Autism—a behavioural disorder that affects about 1 of every 88 children in the US, according to the Centers for Disease Control (CDC).

Earlier work had identified, in children with Autism, a greater frequency of rare DNA deletions or duplications, known as DNA copy number changes.

These rare and harmful events are found in approximately 5 to 10 percent of cases, raising the question as to what other genetic changes might contribute to the disorders known as autism spectrum disorders.

The new research shows that children with autism have—in addition to these rare events—an excess of duplicated DNA including more common variants not exclusively found in children with autism, but are found at elevated levels compared to typically developing children.

The investigators also found that the balance of DNA duplications and deletions in children with autism was different from that found in more severe developmental disorders, such as intellectual disability or multiple congenital anomalies, where the levels of both deletions and duplications are increased compared to controls, and are even higher than in children with autism.

They also found that children who had more difficulty with daily living skills also had the greatest level of copy number change throughout their genome.

Scott Selleck

"These measures of adaptive behaviour provide an indication of the severity of the impairment in the children with autism. These behaviours were significantly correlated with the amount of DNA copy number change," Selleck said, emphasizing that the research revealed "clear and graded effects of the genetic change."

"These results beg the question as to the origin of this genetic change," Selleck said. "The increased levels of both rare and common variants suggests the possibility that these individuals are predisposed to genetic alteration."

The research collaboration includes groups led at Penn State by Scott Selleck; at the University of California Davis /MIND Institute by Isaac Pessah, Irva Hertz-Picciotto, Flora Tassone, and Robin Hansen; and at the University of Washington by Evan Eichler.

CHARGE
The University of California Davis /MIND Institute group directs a large population-based case-control study of autism called CHARGE (Childhood Autism Risks from Genetics and Environment).

In this multiyear study, clinical history, environmental, nutritional, family, and medical data are collected from the families of children with autism and other developmental disorders, as well as from randomly selected control children from the general population.

The research took advantage of the CHARGE study, supported by the National Institute of Environmental Health Sciences and the Environmental Protection Agency.

"The CHARGE study is a true population-based case-control cohort for the study of autism, the only one of its kind that I am aware of " says Selleck, and allows for comparisons between the children with autism and controls matched for geographical location and time of birth.

The research team plans to continue its collaboration to further characterize the more common genetic variants found to be associated with autism and to explore the relationship between genome variation and environmental exposures.

Reference
Global increases in both common and rare copy number load associated with autism;  hmg.ddt136.abstract

Development of new diagnostic tools and treatments for people with rare diseases

Prof Hanns Lochmuller

A multi-million Euro initiative is bringing together researchers from across the world to develop new diagnostic tools and new treatments for people with rare diseases and to connect research data in this area on a global scale.

Rare diseases - while individually uncommon - affect one person in every 17. 80% of rare diseases have a genetic component, and they include genetic kidney diseases like nephrotic syndrome and conditions like Huntington's disease, ataxia and muscular dystrophy.

Today, the EU has announced 38 million Euro funding for research towards new treatments and for the development of a central global rare disease hub involving 70 institutions that will allow scientists to share data from their genomics research projects.

This will lead to faster diagnosis and better treatments and improve the quality of life for patients with rare diseases.

The revolution in DNA sequencing, which means an entire human genome can now be sequenced within days and for less than 10,000 Euro, has brought the hope of personalized treatments for many of these diseases a step closer.

Professor Hanns Lochmuller of Newcastle University, UK, who is leading the new rare disease hub, said: "Being able to sequence a person's entire genetic code is an important advance, particularly for people living with the many rare genetic disorders, but it has also shown us that sequencing is only the first part of the story. It doesn't replace clinical expertise - in fact, being able to combine genetic data with clinical data is more important than ever."

Read the full article here

Autism: Many DNA genetic keys needed to unlock it

Hundreds of small genetic variations are associated with autism spectrum disorders, including an area of DNA that may be a key to understanding why humans are social animals, according to a multi-site collaborative study led by researchers at Yale University.

Published in the June 9 issue of the journal Neuron, the study reinforces the theory that autism, a disorder that develops in early childhood involving impairments in social interaction, language deficits and distinctive behaviours, is not caused by one or two major genetic defects, but by many small variations, each associated with a small percentage of cases.

The study -- led by Matthew State, M.D., Ph.D., the Donald J. Cohen Associate Professor of Child Psychiatry, Psychiatry and Genetics -- looked at more than 1,000 families in which there was a single child with an autism spectrum disorder, an unaffected sibling and unaffected parents.

The team, including postdoctoral fellow and first author Stephan Sanders from Yale, compared individuals with autism to their siblings to determine what types of genetic changes distinguished the affected child from the unaffected child.

"Thanks to an ambitious collaboration among a large group of autism researchers from around the country, supported by the Simons Foundation, we were able to focus on an ideal study population," said State, who is co-director of the Yale Program on Neurogenetics. "It made all the difference in our ability to identify several regions of the genome clearly contributing to autism."

One of the most intriguing of these findings points to the same small section of the genome that causes Williams syndrome -- a developmental disorder marked by high sociability and an unusual aptitude for music.

In autism, there is an increase in the chromosomal material, an extra copy of this region, and in Williams syndrome, there's a loss of that same material," said State. "What makes this observation particularly interesting is that Williams syndrome is known for a personality type that is highly empathetic, social, and sensitive to the emotional state of others.

Individuals with autism often have difficulties in the opposite direction. This suggests that there is an important key in that region to understanding the nature of the social brain."

State and his team also found about 30 other regions in the genome that are very likely contributing to autism and are focused on about six of those regions that showed the strongest evidence.

"We're now moving on to a second phase of the study looking at an additional 1,600 families and should be able to identify multiple new regions that are strongly implicated in autism," he said.

Read More: Many genetic keys needed to unlock autism, researchers discover

Download the full article text, in PDF, from Neuron's 9th June issue

Could Autism and Schizophrenia be Genetic?

Autism and schizophrenia may be two sides of the same coin, suggests a review of genetic data associated with the conditions. The finding could help design complementary treatments for the two disorders.

Though autism was originally described as a form of schizophrenia a century ago, evidence for a link has remained equivocal. One theory puts the conditions at opposite ends of a developmental spectrum.

To investigate, Bernard Crespi, an evolutionary biologist at Simon Fraser University in Vancouver, Canada, and colleagues gathered data on all known genetic variants associated with each condition, then looked for patterns of co-occurrence.

The researchers found four regions in the genome which dramatically affect the risk of autism or schizophrenia. Called "copy-number variants", these are stretches of DNA with seemingly accidental duplications or deletions. Crespi's team found that the presence of a particular variant – a duplication, say – was often associated with autism while the opposite variation – a deletion of the genetic material – was linked to schizophrenia.

The results fit with other evidence that autism may be caused by overdevelopment of specific brain regions and schizophrenia by underdevelopment, says Crespi.

If they are indeed opposites, work on one disorder may inform work on its counterpart, he says.

Journal reference: Proceedings of the National Academy of Sciences, DOI: 10.1073/pnas.0906080106