autism and genetics

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PAC1R mutation may be linked to severity of social deficits in autism

 

This is Joshua G. Corbin, Ph.D., interim director of the Center for Neuroscience Research at Children’s National Health System and the study’s co-senior author. CREDIT Children’s National Health System

A mutation of the gene PAC1R may be linked to the severity of social deficits experienced by kids with autism spectrum disorder (ASD), finds a study from a multi-institutional research team led by Children’s faculty. If the pilot findings are corroborated in larger, multi-center studies, the research published online Dec. 17, 2018, in Autism Research represents the first step toward identifying a potential novel biomarker to guide interventions and better predict outcomes for children with autism.

As many as 1 in 40 children are affected by ASD. Symptoms of the disorder – such as not making eye contact, not responding to one’s name when called, an inability to follow a conversation of more than one speaker or incessantly repeating certain words or phrases – usually crop up by the time a child turns 3.

The developmental disorder is believed to be linked, in part, to disrupted circuitry within the amygdala, a brain structure integral for processing social-emotional information. This study reveals that PAC1R is expressed during key periods of brain development when the amygdala – an almond-shaped cluster of neurons – develops and matures. A properly functioning amygdala, along with brain structures like the prefrontal cortex and cerebellum, are crucial to neurotypical social-emotional processing.

“Our study suggests that an individual with autism who is carrying a mutation in PAC1R may have a greater chance of more severe social problems and disrupted functional brain connectivity with the amygdala,” says Joshua G. Corbin, Ph.D., interim director of the Center for Neuroscience Research at Children’s National Health System and the study’s co-senior author. “Our study is one important step along the pathway to developing new biomarkers for autism spectrum disorder and, hopefully, predicting patients’ outcomes.”

The research team’s insights came through investigating multiple lines of evidence:

They looked at gene expression in the brains of an experimental model at days 13.5 and 18.5 of fetal development and day 7 of life, dates that correspond with early, mid and late amygdala development. They confirmed that Pac1r is expressed in the experimental model at a critical time frame for brain development that coincides with the timing for altered brain trajectories with ASD.

They looked at gene expression in the human brain by mining publicly available genome-wide transcriptome data, plotting median PAC1R expression values for key brain regions. They found high levels of PAC1R expression at multiple ages with higher PAC1R expression in male brains during the fetal period and higher PAC1R expression in female brains during childhood and early adulthood.

One hundred twenty-nine patients with ASD aged 6 to 14 were recruited for behavioral assessment. Of the 48 patients who also participated in neuroimaging, 20 were able to stay awake for five minutes without too much movement as the resting state functional magnetic resonance images were captured. Children who were carriers of the high-risk genotype had higher resting-state connectivity between the amygdala and right posterior temporal gyrus. Connectivity alterations in a region of the brain involved in processing visual motion may influence how kids with ASD perceive socially meaningful information, the authors write.

Each child also submitted a saliva sample for DNA genotyping. Previously published research finds that a G to C single nucleotide polymorphism, a single swap in the nucleotides that make up DNA, in PAC1R is associated with higher risk for post traumatic stress disorder in girls. In this behavioral assessment, the research team found children with autism who carried the homozygous CC genotype had higher scores as measured through a validated tool, meaning they had greater social deficits than kids with the heterozygous genotype.

All told, the project is the fruit of six years of painstaking research and data collection, say the researchers. That includes banking patients’ saliva samples collected during clinical visits for future retrospective analyses to determine which genetic mutations were correlated with behavioral and functional brain deficits, Corbin adds.

“Lauren Kenworthy, who directs our Center for Autism Spectrum Disorders, and I have been talking over the years about how we could bring our programs together. We homed in on this project to look at about a dozen genes to assess correlations and brought in experts from genetics and genomics at Children’s National to sequence genes of interest,” he adds. “Linking the bench to bedside is especially difficult in neuroscience. It takes a huge amount of effort and dozens of discussions, and it’s very rare. It’s an exemplar of what we strive for.”

 

Posted on Autism

Unraveling a genetic network linked to autism

 

A network of more than 200 genes encoding proteins with diverse cellular roles was revealed in a non-biased CRISPR screen for regulators of microexon splicing. Many of the genes have previously been linked to autism from Thomas Gonatopoulos-Pournatzis

Donnelly Centre researchers have uncovered a genetic network linked to autism. The findings, described in the journal Molecular Cell, will facilitate developing new therapies for this common neurological disorder.

