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<\/p>\nLeft to right: Ira Hall, University of Virginia, Michael McConnell, University of Virginia, and Fred H. Gage, Professor, Laboratory of Genetics, Salk Institute for Biological Studies.\n <\/p>\n
\nImage: Courtesy of Salk Institute for Biological Studies\n<\/p>\n<\/div>\n
\n“Contrary to what we once thought, the genetic makeup of neurons in the brain aren’t identical, but are made up of a patchwork of DNA,” says corresponding author Fred Gage<\/a>, Salk’s Vi and John Adler Chair for Research on Age-Related Neurodegenerative Disease.\n <\/p>\n \nIn the study, led by Mike McConnell<\/a>, a former junior fellow in the Crick-Jacobs Center for Theoretical and Computational Biology<\/a> at the Salk, researchers isolated about 100 neurons from three people posthumously. The scientists took a high-level view of the entire genome\u2014looking for large deletions and duplications of DNA called copy number variations or CNVs\u2014and found that as many as 41 percent of neurons had at least one unique, massive CNV that arose spontaneously, meaning it wasn’t passed down from a parent. The CNVs are spread throughout the genome, the team found.\n <\/p>\n \nThe miniscule amount of DNA in a single cell has to be chemically amplified many times before it can be sequenced. This process is technically challenging, so the team spent a year ruling out potential sources of error in the process.\n <\/p>\n \n“A good bit of our study was doing control experiments to show that this is not an artifact,” says Gage. “We had to do that because this was such a surprise\u2014finding out that individual neurons in your brain have different DNA content.”\n <\/p>\n \nThe group found a similar amount of variability in CNVs within individual neurons derived from the skin cells of three healthy people. Scientists routinely use such induced pluripotent stem cells (iPSCs) to study living neurons in a culture dish. Because iPSCs are derived from single skin cells, one might expect their genomes to be the same.\n <\/p>\n \n“The surprising thing is that they’re not,” says Gage. “There are quite a few unique deletions and amplifications in the genomes of neurons derived from one iPSC line.”\n <\/p>\n \nInterestingly, the skin cells themselves are genetically different, though not nearly as much as the neurons. This finding, along with the fact that the neurons had unique CNVs, suggests that the genetic changes occur later in development and are not inherited from parents or passed to offspring.\n <\/p>\n \nIt makes sense that neurons have more diverse genomes than skin cells do, says McConnell, who is now an assistant professor of biochemistry and molecular genetics at the University of Virginia School of Medicine in Charlottesville<\/a>. “The thing about neurons is that, unlike skin cells, they don’t turn over, and they interact with each other,” he says. “They form these big complex circuits, where one cell that has CNVs that make it different can potentially have network-wide influence in a brain.”\n <\/p>\n \nSpontaneously occurring CNVs have also been linked to risk for brain disorders such as schizophrenia and autism, but those studies usually pool many blood cells. As a result, the CNVs uncovered in those studies affect many if not all cells, which suggests that they arise early in development.\n <\/p>\n \nThe purpose of CNVs in the healthy brain is still unclear, but researchers have some ideas. The modifications might help people adapt to new surroundings encountered over a lifetime, or they might help us survive a massive viral infection. The scientists are working out ways to alter genomic variability in iPSC-derived neurons and challenge them in specific ways in the culture dish.\n <\/p>\n \nCells with different genomes probably produce unique RNA and then proteins. However, for now, only one sequencing technology can be applied to a single cell.\n <\/p>\n \n“If and when more than one method can be applied to a cell, we will be able to see whether cells with different genomes have different transcriptomes (the collection of all the RNA in a cell) in predictable ways,” says McConnell.\n <\/p>\n \nIn addition, it will be necessary to sequence many more cells, and in particular, more cell types, notes corresponding author Ira Hall<\/a>, an associate professor of biochemistry and molecular genetics at the University of Virginia. “There’s a lot more work to do to really understand to what level we think the things we’ve found are neuron-specific or associated with different parameters like age or genotype,” he says.\n <\/p>\n \nOther authors on the study are Michael Lindberg and Svetlana Shumilina of the Department of Biochemistry and Molecular Genetics at the University of Virginia School of Medicine; Kristen Brennand<\/a>, now at the Icahn School of Medicine at Mount Sinai<\/a> in New York; Julia Piper, now at Harvard University<\/a> in Cambridge, Massachusetts; Thierry Voet and Joris Vermeesch of the Center for Human Genetics<\/a>, KU Leuven, Leuven, Belgium; Chris Cowing-Zitron of Salk’s \u9057\u4f20\u5b9e\u9a8c\u5ba4<\/a>; and Roger Lasken of the J. Craig Venter Institute<\/a> in San Diego.\n <\/p>\n \nThis work was supported by the Crick-Jacobs Center for Theoretical and Computational Biology<\/a>, the G. Harold & Leila Y. Mathers Foundation<\/a>, the National Institutes of Health<\/a>, the Leona M. and Harry B. Helmsley Charitable Trust<\/a>, the JPB Foundation<\/a>, and the Burroughs Wellcome Fund<\/a>.\n <\/p>\n \nFaculty achievements have been recognized with numerous honors, including Nobel Prizes and memberships in the National Academy of Sciences. Founded in 1960 by polio vaccine pioneer Jonas Salk, M.D., the Institute is an independent nonprofit organization and architectural landmark.<\/p>","protected":false},"featured_media":0,"template":"","faculty":[76],"disease-research":[124],"class_list":["post-2458","disclosure","type-disclosure","status-publish","hentry","faculty-rusty-gage","disease-research-neuroscience-and-neurological-disorders"],"acf":[],"yoast_head":"\n
\nAbout the Salk Institute for Biological Studies:<\/strong>
\nThe Salk Institute for Biological Studies is one of the world’s preeminent basic research institutions, where internationally renowned faculty probe fundamental life science questions in a unique, collaborative, and creative environment. Focused both on discovery and on mentoring future generations of researchers, Salk scientists make groundbreaking contributions to our understanding of cancer, aging, Alzheimer’s, diabetes and infectious diseases by studying neuroscience, genetics, cell and plant biology, and related disciplines.\n <\/p>\n