Summary: For years, a significant portion of the genetic basis of autism has remained a mystery—a gap scientists call “missing heritability.” Now, researchers have utilized a “game-changing” technology called Long-Read Whole Genome Sequencing (LR-WGS) to find what was previously hidden.
Unlike traditional methods that read DNA in short snippets, LR-WGS reads massive sections of the genome at once. This allowed the team to discover 33% more structural variants and 38% more tandem repeats in families with autism. By pairing this with data on DNA methylation, the study reveals not just which genes are mutated, but how those mutations disrupt brain function, paving the way for hyper-targeted diagnostics and therapies.
Key Facts
- Superior Discovery: LR-WGS identified over 30% more gene-disrupting mutations compared to traditional short-read sequencing.
- Complex Rearrangements: The technology uncovered complex genetic “shuffling” that was previously invisible, explaining why some cases of autism appeared to have no clear genetic cause.
- Functional Insights: By analyzing DNA methylation (chemical tags on DNA), researchers can now see how these mutations turn genes “on” or “off,” specifically in regions like the FMR1 gene linked to intellectual disability.
- The “Missing Heritability” Gap: Senior author Jonathan Sebat hypothesizes that this technology could eventually double the amount of heritability we can explain for certain variant types.
- Large-Scale Study: The team analyzed 267 genomes, marking one of the first and largest applications of long-read sequencing in autism research.
Source: UCSD
Researchers at the University of California San Diego have identified new genetic variants associated with autism spectrum disorder (ASD) by using long-read whole genome sequencing (LR-WGS), an emerging approach that reads large sections of the genome at once, making it easier for scientists to find new genetic variants and understand how genetic variants affect the function of a gene.
The team found that compared to traditional short-read approaches, LR-WGS enhanced the discovery of several categories of genetic variants.
The findings may pave the way for more accurate genetic tests and could enable new therapies targeting specific genetic mechanisms underlying ASD.
Despite significant progress in understanding the genetics of autism, a substantial portion of its genetic basis remains unexplained. This gap is what researchers call the “missing heritability.”
In their latest study, the researchers show that long-read sequencing can discover new gene mutations that were hidden from view when they used more traditional short-read sequencing technologies. This is one of the first studies of autism to utilize this approach at scale.
“Long-read technologies are game changers in terms of the diverse functional information we can get from a single genome sequence,” said senior author Jonathan Sebat, professor of psychiatry and cellular and molecular medicine at the UC San Diego School of Medicine.
“This technology can improve our understanding of the genetic basis of autism and other neurodevelopmental disorders, and may ultimately lead to better diagnostics and targeted therapies.”
Analyzing 267 genomes from families with autism, the study found:
- LR-WGS enhances the discovery of gene-disrupting structural variants (changes in genes) and tandem repeats (repeated sections of DNA) by 33% and 38%, respectively, compared to traditional short-read sequencing.
- Some of the new mutations found are complex rearrangements of genes, which can disrupt gene function and contribute to the development of autism.
- By analyzing data on genetic variants in tandem with DNA methylation — small chemical modifications that regulate the activity of a gene — the researchers could determine how mutations impact the function of a gene.
The researchers caution that though this study is the largest of its kind to date, even larger studies analyzing more genomes will be required to estimate exactly how much of the missing heritability can now be explained with long reads. Sebat hypothesizes that LR-WGS could double the amount of heritability explained by certain types of variants, such as tandem repeats and structural variants.
For now, the study offers new insights into the genetic origins of autism and highlights the potential of LR-WGS to reveal complex genetic variations and their functional consequences with a single test.
Funding: The study was published in Cell Genomics and funded, in part, by grants from the National Institute for Mental Health (MH113715, MH133899), the National Institute of Drug Abuse (U01DA051234), and the National Human Genome Research Institute (1R01HG010149). The authors declare no competing interests.
Key Questions Answered:
A: Imagine trying to put together a 10,000-piece puzzle by only looking at 2 pieces at a time. That was “short-read” sequencing. Long-read sequencing is like seeing the whole picture at once. It allows scientists to see massive chunks of DNA, making it much easier to spot where sections have been flipped, repeated, or moved around.
A: No. Autism is incredibly complex and involves hundreds of different genetic variations. What this study does is give us a much better “microscope” to see those variations. It helps explain why two people with the same diagnosis might have very different genetic backgrounds.
A: Currently, many families go through a “diagnostic odyssey” where tests come back inconclusive. This technology could lead to a single, more accurate test that finds the specific mutation responsible. In the long run, knowing the exact genetic “glitch” allows doctors to develop personalized treatments that target that specific biological pathway.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this genetics and autism research news
Author: Miles Martin
Source: UCSD
Contact: Miles Martin – UCSD
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Long-read genome sequencing improves detection and functional interpretation of structural and repeat variants in autism” by Milad Mortazavi, James Guevara, Joshua Diaz, Stephen Tran, Helyaneh Ziaei Jam, Chloe Reeves, Sergey Batalov, Kristen Jepsen, Matthew Bainbridge, Aaron D. Besterman, Melissa Gymrek, Abraham A. Palmer, and Jonathan Sebat. Cell Genomics
DOI:10.1016/j.xgen.2026.101186
Abstract
Long-read genome sequencing improves detection and functional interpretation of structural and repeat variants in autism
Long-read whole-genome sequencing (LR-WGS) technologies enhance the discovery of structural variants (SVs) and tandem repeats (TRs). We performed LR-WGS on 267 individuals from 63 autism spectrum disorder (ASD) families and generated an integrated call set combining long- and short-read data.
LR-WGS increased detection of gene-disrupting SVs and TRs by 33% and 38%, respectively, and enabled identification of novel exonic de novo germline and somatic SVs. We observed complex SV patterns, including a class of nested duplication-deletion events.
By joint analysis of phased genetic variation and DNA methylation, we identified deletions of imprinted genes and demonstrated the effect of intermediate TR expansions (35–54 CGG) on the methylation of FMR1 promoter. Rare SVs, TRs, and damaging SNVs together accounted for 7.4% (95% confidence interval [CI], 2.7%–17%) of the heritability of ASD.
These findings demonstrate how LR-WGS can resolve complex genetic variation and its functional consequences and regulatory effects in a single assay.