As part of a collaborative research program focusing on autism led by Benjamin Blencowe, a professor in the University of Toronto’s Donnelly Centre for Cellular and Biomolecular Research, postdoctoral fellow Thomas Gonatopoulos-Pournatzis, lead author of the study, uncovered a network of more than 200 genes involved in controlling alternative splicing events that are often disrupted in autism spectrum disorder (ASD). Alternative splicing is a process that functionally diversifies protein molecules–cells’ building blocks–in the brain and other parts of the body. Blencowe’s laboratory previously showed that disruption of this process is closely linked to altered brain wiring and behaviour found in autism.

“Our study has revealed a mechanism underlying the splicing of very short coding segments found in genes with genetic links to autism,” says Blencowe, who is also a professor in the Department of Molecular Genetics and holds the Banbury Chair of Medical Research at U of T.

“This new knowledge is providing insight into possible ways of targeting this mechanism for therapeutic applications”.

Best known for its effects on social behaviour, autism is thought to be caused by mishaps in brain wiring laid down during embryo development. Hundreds of genes have been linked to autism, making its genetic basis difficult to untangle. Alternative splicing of small gene fragments, or microexons, has emerged as a rare, unifying concept in the molecular basis of autism after Blencowe’s team previously discovered that microexons are disrupted in a large proportion of autistic patients.

Learn how microexons contribute to autism

As tiny protein-coding gene segments, microexons impact the ability of proteins to interact with each other during the formation of neural circuits. Microexons are especially critical in the brain, where they are included into the RNA template for protein synthesis during the splicing process. Splicing enables the utilization of different combinations of protein-coding segments, or exons, as a way of boosting the functional repertoires of protein variants in cells.

And while scientists have a good grasp of how exons, which are about 150 DNA letters long, are spliced, it remained unclear how the much-smaller microexons– a mere 3-27 DNA letters long–are utilized in nerve cells.

“The small size of microexons’ presents a challenge for the splicing machinery and it has been a puzzle for many years how these tiny exons are recognized and spliced,” says Blencowe.

To answer this question, Gonatopoulos-Pournatzis developed a method for identifying genes that are involved in microexon splicing. Using the powerful gene editing tool CRISPR, and working with Mingkun Wu and Ulrich Braunschweig in the Blencowe lab as well as with Jason Moffat’s lab in the Donnelly Centre, Gonatopoulos-Pournatzis removed from cultured brain cells each of the 20,000 genes in the genome to find out which ones are required for microexon splicing. He identified 233 genes whose diverse roles suggest that microexons are regulated by a wide network of cellular components.

“A really important advantage of this screen is that we’ve been able to capture genes that affect microexon splicing both directly and indirectly and learn how various molecular pathways impinge on this process,” says Blencowe.

Furthermore, Gonatopoulos-Pournatzis was able to find other factors that work closely with a previously identified master regulator of microexon splicing, a protein called nSR100/SRRM4, discovered previously in the Blencowe lab. Working with Anne-Claude Gingras’ team at Sinai Health System’s Lunenfeld-Tanenbaum Research Institute, they identified proteins called Srsf11 and Rnps1 as forming a molecular complex with nSR100.

Knowing the precise molecular mechanisms of microexon splicing will help guide future efforts to develop potential therapeutics for autism and other disorders. For example, because the splicing of microexons is disrupted in autism, researchers could look for drugs capable of restoring their levels to those seen in unaffected individuals.

“We now better understand the mechanism of how the microexons are recognized and spliced specifically in the brain,” says Gonatopoulos-Pournatzis, who recently won the Donnelly Centre’s newly established Research Excellence Award . “When you know the mechanism, you can potentially target it using rational approaches to develop therapies for neurodevelopmental disorders.”

 

Posted on Autism

Whole genome sequencing identifies new genetic signature for autism

 

At a UW Medicine research lab, Tychele Turner studies gene mutations suspected in autism. These mutations appear in affected children, but not in their parents, and are found in both coding and non-coding regions of the genome   Michael McCarthy/UW Medicine

 

Most cases of autism appear to be associated with the appearance of new mutations that are not inherited from the child’s parents, researchers from the University of Washington School of Medicine report.

