Corporate Banner
Satellite Banner
Genomics
Scientific Community
 
Become a Member | Sign in
Home>News>This Article
  News
Return

Scientists Pinpoint Cell Type and Brain Region Affected by Gene Mutations in Autism

Published: Tuesday, November 26, 2013
Last Updated: Tuesday, November 26, 2013
Bookmark and Share
UCSF-led study zeroes in on when and where disrupted genes exert effects.

A team led by UC San Francisco (UCSF) scientists has identified the disruption of a single type of cell – in a particular brain region and at a particular time in brain development – as a significant factor in the emergence of autism.

The finding, reported in the Nov. 21 issue of Cell, was made with techniques developed only within the last few years and marks a turning point in autism spectrum disorders (ASDs) research.

Large-scale gene-sequencing projects are revealing hundreds of autism-associated genes. Scientists have begun to leverage new methods to decipher how mutations in these disparate genes might converge to exert their effects in the developing brain.

The new research focused on just nine genes, those most strongly associated with autism in recent sequencing studies, and investigated their effects using precise maps of gene expression during human brain development.

Led by Jeremy Willsey, a graduate student in the laboratory of senior author Matthew W. State, MD, PhD, of UCSF, the group showed that this set of genes contributes to abnormalities in brain cells known as cortical projection neurons in the deepest layers of the developing prefrontal cortex, during the middle period of fetal development.

Though a range of developmental scenarios in multiple brain regions is surely at work in ASDs, the researchers said the ability to place these specific genetic mutations in one specific set of cells – among hundreds of cell types in the brain, and at a specific point in human development – is a critical step in beginning to understand how autism comes about.

“Given the small subset of autism genes we studied, I had no expectation that we would see the degree of spatiotemporal convergence that we saw,” said State, an international authority on the genetics of neurodevelopmental disorders.

“This strongly suggests that, though there are hundreds of autism risk genes, the number of underlying biological mechanisms will be far fewer," he said. "This is a very important clue to advance precision medicine for autism toward the development of personalized and targeted therapies.”

Complex Genetic Architecture of ASDs

ASDs, which are marked by deficits in social interaction and language development, as well as by repetitive behaviors and/or restricted interests, are known to have a strong genetic component.

But these disorders are exceedingly complex, with considerable variation in symptoms and severity, and little consistency in the mutations among affected individuals.

Instead, with the rise of new sequencing methods over the past several years, researchers have identified many rare, non-inherited, spontaneous mutations that appear to act in combination with other genetic and non-genetic factors to cause ASDs. According to some estimates, mutations in as many as 1,000 genes could play a role in the development of these disorders.

While researchers have been heartened that specific genes are now rapidly being tied to ASDs, State said the complex genetic architecture of ASDs is also proving to be challenging.

“If there are 1,000 genes in the population that can contribute to risk in varying degrees and each has multiple developmental functions, it is not immediately obvious how to move forward to determine what is specifically related to autism," State said. "Without this, it is very difficult to think about how to develop new and better medications,” he said.

Focusing on Nine Genes

To begin to grapple with those questions, the researchers involved in the new study first selected as “seeds” the nine genes that have been most strongly tied to ASDs in recent sequencing research from their labs and others.

Importantly, these nine genes were chosen solely because of the statistical evidence for a relationship to ASDs, not because their function was known to fit a theory of the cause of ASDs. “We asked where the leads take us, without any preconceived idea about where they should take us,” said State.

The team then took advantage of BrainSpan, a digital atlas assembled by a large research consortium, including co-author Nenad Šestan, MD, PhD, and colleagues at Yale School of Medicine. Based on donated brain specimens, BrainSpan documents how and where genes are expressed in the human brain over the lifespan.

The scientists, who also included Bernie Devlin, PhD, of The University of Pittsburgh School of Medicine; Kathryn Roeder, PhD, of Carnegie-Mellon University; and James Noonan, PhD, of Yale School of Medicine, used this tool to investigate when and where the nine seed genes join up with other genes in “co-expression networks” to wire up the brain or maintain its function.

The resulting co-expression networks were then tested using a variety of pre-determined criteria to see whether they showed additional evidence of being related to ASDs. Once this link was established, the authors were then able to home in on where in the brain and when in development these networks were localizing. This proved to be in cortical projection neurons found in layers 5 and 6 of the prefrontal cortex, and during a time period spanning 10 to 24 weeks after conception. Notably, a study using different methods and published in the same issue of Cell also implicates cortical projection neurons in ASDs.

“To see these gene networks as highly connected as they are, as convergent as they are, is quite amazing,” said Willsey “An important outcome of this study is that, for the first time, it gives us the ability to design targeted experiments based on a strong idea about when and where in the brain we should be looking at specific genes with specific mutations.”

In addition to its importance in ASD research, State sees the new work as a reflection of the tremendous value of “big science” efforts, such as large-scale collaborative genomic studies and the creation of foundational resources such as the BrainSpan atlas.

“We couldn’t have done this even two years ago,” State said, “because we didn’t have the key ingredients: a set of unbiased autism genes that we have confidence in, and a map of the landscape of the developing human brain. This work combines large-scale ‘-omics’ data sets to pivot into a deeper understanding of the relationship between complex genetics and biology.”

UCSF is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. It includes top-ranked graduate schools of dentistry, medicine, nursing and pharmacy, a graduate division with nationally renowned programs in basic biomedical, translational and population sciences, as well as a preeminent biomedical research enterprise and two top-ranked hospitals, UCSF Medical Center and UCSF Benioff Children’s Hospital.


Further Information

Join For Free

Access to this exclusive content is for Technology Networks Premium members only.

