Variants in non-coding DNA contribute to inherited autism risk

April 19, 2018, University of California - San Diego
Credit: CC0 Public Domain

In recent years, researchers have firmly established that gene mutations appearing for the first time, called de novo mutations, contribute to approximately one-third of cases of autism spectrum disorder (ASD). In a new study, an international team led by scientists at University of California San Diego School of Medicine have identified a culprit that may explain some of the remaining risk: rare inherited variants in regions of non-coding DNA.

The findings are published online in the April 20, 2018 issue of Science.

The newly discovered risk factors differ from known of autism in two important ways. First, these variants do not alter the genes directly but instead disrupt the neighboring DNA control elements that turn genes on and off, called cis-regulatory elements or CREs. Second, these variants do not occur as new mutations in children with autism, but instead are inherited from their parents.

"For ten years we've known that the genetic causes of autism consist partly of de novo mutations in the protein sequences of genes" said Jonathan Sebat, a professor of psychiatry, cellular and molecular medicine and pediatrics at UC San Diego School of Medicine and chief of the Beyster Center for Genomics of Psychiatric Genomics. "However, gene sequences represent only 2 percent of the genome."

To investigate the other 98 percent of the genome in ASD, Sebat and his colleagues analyzed the complete genomes of 9,274 subjects from 2,600 families. One thousand were sequenced in San Diego at Human Longevity Inc. (HLI) and at Illumina Inc., and DNA sequences were analyzed at the San Diego Supercomputer Center at UC San Diego. These data were then combined with other large studies from the Simons Simplex Collection and the Autism Speaks MSSNG Whole Genome Sequencing Project.

The researchers then analyzed structural variants, deleted or duplicated segments of DNA that disrupt regulatory elements of , dubbed CRE-SVs. From the complete genomes of families, the researchers found that CRE-SVs that are inherited from parents also contributed to ASD.

"We also found that CRE-SVs were inherited predominantly from fathers, which was a surprise," said co-first author William M. Brandler, PhD, a postdoctoral scholar in Sebat's lab at UC San Diego and bioinformatics scientist at HLI.

"Previous studies have found evidence that some protein-coding variants are inherited predominantly from mothers, a phenomenon known as a maternal origin effect. The paternal origin effect we see for non-coding variants suggests that the inherited genetic contribution from mothers and fathers may be qualitatively different."

Sebat said current research does not explain with certainty what mechanism determines these parent-of-origin effects, but he has proposed a plausible model.

"There is a wide spectrum of genetic variation in the human population, with coding variants having strong effects and noncoding variants having weaker effects", he said. "If men and women differ in their capacity to tolerate such variants, this could give rise to the parent-of-origin effects that we see."

Explore further: Genetic changes that cause autism are more diverse than previously thought

More information: Paternally inherited cis-regulatory structural variants are associated with autism, Science (2018). DOI: 10.1126/science.aan2261

Related Stories

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 ...

Largest study of its kind finds rare genetic variations linked to schizophrenia

November 22, 2016
Many of the genetic variations that increase risk for schizophrenia are rare, making it difficult to study their role in the disease. To overcome this, the Psychiatric Genomics Consortium, an international team led by Jonathan ...

Rare genetic mutations linked to bipolar disorder

December 21, 2011
An international team of scientists, led by researchers at the University of California, San Diego School of Medicine, reports that abnormal sequences of DNA known as rare copy number variants, or CNVs, appear to play a significant ...

Genomic 'hotspots' offer clues to causes of autism, other disorders

December 20, 2012
An international team, led by researchers from the University of California, San Diego School of Medicine, has discovered that "random" mutations in the genome are not quite so random after all. Their study, to be published ...

Autism risk genes linked to evolving brain

February 27, 2017
Genetic variants linked to autism spectrum disorders (ASD) may have been positively selected during human evolution because they also contribute to enhanced cognition, a new Yale study suggests.

The genetic architecture of risk for autism spectrum disorder

May 16, 2017
A new study of inherited genetic risk indicates that common genetic variations throughout the genome act in addition to rare, deleterious mutations in autism-associated genes to create risk for autism.

Recommended for you

Researchers identify new genetic disorder

September 21, 2018
Researchers from Michigan State University College of Human Medicine and physicians from Spectrum Health have identified for the first time in a human patient a genetic disorder only previously described in animal models.

Test could detect patients at risk from lethal fungal spores

September 20, 2018
Scientists at The University of Manchester have discovered a genetic mutation in humans linked to a 17-fold increase in the amount of dangerous fungal spores in the lungs.

Researchers identify a new cause of childhood mitochondrial disease

September 20, 2018
A rapid genetic test developed by Newcastle researchers has identified the first patients with inherited mutations in a new disease gene.

Why some human genes are more popular with researchers than others

September 18, 2018
Historical bias is a key reason why biomedical researchers continue to study the same 10 percent of all human genes while ignoring many genes known to play roles in disease, according to a study publishing September 18 in ...

Class of neurological disorders share 3-D genome folding pattern, study finds

September 18, 2018
In a class of roughly 30 neurological disorders that includes ALS, Huntington's Disease and Fragile X Syndrome, the relevant mutant gene features sections of repeating base pair sequences known as short tandem repeats, or ...

Researchers resolve decades-old mystery about the most commonly mutated gene in cancer

September 18, 2018
The most commonly mutated gene in cancer has tantalized scientists for decades about the message of its mutations. Although mutations can occur at more than 1,100 sites within the TP53 gene, they arise with greatest frequency ...

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.