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Whole-Genome Study Explores Biological Basis of Autism and Language Impairment

Monday, January 04, 2016


Photo: Jacob Michaelson, PhD, Assistant Professor of Psychiatry, left, and Bruce Tomblin, PhD, Professor Emeritus from the UI Department of Communication Sciences and Disorders, at Michaelson’s laboratory. 

By ANDY GOODELL, Communications Coordinator 

Department of Psychiatry 

Jacob Michaelson, PhD, an Assistant Professor of Psychiatry, has been awarded a $3 million NIH grant to study the biological basis of language impairment over the next five years. The project will be the first ever to perform whole-genome sequencing to examine this condition. 

“The genetics component of this grant is cutting edge, in that it will use the very latest and greatest approach, known as whole genome sequencing, to examine variation in the DNA of the volunteers in the study,” saysJames B. Potash, MD, MPH, Chair and Department Executive Officer of Psychiatry. “This is the ultimate genetic investigation, as it spells out each and every chemical letter in the DNA alphabet across a person’s three billion letter genome. It is the most comprehensive kind of genetic study imaginable.” 

Prior research has shown that much of the risk for language impairment is familial, implying a genetic cause for the condition. With this in mind, Michaelson says he hopes this study, which is being done in collaboration with Bruce Tomblin, PhD, Professor Emeritus from the Department of Communication Sciences and Disorders, will be a first step in eventually enabling clinicians to identify children at risk for language impairment earlier than is currently possible. He notes that clinical whole-genome sequencing could eventually identify risk factors for language impairment long before a child would typically be expected to reach any language milestones. This knowledge could help parents and clinicians plan so they can intervene early to mitigate the effects of the child’s innate language deficits. 

Because of the extreme rarity of the genetic variants that are likely to contribute significantly to language impairment, Michaelson thinks it’s important to group these variants according to the function of the genes they impact. Then, the association becomes one between language impairment and a collection of functionally similar variants, rather than individual variants (which may have a statistically tenuous association). 

Michaelson says this study also seeks a better understanding of the relationship between autism and language impairment. The two are often thought of as “cousin conditions” because they share some similarities in their communication deficits as well as some common genetic risk factors. But the extent of their genetic similarities and differences is currently an unknown that this study aims to bring to light. 

Tomblin explained that, although there has been a big push toward research in the neurobiology of the autism spectrum, less has been done when looking at the neurobiological underpinnings of language disorders among researchers. This speaks to the importance of his collaboration with Michaelson since there is so much yet to uncover.

Power of collaboration

Michaelson says the current NIH-funded study will gain more statistical power by looking at extremes of language ability (i.e., highly impaired and highly proficient). The team will study the DNA of 200 school age children with severe language impairment and 200 other children with excellent language ability. A second sample of 400 children will be used to verify the findings of the first study. Previous work by Tomblin gathered the DNA being used in the current collaborative effort. 

“I’m grateful he had the foresight to collect the DNA,” says Michaelson. “It put us in a good position.” 

For Michaelson, collaboration has been an essential part of his career. He pursued a PhD in computational genetics under Andreas Beyer and in collaboration with Gerd Kempermann at the Center for Regenerative Therapies TU Dresden in Germany, working in a collaborative group focused on finding genetic factors that influence the brain’s ability to make new neurons. Here, he gained an appreciation that the brain, and consequently how humans learn and interact with the world, can be influenced profoundly by genetic factors. 

After his graduate work he took a postdoctoral position at the University of California, San Diego in the lab of Jonathan Sebat, a pioneer in the field of genomic structural variation in psychiatric conditions. At that time, whole genome sequencing was prohibitively expensive and most research groups chose the less expensive exome sequencing approach (which neglects 97% of the genome). But Sebat was one of only a handful of scientists who opted for whole genome sequencing, and consequently Michaelson benefitted from having early experience with this powerful technology and its unique potential. Now the head of his own lab, Michaelson is eager to capitalize on his experience with whole genome sequencing that he first gained as a postdoc. 

“Since I came to Iowa two years ago we’ve been working largely with data that others have collected,” says Michaelson. “Being primarily a computational group, this isn’t unusual. But it feels empowering to be in the driver’s seat and produce a brand new data set that can be used to answer new and exciting questions about something as fundamental as human language.” 

Tomblin, now a professor emeritus, has been with the University of Iowa since 1972. In that time, he has not only contributed greatly to advancing knowledge in the field of communication sciences and disorders, but he’s seen the benefits of collaborating with the UI Department of Psychiatry. Near the beginning of his time with the UI, Tomblin collaborated with Mark Stewart from Psychiatry in a study of autism. He also worked alongside UI Psychiatry faculty members Joe Piven and Remi Cadoret. Taking into account perspectives from UI Psychiatry has had a marked influence on Tomblin’s research, setting a significant direction for his work. 

“You need people who know what you do not,” explained Tomblin, complimenting Michaelson’s prodigious computational skills. Michaelson, for his part, is honored to be partnering with Tomblin, who brings deep knowledge of language impairment and represents Iowa’s formidable legacy in studying communication disorders. Together, this team aims to show how disruptions in the syntax and grammar of DNA can ultimately lead to deficits in human communication.