According to a new study of human neurons, deletion of the region of chromosome 22 results in extensive changes in the expression of many genes associated with autism and schizophrenia.
People who miss this area, called 22q11.2, are more likely to suffer from any of many neuropsychiatric and developmental conditions, such as autism, schizophrenia, intellectual disability, and epilepsy. ..
How deletion contributes to these various states is confusing to researchers, as studies have so far failed to identify a single gene within the 22q11.2 region that contributes to these states. Says co-principal researcher Ralda Nehme, deputy director of the stem cell program. The Broad Institute’s Stanley Psychiatric Research Center in Cambridge, Massachusetts.
“People have been more focused on deleted genes in the past,” says Nehme. When she and her colleagues analyzed gene expression levels in neurons derived from people with a 22q11.2 deletion, they were significant in genes elsewhere in the genome that were strongly associated with autism and schizophrenia. I found a change.
“It suggests that there is a convergence of this mechanism” between the effects of deletion and the pathways known to contribute to these conditions, says Psychiatry and Biobehavioral Sciences and Psychology at the University of California, Los Angeles. Carrie Bearden, a professor at the University of California, said. I was involved in the research.
Nehme and her colleagues generated induced pluripotent stem cells from 19 people with a deletion of 22q11.2 and 29 without such a deletion. The team compared the expression levels of the non-deletion gene in the cells as they were reprogrammed into neural progenitor cells and mature excitatory neurons.
The team found that cells carrying the deletion expressed a different set of genes than control cells, but that set changed throughout development. As stem cells and progenitor cells, carriers and non-carriers have different expression of 380 genes, seven of which are associated with autism and developmental delay such as FOXP2 and PAX5. As excitatory neurons, the expression of 86 genes was altered, including a statistically significant increase in those associated with schizophrenia.
The team is similar in stem cells, neural progenitor cells, and excitatory neurons derived from human embryonic stem cells, compared to those with the same genetic background edited via CRISPR to have a 22q11.2 deletion. I found a difference in gene expression.
The findings suggest that the deletion itself leads to differences in gene expression, says Jacob Wolstmann, an associate professor of psychiatry at the University of Toronto, Canada, who was not involved in the study.
To understand how the deletion of 22q11.2 shapes the expression of other genes, the team mapped the interactions between proteins encoded by the genes whose expression was altered in the cells carrying the deletion. Did. The team found that the network that links one protein to another through as few intermediate proteins as possible also contains many of the proteins encoded by the genes in the deleted region. did. Olli Pietiläinen, Group Leader and Co-Principal Investigator at the University of Helsinki, Finland, found that the results show how the 22q11.2 gene loss ultimately results in characteristics associated with autism or schizophrenia. Emphasizes what it could bring to.
Survey results were published in June Nature Communications..
MResearchers have found that any gene with altered expression in a neuron carrying a deletion is known to shape synaptic transmission. Neurons also had a lower firing rate than control neurons, the team found when recording cell activity using a multi-electrode array. The team found that genes with altered expression in neural progenitor cells are associated with skeletal system development, but genes with different expression as stem cells do not fall into a particular functional category.
“It’s the individual pieces of the puzzle that seem to fit everything at this stage, but of course we need to dig deeper to be sure,” says Nehme.
Although this study cannot identify the exact factors that drive a person with a 22q11.2 deletion towards a diagnosis, the findings show that “between two different important windows of neurological development. Comprehensive changes in gene expression caused by deletions increase the risk for people with either autism or schizophrenia, “said BioMarin Pharmaceuticals, a company based in San Rafael, California, for research and initial development. Kevin Eggan, a former Broad Institute co-principal researcher who is responsible for the research, said.
He also says that other aspects of human genetics may “cooperate with the deletion” in ways that increase the likelihood of autism and schizophrenia.
Comparing gene expression in cells generated from people with the 22q11.2 deletion with or without autism or schizophrenia is one way to investigate the factors that shape that risk, Vorstman said. Says. Deletion increases the likelihood that a person will be in either state, but not everyone will exceed the diagnostic threshold, he says. “Apparently, their genetic background is something that drives some of them to the other side.”
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