In our cells is written the language of DNA that makes each one of us unique. A tandem repeat occurs in DNA when a pattern of one or more nucleotides – the basic structural unit of DNA encoded by the basic chemicals cytosine (C), adenine (A), guanine (G) and thymine (T) – occurs – is repeated several times along with. An example might be: CAG CAG CAG where the CAG pattern is repeated three times.
Now, using cutting-edge whole genome sequencing and machine learning techniques, the UNC School of Medicine laboratory of Jin Szatkiewicz, PhD, associate professor of genetics, and colleagues have conducted one of the first and largest investigations into tandem repeats in schizophrenia and elucidated their contribution to the development of this devastating one Illness.
The study, published in the journal Molecular Psychiatry, shows that people with schizophrenia had a significantly higher rate of rare tandem repeats in their genome – 7% more than people without schizophrenia. And they observed that the tandem repeats were not randomly arranged throughout the genome; They were mainly found in genes critical to brain function and known to be important in schizophrenia, according to previous studies.
“We believe this finding opens doors for future functional studies of the precise biological mechanism of these variants,” said Szatkiewicz, who is also an associate assistant professor of psychiatry. “Understanding the biological cause of schizophrenia will enable the future development of diagnostic tests, effective drugs and personalized treatments.”
Tandem reps generally have no negative health effects. However, depending on where the tandem repeats are located in the genome and how long they have existed, they can contribute to disease. For example, Huntington’s disease is caused by an abnormally developed tandem repeat in the HTT gene. The disease begins when the cytosine-adenine-guanine (CAG) sequence is repeated more than 36 times on the HTT gene. Longer repeated expansions lead to abnormal protein products with an extended glutamine trace, which is toxic to brain cells. These repeats are hereditary and tend to get longer and longer in successive generations with increasing disease severity or decreasing age of onset.
In their current study, Szatkiewicz and his team scanned the entire genomes of 2,100 individuals to find tandem repeats that were unusually long and unique or rare. Because all participants gave access to their medical records, the team was able to compare these samples of long and rarely repeated DNA sequences from people with schizophrenia with samples from people in the study who didn’t have it. In this way, the researchers were able to determine which of these tandem repeats might be involved in the development of schizophrenia.
Using gene network analysis, the authors of this study showed that rare tandem repeat genes found in schizophrenia mainly affect synaptic and neuronal signaling functions. Furthermore, these genes are highly conserved throughout evolution, indicating important biological functions and therefore the significant impact that tandem repeats could have.
The UNC School of Medicine researchers then worked with scientists at Toronto’s Hospital for Sick Children to see if this increased amount of rare tandem variants would also be found in a different set of independently collected samples. Szatkiewicz’s findings were echoed in the Canadian investigation, suggesting that this newfound link between tandem repetition and schizophrenia is quite strong.
“We think this is an important study,” said co-senior author Ryan Yuen, PhD, principal investigator at the Hospital for Sick Children and assistant professor of molecular genetics at the University of Toronto. “We are confident that our work will shed significant light on the role that DNA tandem repeat mutations play in the development of schizophrenia.”
The other authors of the article are Jia Wen, Brett Trost, Worrawat Engchuan, Matthew Halvorsen, Linda M. Pallotto, Aleksandra Mitina, NaEshia Ancalade, Martilias Farrell, Ian Backstrom, Keyi Guo, Giovanna Pellecchia, Bhooma Thiruvahindrapuram, Paola Giusti-Rodriguez. Jonathan David Rosen, Yun Li, Hyejung Won, Patrik KE Magnusson, Ulf Gyllensten, Anne S Bassett, Christina M Hultman, and Patrick F Sullivan.
This research was funded primarily by grants from the National Institute of Mental Health and the National SciLifeLab Project.