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Scientists at Harvard University, the Broad Institute of MIT and Harvard and MIT have developed a technology to study the function of many different genes in many different cell types at once, in a living organism. They applied the method on a large scale to study dozens of genes associated with autism spectrum disorder, identifying how specific cell types in the developing mouse brain are affected by the mutations.
The “Perturb-Seq” method, published in the journal Science, is an efficient way to identify the potential biological mechanisms underlying autism spectrum disorder, which is an important first step towards developing treatments for the complex disease. The method is also widely applicable to other organs, allowing scientists to better understand a wide range of normal diseases and processes.
“For many years, genetic studies have identified a multitude of risk genes associated with the development of autism spectrum disorder. The challenge in the field has been to establish the connection between knowing what genes are and understanding how genes actually affect. cells and ultimately behavior, ”said senior co-author Paola Arlotta, professor of stem cell and regenerative biology for the Golub family at Harvard. “We have applied Perturb-Seq technology to an intact developing organism for the first time, showing the potential to measure gene function on a large scale to better understand a complex disorder,” added Arlotta.
The study was also led by co-senior authors Aviv Regev, who was a principal member of the Broad Institute during the study and is currently Executive Vice President of Genentech Research and Early Development, and Feng Zhang, a principal member of the Broad Institute and a investigator at MIT’s McGovern Institute. To study gene function on a large scale, the researchers combined two powerful genomic technologies. They used CRISPR-Cas9 genome editing to make precise changes, or perturbations, in 35 different genes linked to the risk of autism spectrum disorder.
Then, they analyzed changes in the developing mouse brain using single-cell RNA sequencing, which allowed them to see how gene expression changed in more than 40,000 single cells. By looking at the level of individual cells, the researchers were able to compare how risk genes affected the different types of cells in the cortex, the part of the brain responsible for complex functions including cognition and sensation. They analyzed networks of risk genes together to find common effects.
“We found that both neurons and glia – the non-neuronal cells in the brain – are directly affected by several groups of these risk genes,” said Xin Jin, lead author of the study and a Junior Fellow of the Harvard Society of Fellows. “Genes and molecules don’t generate cognition by themselves – they need to impact specific cell types in the brain to do so. We are interested in how these different cell types can contribute to the disorder,” Jin added.
To get an idea of the model’s potential relevance to the disorder in humans, the researchers compared their results with post-mortem human brain data. Overall, they found that in post mortem human brains with autism spectrum disorder, some of the key genes with altered expression were also affected in the Perturb-seq data. “We now have a really rich dataset that allows us to draw insights and we are still learning a lot about this every day. As we go into studying disease mechanisms in more depth, we can focus on the types of cells that can be very important, “Jin said.
“The field has been limited by the time and effort required to create one model at a time to test the function of individual genes. Now, we have demonstrated the potential to study gene function in a developing organism in a scalable fashion, which is an exciting first step to understanding the mechanisms that lead to autism spectrum disorder and other complex psychiatric conditions, and to eventually developing treatments for these devastating conditions, “said Arlotta, who is also a member of the Broad Institute and part of Broad’s Stanley Center for Psychiatric Research. “Our work also paves the way for the application of Perturb-Seq to organs beyond the brain, to allow scientists to better understand the development or function of different types of tissue, as well as pathological conditions,” he added. Arlotta.
“Through genome sequencing efforts, a very large number of genes have been identified which, when mutated, are associated with human diseases. Traditionally, understanding the role of these genes would require in-depth studies of each gene individually. Developing Perturb-seq for in vivo applications, we can begin screening all of these genes in animal models much more efficiently, allowing us to mechanically understand how mutations in these genes can lead to disease, “said Zhang, who is also James and Patricia Poitras Professor of Neuroscience at MIT and Professor of Brain and Cognitive Sciences and Biological Engineering at MIT. (ANI)
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