Late-breaking mutations may play an important role in autism

July 17, 2017, Children's Hospital Boston
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

15 new genes identified that shape human faces

February 20, 2018
Researchers from KU Leuven (Belgium) and the universities of Pittsburgh, Stanford, and Penn State have identified 15 genes that determine facial features. The findings were published in Nature Genetics.

New algorithm can pinpoint mutations favored by natural selection in large sections of the human genome

February 20, 2018
A team of scientists has developed an algorithm that can accurately pinpoint, in large regions of the human genome, mutations favored by natural selection. The finding provides deeper insight into how evolution works, and ...

New software helps detect adaptive genetic mutations

February 20, 2018
Researchers from Brown University have developed a new method for sifting through genomic data in search of genetic variants that have helped populations adapt to their environments. The technique, dubbed SWIF(r), could be ...

Highly mutated protein in skin cancer plays central role in skin cell renewal

February 20, 2018
Approximately once a month, our skin completely renews itself. If this highly coordinated process goes awry, it can lead to a variety of skin diseases, ranging from skin cancer to psoriasis. Cells lining such organs as skin ...

Study of smoking and genetics illuminates complexities of blood pressure

February 15, 2018
Analyzing the genetics and smoking habits of more than half a million people has shed new light on the complexities of controlling blood pressure, according to a study led by researchers at Washington University School of ...

New mutation linked to ovarian cancer can be passed down through dad

February 15, 2018
A newly identified mutation, passed down through the X-chromosome, is linked to earlier onset of ovarian cancer in women and prostate cancer in father and sons. Kunle Odunsi, Kevin H. Eng and colleagues at Roswell Park Comprehensive ...

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.