University of Iowa professors are using fruit flies to identify what genes cause intellectual disability, a common and often lifelong condition that limits people’s intellectual function and social skills. 

John Manak, a professor in the UI’s biology department, and Benjamin Darbro, the director of the Cytogenetics and Molecular Laboratory in the Carver College of Medicine, received a $6,000 grant in late January to study what causes the disability at the genetic level.

According to the National Institute of Health , 2 to 3 percent of children are diagnosed with intellectual disability. Manak said disorders are often labeled common when more than one percent of patients are diagnosed with it. 

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Manak said the limits patients face with the disability are in intellectual functioning, meaning learning, memory, problem-solving. Manak said the disability is also characterized by limitations in adaptive behavior, or social interactions and communication with other people.

Manak said the genetic causes of common disorders, such as intellectual disability, are harder to trace than rare disorders because they aren’t usually caused by a single gene. They instead involve many small genetic changes, or variants, with each having a minor effect of its own. 

Manak said these small variants are widespread and usually harmless on their own. The condition develops when someone inherits enough of them together, and they push the body past a threshold.

“It’s kind of like Jenga,” he said.  “Imagine that each of those little blocks that you’re pulling out is one of these variants affecting a single gene, compromising the gene’s function ever so slightly.”

Manak said at a certain point, one inherits so many of the common variants that the tower topples, making a patient develop the disorder. 

In their research, Manak said Darbro will analyze large patient DNA databases to look for gene mutations that repeatedly appear in people with intellectual disability. If one gene keeps appearing, it is likely linked to causing the condition. 

Manak said he will then find a fruit fly version of the identified human gene and do an experiment in which they remove the gene in the fly’s brain and test to see if the fly still has intellectual disability. 

Manak said they will test if the flies have intellectual disability after the gene removal by using a T-mazed apparatus, a testing tool that pairs a shocker with a sensory cue — such as a smell — and analyzes whether the fly learns to avoid the sense to avoid getting a shock. 

“It would be very difficult to be able to pick that up if you’re doing this in mice, versus if you’re doing it in fruit flies, where you’re able to screen hundreds of flies and compare the control, we’re able to actually generate statistically significant data,” he said. 

Jodi Tate, a psychiatrist in UI Health Care, said she often works with adults with intellectual disability and mental illness. 

“Individuals with intellectual disability have a significant increase mortality and morbidity compared to folks without an intellectual disability,” she said. “One of the big reasons is that health care providers receive very little training or education on how to work with this population.”

Tate said one of the main reasons patients with intellectual disability see a psychiatrist is they are dealing with challenging behavior.

“What happens is that health care providers think that’s because of their intellectual disability,” she said. “The reality of the situation, it is likely because they have an undiagnosed medical condition or mental condition, and that phenomenon is called diagnostic overshadowing.”

Tate said diagnostic overshadowing leads to an increase in a patient’s medical pain and mortality because health care providers overlook the health problems a patient is going through. 

“Part of having intellectual disability is sometimes having difficulty communicating and advocating,” she said. “Teaching folks that they deserve to get the best care possible is appropriate. It’s appropriate to advocate, but that’s easier said than done.”

Years down the road, Manak said he hopes his research with Darbro will help produce treatments for the disorder that many health care officials aren’t adequately trained to handle. 

Manak said after they identify which genes cause traits of intellectual diversity, the research  will examine the flies’ brains to see which other genes become more or less active, creating a kind of “genetic signature” of the disorder. 

Manak said they would compare the genetic signature to databases showing how different drugs affect gene activity in human cells. If a drug produces the opposite pattern, reversing the gene changes found in the fly, it could potentially counteract the disorder and be repurposed as a treatment.

“That will get us to some drug that might actually work to effectively treat intellectual disability,” he said. “That’s years in the future, in which we would test mouse models of our intellectual disability model.”