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For decades, Cold Spring Harbor Laboratory scientists and collaborators have invested millions of dollars into deciphering the genetic causes of autism Cold Spring Harbor Laboratory

Cold Spring Harbor Laboratory (CSHL) researchers have flipped the script on autism ) genetics.

Scientists long thought that siblings born with autism share more of their mother’s genome than their father’s. But CSHL Associate Professor Ivan Iossifov and Professor Michael Wigler have now shown that, in many cases, it’s dad who might be playing a bigger genetic role.

Autism spectrum disorders cover a range of neurological and developmental conditions. They can affect how a person communicates, socializes, learns, and behaves. Autism may also manifest as repetitive behaviors or restricted interests. In the United States, it affects around one in 36 children. 

“There are children diagnosed with autism who are high functioning,” Iossifov says. “They have a completely productive life, although they have some minor troubles in social interactions, as most of us do. But also, there are children diagnosed with autism who never learn to speak, and they have definitely a difficult life.”

Over the last two decades, CSHL scientists have led a multimillion-dollar effort to uncover the genetic origins of autism. They discovered thousands of genes that, when damaged, may cause a child to be born with autism. But their work was not able to account for all cases of autism. So Iossifov and Wigler set out to find the missing sources.

The duo analyzed the genomes of over 6,000 volunteer families. They found that in families that have two or more children with autism, the siblings shared more of their father’s genome. Meanwhile, in families where only one sibling had autism , the children shared less of their father’s genome. While the discovery reveals a new potential source of autism, it also poses a provocative question. Could other disorders play by the same genetic rules?

No one is sure how dad’s genome makes its mark on children with autism. But Iossifov has a couple interesting ideas. He thinks some fathers may carry protective mutations that fail to get passed on. Or fathers may pass down mutations that trigger the mother’s immune system to attack the developing embryo. Both theories offer hope for parents of children with autism .

“Our future research is exciting,” Iossifov says. “If one of those theories or two of them prove to be true, then it opens different treatment strategies, which can, in the future, affect quite a lot of families.”

In addition, this research offers helpful tools for educators and therapists. It may allow for earlier diagnoses and a better overall understanding of autism.

Study finds that major vault protein is needed for homeostatic plasticity.David Orenstein

The MVP protein appears green in these stained neurons (red denotes neuronal marker SATB2). Credits: Image courtesy of the Sur Lab

In a new study of one of the most common genetic causes of autism, neuroscientists at MIT’s Picower Institute for Learning and Memory have identified a molecular mechanism that appears to undermine the ability of neurons in affected mice to properly incorporate changes driven by experience. The findings, published in the Journal of Neuroscience, suggest that a particular gene, MVP, is likely consequential in people with 16p11.2 deletion syndrome.

Accounting for up to 1 percent of autism cases, 16p11.2 deletion occurs in people who are missing a small region of DNA near the center of one copy of chromosome 16. For years, scientists have been working to determine exactly how the reduced presence of 29 protein-encoding genes leads to clinical symptoms of the syndrome, such as autism-like behaviors, developmental delay, and intellectual disability.

“This has been a major problem for the field,” says senior author Mriganka Sur, the Newton Professor of Neuroscience at the Picower Institute and director of the Simons Center for the Social Brain at MIT. “People have looked at the entire region in mice. Our strategy was different. We thought, can we make a hypothesis about a critical gene that should play an important role?”

The team, led by postdoc Jacque Pak Kan Ip, focused on MVP, which is known for encoding a protein that shuttles RNAs and proteins from the nucleus to the rest of cells — a generally vital function. It is particularly important in the immune system and is known to regulate other genes as well. Although MVP is also known to be among the 29 genes affected in people with 16p11.2 deletion syndrome, its specific function in neurons has barely been investigated. To change that, the researchers devised a series of tests of MVP in a well-understood region in the visual cortex, where the brain processes sight from both eyes.

Keeping an eye open for change

Ip and the co-authors employed the time-honored protocol of monocular deprivation, or temporarily shutting one eye for a week. Normally, responses in visual cortex neurons related to the closed eye become weaker, but responses related to the remaining open eye become stronger, as if to compensate for the change in ability. This neural circuit adjustment to experience is called homeostatic plasticity.

In the normal mice, closing an eye for a week had the expected effect. But in mice with one copy of MVP missing, the researchers observed a telling difference. Responses related to the closed eye still weakened, but responses from the open eye did not get stronger. Homeostatic plasticity was disrupted.