Join Technology Networks Premium for free access to:

  • Exclusive articles
  • Presentations from international conferences
  • Over 3,200+ scientific posters on ePosters
  • More than 4,700+ scientific videos on LabTube
  • 35 community eNewsletters


Sign In



Forgotten your details? Click Here
If you are not a member you can join here

*Please note: By logging into TechnologyNetworks.com you agree to accept the use of cookies. To find out more about the cookies we use and how to delete them, see our privacy policy.

Related Content

Transcription Factor Isoforms Implicated in Colon Diseases
UC Riverside study explains how distribution of two forms of a transcription factor in the colon influence risk of disease.
Thursday, May 19, 2016
Fructose Alters Hundreds of Brain Genes
UCLA scientists report that diet rich in omega-3 fatty acids can reverse the damage.
Tuesday, April 26, 2016
Study Yields the Key to Effective Personalized Medicine
A team of UCLA bioengineers and surgeons has taken a major step toward making personalized medicine a reality.
Monday, April 11, 2016
Crowdfunding the Fight Against Cancer
From budding social causes to groundbreaking businesses to the next big band, crowdfunding has helped connect countless worthy projects with like-minded people willing to support their efforts, even in small ways. But could crowdfunding help fight cancer?
Monday, February 08, 2016
Science Magazine Names CRISPR ‘Breakthrough of the Year’
In its year-end issue, the journal Science chose the CRISPR genome-editing technology invented at UC Berkeley 2015’s Breakthrough of the Year.
Monday, December 21, 2015
CRISPR-Cas9 Helps Uncover Genetics of Exotic Organisms
A new study illustrates the ease with which CRISPR-Cas9 can knock out genes in exotic animals to learn how those genes control growth and development.
Friday, December 11, 2015
New Method for Screening Cancer Cells
Parallel microfiltration could lead to better treatments for a number of diseases, UCLA-led study says.
Thursday, December 03, 2015
RNA-Based Drugs Give More Control Over Gene Editing
CRISPR/Cas9 gene editing technique can be transiently activated and inactivated using RNA-based drugs, giving researchers more precise control in correcting and inactivating genes.
Monday, November 23, 2015
Clearest Ever Images of Enzyme that Plays Key Roles in Aging, Cancer
UCLA-led research on telomerase could lead to new strategies for treating disease
Monday, October 19, 2015
Crop Cure
Scientists in new center to use medical research techniques to help food crops withstand drought and climate change.
Friday, October 16, 2015
Rare Childhood Leukemia Reveals Surprising Genetic Secrets
A coalition of leukemia researchers led by scientists from UC San Francisco has discovered surprising genetic diversity in juvenile myelomonocytic leukemia (JMML), a rare but aggressive childhood blood cancer.
Thursday, October 15, 2015
Double Enzyme Hit May Explain Common Cancer Drug Side Effect
Mouse study suggests genomic screening before treatment may help prevent anemia.
Wednesday, October 14, 2015
New Autism Genes Are Revealed in Largest-Ever Study
Work draws more detailed picture of genetic risk, sheds light on sex differences in diagnosis.
Wednesday, September 30, 2015
Scientists Create CRISPR/Cas9 Knock-In Mutations in Human T Cells
In a project spearheaded by investigators at UC San Francisco, scientists have devised a new strategy to precisely modify human T cells using the genome-editing system known as CRISPR/Cas9.
Tuesday, July 28, 2015
Simple Technology Makes CRISPR Gene Editing Cheaper
University of California, Berkeley, researchers have discovered a much cheaper and easier way to target a hot new gene editing tool, CRISPR-Cas9, to cut or label DNA.
Friday, July 24, 2015
Scientific News
Benchtop Automation Trends
Gain a better understanding of current interest in and future deployment of benchtop automated systems.
New Cancer Drug Target Found in Dual-Function Protein
Findings from a study from TSRI have shown that targeting a protein called GlyRS might help to halt cancer growth.
Alzheimer's Genetics Point To New Research Direction
A University of Adelaide analysis of genetic mutations which cause early-onset Alzheimer’s disease suggests a new focus for research into the causes of the disease.
Contagious Cancers Are Spreading in Shellfish
Direct transmission of cancer among some marine animals may be more common than once thought, suggests a new study published in Nature by researchers at Columbia University Medical Center (CUMC).
Contagious Cancers Are Spreading in Shellfish
Direct transmission of cancer among some marine animals may be more common than once thought, suggests a new study published in Nature by researchers at Columbia University Medical Center (CUMC).
Fix for 3-Billion-Year-Old Genetic Error
Researchers at The University of Texas at Austin have developed a fix that allows RNA to accurately proofread for the first time.
Higher Frequency of Huntington's Disease Mutations Discovered
University of Aberdeen study shows that the gene change that causes Huntington's disease is much more common than previously thought.
Revealing the Genetic Causes of Bowel Cancer
A landmark study has given the most detailed picture yet of the genetics of bowel cancer — the UK's fourth most common cancer.
The Epigenetic Influences of Chronic Pain
Researchers at Drexel University College of Medicine are aiming to identify new molecular mechanisms involved in pain.
Fighting Resistant Blood Cancer Cells
Biologists present new findings on chronic myeloid leukemia and possible therapeutic approaches.
Skyscraper Banner

SELECTBIO Market Reports
Go to LabTube
Go to eposters
 
Access to the latest scientific news
Exclusive articles
Upload and share your posters on ePosters
Latest presentations and webinars
View a library of 1,800+ scientific and medical posters
3,200+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
4,700+ scientific videos
Close
Premium CrownJOIN TECHNOLOGY NETWORKS PREMIUM FOR FREE!