These new mutations occur in regions of the genome that contain genes, which code for proteins, as well as in “non-coding” regions, which do not contain genes but which regulate gene activity, the researchers found.

“We are excited by these early findings because they suggest that multiple new mutations in a child, both coding and non-coding, are important to understanding the genetics of the disease,” said Evan Eichler, UW professor of genome sciences, who led the team that conducted the study.

 

 

Children with autism (red bars) were significantly more likely to have three or more genetic variations than their unaffected siblings (blue bars). Turner et al./Cell 2017

 

 

The first author of the study, which was published online in the journal Cell, was Tychele Turner, a postdoctoral fellow in the Eichler Lab.

Although some forms of autism appear to run in families, most cases occur in families with no history of the disorder. This form of autism, called simplex autism, is thought to occur from new mutations that first appear when the the parents’ sperm or eggs form.

These newly formed, or de novo, mutations are found in the affected child’s genome, but not in either parent’s genome. They are unlikely to occur in the affected child’s siblings.

In the new study, researchers used a huge genomic database created by the Simons Foundation Autism Research Initiative. The scientists compared the genomes of 516 individuals who had simplex autism with the genomes of their parents and one sibling who was not affected by the disorder.

By comparing these family members, researchers hoped to identify new mutations that were more likely to appear in the affected child and more likely to be associated with an increased risk of developing autism.

Most previous studies had limited such comparisons to the small portion of the genome that includes the instructions for the synthesis of proteins. This coding region contains genes. The new study compared almost the entire genomes of the study participants, including the regions that do not include genes.

Although these “non-coding” regions do not include instructions for making proteins, they play an important role in regulating protein production by turning genes on and off and dialing their activity up or down.

The researchers observed that mutations that tended to appear in non-coding regions of the genomes occurred in areas known to influence gene activity in neurons located deep in the brain in a structure called the striatum.

This part of the brain is thought to play a role in some of autism behaviors. Typically, the striatum coordinates planning, reward perception, motivation and other cognitive functions.

Mutations were also located in areas of the genome that influence genes for embryonic stem cell development and fetal brain development.

The findings suggest that relatively few of the new mutations in genes linked to autism risk were needed to increase the odds of having the disorder. The risk rose with as few as two of these newly appearing mutations.

Eichler said that, to nail down the autism risk role played by mutations in the regulatory, non-coding regions of the genome, it will be necessary to repeat the study with many more sets of parents and their children.

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Scientists identify gene pattern linked to autism

Autism and genetics

Autism and genetics

The Independent reports that “Scientists have identified a genetic pattern common to people with autism that is linked to the way messages are sent in the brain”.

These findings come from a study that looked at genetic variations – alterations in the genetic code that can sometimes have serious effects on the body.

The researchers were looking at the genes affected by one specific group of rare genetic variations that had been found in 181 people with autistic spectrum disorder. Autistic spectrum disorders (ASDs) are a range of disorders that affect behaviour, social interaction and language and communication skills.

The researchers wanted to find out whether there was any relationship between the biological roles of the many different genes affected by these variations. They hoped that this might help to explain why changes to different genes could result in the same types of ASD symptoms.

The researchers found that in around half of the people the variations affected a genes or genes that could be shown to have interrelated biological roles. Many of these roles were linked to how nerve cells pass messages to each other. This suggests that some of the symptoms of ASD could be caused by abnormal signalling inside the brain.

The genetics of autistic spectrum disorders is complex, with many different genes seeming to play a role in different people. This study focused on one type of genetic variation, but other genetic variations as well as environmental factors could also contribute to ASD.

This type of study helps researchers to understand the biology and genetics of these disorders. For now, the findings do not have direct implications for the diagnosis or treatment of these conditions.

 

Copy number variations

This study was looking at what are known as copy number variations. Copy number variations are when a person has more than the usual number of copies of a piece of DNA or, alternatively, they are missing copies of a piece of DNA. These pieces of DNA can be large and can include one or more genes.

Some studies have linked copy number variations to a number of conditions such as schizophrenia, lupus and some types of lung cancer.

Where did the story come from?