“After seeing that MVP is responsible, we asked how MVP does it,” Ip says.

In those further tests, the team found that neurons in MVP-reduced mice experienced less electrical current across their excitatory synapse connections with other neurons, suggesting reduced functional excitatory synapses. They found other differences, too. MVP-reduced mice overexpressed the gene STAT1, an immune-system gene known to be regulated by MVP.

In 2014, Sur’s lab had found that mice without STAT1 have unusually strong open-eye responses after monocular deprivation. Now in the new study, with less MVP than usual and too much STAT1, mice experienced the opposite. Sure enough, when the researchers knocked down STAT1 as well as MVP, they were able to bring back a near-normal open-eye response to monocular deprivation, suggesting that loss of MVP disrupts homeostatic plasticity by allowing for an overabundance of STAT1.

Then Ip, Sur, and co-authors dug even deeper. They found that in MVP-reduced mice, neurons weren’t producing the expected open-eye responses because they weren’t expressing a key receptor, the GluA1 AMPA receptor, on the surface of dendritic spines.

Even though the findings were made, by design, in the visual cortex, the authors said they expect the disruption of homeostatic plasticity to occur elsewhere as well.

“This gene’s presence is reduced everywhere in the brain,” Sur notes.

The research adds to what scientists know about the connection between copy number variants (repeats or deletions of genes) and autism spectrum disorder, says Mustafa Sahin, a professor of neurology at Harvard University and director of the Translational Neuroscience Center and the Translational Research Program at Boston Children’s Hospital.

“Copy number variations in our genome are commonly associated with intellectual disability and autism spectrum disorder,” says Sahin, who holds the Rosamund Stone Zander Chair. “While 16p11.2 microdeletion was identified as a genetic cause of autism 10 years ago, identifying which gene or genes in this region play a crucial role in brain development and function has been a holy grail of research in this field. Sur lab has made major inroads into this question by demonstrating the MVP+/- mice show deficits similar to 16p11.2 mutant mice and even identifying potential therapeutic targets downstream of the MVP gene.” 

Relationship with immune system

In addition to illustrating how a specific gene may contribute to the symptoms of 16p11.2 deletion syndrome, Sur said, the findings also raise an intriguing, broader question about the central nervous system: Is it perhaps not a coincidence that some of its ability to adjust to and incorporate experience comes from genes that are also active in the immune system?

“The immune system is really a system of learning and memory,” Sur says. “You get infected and the body makes antibodies and the next time there is a memory of the infection. It is conceptually a very similar idea.”

Workflow of M-DATA CREDIT Yuhan Xie, CC-BY 4.0 (https://creativecommons.org/licenses/by/4.0/)

Researchers identified almost two dozen genes that contribute to heart defects by studying genetic data from people born with congenital heart disease or autism. Hongyu Zhao of Yale University and colleagues developed a new algorithm to analyze genetic data from related conditions, which they describe in a new paper publishing November 4^th in the journal PLOS Genetics.

Multiple diseases that start early in life appear to be linked to mutations in the same genes.  Recent research looking at de novo mutations—new mutations that pop up in children that were not present in the parents—has demonstrated a connection between congenital heart defects and autism. However, sequencing de novo mutations is expensive, so small studies of individual diseases have limited power to identify genes that increase a person’s risk of the disease.

In the new study, researchers developed an algorithm called M-DATA (Multi-trait De novo mutation Association Test with Annotations) that combines sequencing data from people with related conditions to identify genes that contribute to disease. They applied the new method to genetic data from people with congenital heart disease or autism and successfully identified 23 genes for congenital heart disease, including 12 that were previously unknown.

The researchers conclude that M-DATA is more effective at identifying genes that increase a person’s risk than analyses focusing on a single disease. This is because instead of analyzing a small number of genomes from affected individuals, M-DATA analyzes a larger number of combined genomes from multiple groups of people. The new method may help researchers identify previously unknown genes linked to disease and improve our understanding of the cause and potential treatment for different conditions.

Zhao adds, “By jointly analyzing de novo mutations from congenital heart disease (CHD) and autism, we identified novel genes that may play an important role in explaining the shared genetic etiology of CHD and autism.”

Yuhan Xie, the lead student of the research, says, “As a biostatistics student, it’s very motivating to find what could be meaningful to the patients and their families.”