Late-breaking mutations may play an important role in autism

July 17, 2017
Lim, Walsh and colleagues overlapped the post-zygotic mutations they identified from blood DNA samples with publicly available gene expression data from brain autopsies (via the BrainSpan Project). This enabled them to roughly map the brain regions in which the mutated genes are expressed. In this image, representing prenatal brain samples, the biggest hit was the amygdala (AMY), in red. There were minor hits in the striatum (STR) and cerebellar cortex (CBC) that did not reach statistical significance. Credit: Mohammed Uddin

A study of nearly 6,000 families, combining three genetic sequencing technologies, finds that mutations that occur after conception play an important role in autism. A team led by investigators at Boston Children's Hospital and the Broad Institute of MIT and Harvard reports the findings today in Nature Neuroscience.

Over the past decade, mutations to more than 60 different have been linked with (ASD), including spontaneous, non-inherited (de novo) mutations. But much of autism still remains unexplained. The study, led by first author Elaine Lim, PhD, of Boston Children's, and senior author Christopher Walsh, MD, PhD, of Boston Children's and the Broad Institute, delved into an emerging category of de novo mutations: those found in only a subset of our cells.

De novo mutations can occur in a parent's sperm or egg, or they can occur after fertilization, arising in an embryonic cell. These are known as post-zygotic mutations or PZMs (also known as ). The later PZMs occur during embryonic development, the fewer cells will carry them, making them harder to detect.

"If the mutation is in a very small fraction of all cells, it will be missed by ," says Lim.

Finding post-zygotic mutations

To find PZMs, Lim, Walsh and colleagues obtained whole-exome sequencing data previously gathered from 5,947 families, courtesy of the Simons Foundation Autism Research Initiative (SFARI) Simplex Collection, the Autism Sequencing Consortium and Autism Speaks. They then resequenced some of the DNA from these children using three independent sequencing technologies in parallel.

Based on their findings, they classified 7.5 percent of ASD subjects' de novo mutations as PZMs. Of these, 83 percent had not been picked up in the original analysis of their genome sequence.

Some PZMs affected genes already known to be linked to autism or other neurodevelopmental disorders (such as SCN2A, HNRNPU and SMARCA4), but sometimes affected these genes in different ways. Many others were in genes known to be active in development (such as KLF16 and MSANTD2) but not previously associated with ASD.

The connection of these genes to autism may have been missed before because the earlier studies focused on mutations that knocked down gene function. "Some of the postzygotic mutations we found represented a gain of function, not a loss of function," says Lim, who is also affiliated with the Wyss Institute for Biologically Inspired Engineering.

The amygdala and autism

To estimate the developmental timing of the mutations and the brain regions affected, Lim, Walsh and colleagues compared their sequencing data, which mostly came from blood DNA samples, with publicly available gene expression data from brain autopsies representing different ages (prenatal through adult) via the BrainSpan Project.

"By overlapping the data, we can start to map where in the brain these genes are expressed and when the mutations occurred during development," says Lim.

These analyses showed that PZMs in the subjects with ASD occur disproportionately in genes expressed in the amygdala. "This was exciting to us, in that the amygdala has been proposed as an important region of the brain in autism," says Lim.

Our dynamically developing brains

Overall, the work adds to evidence that complex brain disorders, such as epilepsy, intellectual disability, schizophrenia and brain malformations, can arise from non-inherited that occur at some point during prenatal development.

"We have known that PZMs are an important cause of epilepsy, but this work provides the best evidence so far that they are relevant to as well," says Walsh, who is also an Investigator of the Howard Hughes Medical Institute. "So it is now exciting to consider what other psychiatric conditions might have a role for PZMs."

Explore further: Genetic analysis finds rare, damaging variants contribute to the risk of schizophrenia

More information: Elaine T Lim et al, Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder, Nature Neuroscience (2017). DOI: 10.1038/nn.4598

Related Stories

Genetic analysis finds rare, damaging variants contribute to the risk of schizophrenia

June 27, 2017
(Medical Xpress)—Via genetic analysis, a large international team of researchers has found rare, damaging gene variants that they believe contribute to the risk of a person developing schizophrenia. In their paper published ...

Mutations in life's 'essential genes' tied to autism

December 12, 2016
Genes known to be essential to life—the ones humans need to survive and thrive in the womb—also play a critical role in the development of autism spectrum disorder (ASD), suggests a new study from Penn Medicine geneticists ...

Mutations in 3 genes linked to autism spectrum disorders

April 4, 2012
Mutations in three new genes have been linked to autism, according to new studies including one with investigators at Mount Sinai School of Medicine. All three studies include lead investigators of the Autism Sequencing Consortium ...

Genetic changes that cause autism are more diverse than previously thought

March 24, 2016
The types of gene mutations that contribute to autism are more diverse than previously thought, report researchers at University of California, San Diego School of Medicine in the March 24 online issue of The American Journal ...

Family genetics study reveals new clues to autism risk

May 12, 2015
A study of 2,377 children with autism, their parents and siblings has revealed novel insights into the genetics of the condition.

Genetic analysis supports prediction that spontaneous rare mutations cause half of autism

September 22, 2015
A team led by researchers at Cold Spring Harbor Laboratory (CSHL) this week publishes in PNAS a new analysis of data on the genetics of autism spectrum disorder (ASD). One commonly held theory is that autism results from ...

Recommended for you

Video game improves balance in youth with autism

November 21, 2017
Playing a video game that rewards participants for holding various "ninja" poses could help children and youth with autism spectrum disorder (ASD) improve their balance, according to a recent study in the Journal of Autism ...

New approach to studying chromosomes' centers may reveal link to Down syndrome and more

November 20, 2017
Some scientists call it the "final frontier" of our DNA—even though it lies at the center of every X-shaped chromosome in nearly every one of our cells.

Genome editing enhances T-cells for cancer immunotherapy

November 20, 2017
Researchers at Cardiff University have found a way to boost the cancer-destroying ability of the immune system's T-cells, offering new hope in the fight against a wide range of cancers.

A math concept from the engineering world points to a way of making massive transcriptome studies more efficient

November 17, 2017
To most people, data compression refers to shrinking existing data—say from a song or picture's raw digital recording—by removing some data, but not so much as to render it unrecognizable (think MP3 or JPEG files). Now, ...

Genetic mutation in extended Amish family in Indiana protects against aging and increases longevity (Update)

November 15, 2017
The first genetic mutation that appears to protect against multiple aspects of biological aging in humans has been discovered in an extended family of Old Order Amish living in the vicinity of Berne, Indiana, report Northwestern ...

US scientists try first gene editing in the body

November 15, 2017
Scientists for the first time have tried editing a gene inside the body in a bold attempt to permanently change a person's DNA to try to cure a disease.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.