The study was carried out by researchers from the University of Oxford, as well as other research centres in France, the US and Canada. It was funded by the Medical Research Council and a European Union grant.

The study was published in the peer-reviewed open-access journal PLoS Genetics.

It was covered in an appropriate way by The Independent, without any overstatement of the implications of these findings. For now, these findings largely help researchers to understand autistic spectrum disorders better. They do not currently have direct implications for the diagnosis or treatment of these conditions.

 

What kind of research was this?

This was a laboratory study looking at the genetics of autistic spectrum disorders (ASDs). ASDs are a group of disorders in which the individual’s social interaction and communication are affected.

Studies have suggested that genes play an important role in causing the conditions, but the researchers say that the genetic cause is only known in about 20% of cases.

The researchers who conducted this study hypothesised that different people with ASDs may have different rare genetic variations that contribute to their condition, but that the genes affected may all be involved in the same biological processes or pathways.

In this study they wanted to look at some of the genes that may be involved in causing ASDs to see if their biological roles are interrelated. They hoped that this would improve their understanding of the genetics and biology of ASDs.

 

What did the research involve?

The researchers were interested in a specific type of genetic variation where people have different numbers of copies of certain pieces of their DNA. These are called copy number variations or CNVs. CNVs are a type of genetic variation where people are either missing a piece or pieces of their DNA or have multiple copies of these pieces.

The researchers had information on CNVs that had been found in 181 people with ASDs in previous studies.

The researchers also used information on CNVs from a group of people without any psychiatric condition (a control group).

They did not look at CNVs that were found both in the control group and in the ASD group, as these would be less likely to be contributing to causing the ASDs.

They identified which genes were affected by these CNVs by locating them using maps of the human genome, which are long lists of the ‘letter’ sequence of the building blocks making up human DNA.

They then used a database that collects information on the effect of different mouse genetic mutations to identify what happens in mice that have disrupted versions of these genes. They did this to help them to identify what roles the genes play in the body.

They also looked at what proteins were encoded by the genes, and what other proteins these proteins interact with in the cells.

Using this information they identified what biological processes and pathways the different genes played a role in and how they were all interrelated.

They used computer programmes to come up with an interlinking map or network showing how these genes were related.

 

What were the basic results?

The researchers found that 187 genes affected by copy number variations (CNVs) could be shown to be connected in a single network of interrelated biological roles. CNVs affecting one or more of these 187 genes were found in 45% of the people with ASDs.

This network also contained 22 other genes that have previously been found to be associated with ASDs.

Many of the proteins being produced by these genes were playing roles in the transmission of electrical messages between nerve cells.

The people with ASDs who had these CNVs had an average of three CNVs within this network.

The people with ASDs who only had one CNV tended to have that CNV in a gene that was very central to the network. This was thought to indicate that the single affected gene in these cases was playing an important role.

 

How did the researchers interpret the results?

The researchers concluded that they had identified an extensive biological network of ASD-related genes. This network can show how different genes may cause ASD by affecting interlinked biological processes and pathways.

 

Conclusion

This study has identified a complex network of interrelated functions for some of the genes potentially associated with autistic spectrum disorders.

The genetics of these disorders is complex, with many different genes seeming to play a role in different people.

This study shows how these different genetic variations may result in the same group of conditions.

This study focused on one particular type of genetic variation, known as copy number variations. Other types of genetic variations may also be involved with ASD. There may also be environmental factors involved.

This type of study helps researchers to understand the biology and genetics of these disorders better.

The findings of this study do not currently have direct implications for the diagnosis or treatment of these conditions. They help to add another ‘piece to the puzzle’ of our understanding of ASDs, but the puzzle is still a long way from being fully solved.

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Advances in Autism Genetics – a talk by Daniel H. Geschwind, MD, PhD

Advances in Autism Genetics

Advances in Autism Genetics

We know that there is a relationship between autism and genetics. Indeed we conducted a very revealing poll in the subject a few years back. You can see the results here.

But for an updated overview of autism and genetics please have a look at this fascinating video of a talk by Daniel H. Geschwind. Daniel H. Geschwind is a professor of human genetics at the David Geffen School of Medicine at the University of California, Los Angeles (UCLA). He also directs the Neurogenetics Program and the Center for Autism Research and Treatment at UCLA.