Scientists Link Rare Genetic Phenomenon to Neural Function, Schizophrenia |  Writing

Scientists Link Rare Genetic Phenomenon to Neural Function, Schizophrenia | Writing

Led by Jin Szatkiewicz, PhD, researchers at the UNC School of Medicine and colleagues at the University of Toronto have found that a rare form of a common genetic variant called tandem repeats is strongly associated to the development of schizophrenia.

CHAPEL HILL, NC – In our cells, the language of DNA is written, which makes each of us unique. A tandem repeat occurs in DNA when a pattern of one or more nucleotides – the basic structural unit of DNA encoded in the basis of the chemicals cytosine (C), adenine (A), guanine ( G) and thymine (T) – is repeated several times. times in tandem. An example might be: CAG CAG CAG, in which the CAG pattern is repeated three times.

Now, using state-of-the-art whole genome sequencing and machine learning techniques, the UNC School of Medicine lab in Jin Szatkiewicz, PhDassociate professor of genetics, and his colleagues conducted one of the first and largest investigations of tandem repeats in schizophrenia, elucidating their contribution to the development of this devastating disease.

Published in the journal Molecular psychiatry, research shows that people with schizophrenia had a significantly higher rate of rare tandem repeats in their genomes – 7% more than people without schizophrenia. And they observed that the tandem repeats were not randomly located throughout the genome; they have mainly been found in genes crucial for 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 adjunct assistant professor of psychiatry. “Understanding the biological cause of schizophrenia will enable the future development of diagnostic tests, effective pharmaceuticals, and personalized treatments.”

Tandem reps generally do not have negative health implications. However, depending on where the tandem repeats are located in the genome and how long they last, they may contribute to disease. For example, Huntington’s disease is caused by a tandem repeat in the HT abnormally developed gene. Disease onset will occur once the cytosine-adenine-guanine (CAG) sequence repeats more than 36 times on the HT embarrassed. Longer repeat expansions lead to abnormal protein products with an extended glutamine trail that is toxic to brain cells. These repeats are hereditary and tend to become longer and longer in successive generations with increasing disease severity or decreasing age of onset.

In their current study, Szatkiewicz and his team examined the entire genomes of 2,100 individuals to find tandem repeats that appeared abnormally long and were unique or rare. Because all participants gave access to their medical records, the team was able to compare these samples of long and rare repeated DNA sequences from people with schizophrenia against samples from people in the study who did not. had not. This allowed the researchers to determine which of these tandem repeats may be involved in the development of schizophrenia.

Using gene network analysis, the authors of this study demonstrated that genes with rare tandem repeats found in schizophrenia primarily impact synaptic and neuronal signaling functions. Moreover, these genes are highly conserved during evolution, indicating important biological functions and therefore the significant impact that tandem repeats could exert.

The UNC School of Medicine researchers then collaborated with scientists at the Hospital for Sick Children in Toronto to see if this increased level of rare tandem variants would also be found in another group of independently collected samples. . Szatkiewicz’s findings were replicated in the Canadian investigation, indicating that this newly discovered link between tandem repeats and schizophrenia is quite strong.

“We believe this is an important study,” said co-lead 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 sheds significant light on the role played by DNA tandem repeat mutations 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 primarily funded by grants from the National Institute of Mental Health and the National SciLifeLab Project.

Media contact: Marc DerewiczUNC School of Medicine

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