(Press-News.org) Contact information: Kat Kearney
kkearney@salk.edu
619-296-8455
Salk Institute
Study finds a patchwork of genetic variation in the brain
Salk scientists find a surprising degree of variation among genomes of individual neurons from the same brain
It was once thought that each cell in a person's body possesses the same DNA code and that the particular way the genome is read imparts cell function and defines the individual. For many cell types in our bodies, however, that is an oversimplification. Studies of neuronal genomes published in the past decade have turned up extra or missing chromosomes, or pieces of DNA that can copy and paste themselves throughout the genomes.
The only way to know for sure that neurons from the same person harbor unique DNA is by profiling the genomes of single cells instead of bulk cell populations, the latter of which produce an average. Now, using single-cell sequencing, Salk Institute researchers and their collaborators have shown that the genomic structures of individual neurons differ from each other even more than expected. The findings were published November 1 in Science.
"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, Salk's Vi and John Adler Chair for Research on Age-Related Neurodegenerative Disease.
In the study, led by Mike McConnell, a former junior fellow in the Crick-Jacobs Center for Theoretical and Computational Biology at the Salk, researchers isolated about 100 neurons from three people posthumously. The scientists took a high-level view of the entire genome---- looking for large deletions and duplications of DNA called copy number variations or CNVs---- and 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.
The 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.
"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---- finding out that individual neurons in your brain have different DNA content."
The 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.
"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."
Interestingly, 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.
It 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. "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."
Spontaneously 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.
The 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.
Cells with different genomes probably produce unique RNA and then proteins. However, for now, only one sequencing technology can be applied to a single cell.
"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.
In addition, it will be necessary to sequence many more cells, and in particular, more cell types, notes corresponding author Ira Hall, 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.
INFORMATION:
Other 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, now at the Icahn School of Medicine at Mount Sinai in New York; Julia Piper, now at Harvard University in Cambridge, Massachusetts; Thierry Voet and Joris Vermeesch of the Center for Human Genetics, KU Leuven, Leuven, Belgium; Chris Cowing-Zitron of Salk's Laboratory of Genetics; and Roger Lasken of the J. Craig Venter Institute in San Diego.
This work was supported by the Crick-Jacobs Center for Theoretical and Computational Biology, the G. Harold & Leila Y. Mathers Foundation, the National Institutes of Health, the Leona M. and Harry B. Helmsley Charitable Trust, the JPB Foundation, and the Burroughs Wellcome Fund.
About the Salk Institute for Biological Studies:
The 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.
Faculty 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
Study finds a patchwork of genetic variation in the brain
Salk scientists find a surprising degree of variation among genomes of individual neurons from the same brain
2013-11-02
ELSE PRESS RELEASES FROM THIS DATE:
Results of the GIANT trial reported at TCT 2013
2013-11-01
Results of the GIANT trial reported at TCT 2013
Genetic profiling may provide clinical benefit by identifying heart attack patients that are resistant to blood thinners
SAN FRANCISCO, CA – October 31, 2013 – According to a new study, genetic profiling of patients undergoing ...
Percutaneous repair of valve leaks: A new treatment for patients at high risk of cardiac surgery
2013-11-01
Percutaneous repair of valve leaks: A new treatment for patients at high risk of cardiac surgery
PCI repair can mitigate known risks that accompany increases in implanted valves
MINNEAPOLIS, MN—October 31, 2013—A Paravalvular regurgitation, or leakage, ...
Results of the TATORT-NSTEMI trial presented at TCT 2013
2013-11-01
Results of the TATORT-NSTEMI trial presented at TCT 2013
Removing blood clots during PCI does not improve outcomes compared to standard angioplasty in patients with non-ST-elevation myocardial infarction
SAN FRANCISCO, CA – OCTOBER 31, 2013 – According to a new study, ...
Results of the REPRISE II trial reported at TCT 2013
2013-11-01
Results of the REPRISE II trial reported at TCT 2013
Second generation transcatheter aortic valve shown to successfully address complications of TAVR
SAN FRANCISCO, CA – THURSDAY OCTOBER 31, 2013 – In a clinical trial, a second-generation transcatheter aortic valve demonstrated ...
Experimental drug shows encouraging results in treating most common form of lung cancer
2013-11-01
Experimental drug shows encouraging results in treating most common form of lung cancer
An experimental cancer drug that has shown promise in the treatment of melanoma has also shown early potential as an effective treatment for patients with non-small ...
Oligomeric proanthocyanidin suppresses the death of retinal ganglion cells
2013-11-01
Oligomeric proanthocyanidin suppresses the death of retinal ganglion cells
The death of retinal ganglion cells is a hallmark of many optic neurodegenerative diseases such as glaucoma and retinopathy. Oxidative stress is one of the major reasons to cause the ...
Can Aβ worsen cognitive impairment following cerebral ischemia-reperfusion injury?
2013-11-01
Can Aβ worsen cognitive impairment following cerebral ischemia-reperfusion injury?
Amyloid β-peptide, a major component of senile plaques in Alzheimer's disease, has been impli-cated in neuronal cell death and cognitive impairment. Recently, studies ...
Low-frequency rTMS prevents chronic epileptic seizure
2013-11-01
Low-frequency rTMS prevents chronic epileptic seizure
Although increasing evidence indicates that low-frequency repetitive transcranial magnetic stimulation (rTMS), an emerging technology for neural regulation, has antiepileptic effects, the mechanism remains unclear. ...
Exposure to cortisol-like medications before birth may contribute to emotional problems and brain changes
2013-11-01
Exposure to cortisol-like medications before birth may contribute to emotional problems and brain changes
Reports new study in Biological Psychiatry
Philadelphia, PA, October 31, 2013 – Neonatologists seem to perform miracles in the fight to support the survival of ...
JCI early table of contents for Nov. 1, 2013
2013-11-01
JCI early table of contents for Nov. 1, 2013
Liver tropism is key for B cell deletion immunotherapy
Antibodies against the B cell surface protein CD20 have been used successfully to treat B cell-mediated autoimmune diseases and lymphomas. Antibody binding ...
LAST 30 PRESS RELEASES:
Less intensive works best for agricultural soil
Arctic rivers project receives “national champion” designation from frontiers foundation
Computational biology paves the way for new ALS tests
Study offers new hope for babies born with opioid withdrawal syndrome
UT, Volkswagen Group of America celebrate research partnership
New Medicare program could dramatically improve affordability for cancer drugs – if patients enroll
Are ‘zombie’ skin cells harmful or helpful? The answer may be in their shapes
University of Cincinnati Cancer Center presents research at AACR 2025
Head and neck, breast, lung and survivorship studies headline Dana-Farber research at AACR Annual Meeting 2025
AACR: Researchers share promising results from MD Anderson clinical trials
New research explains why our waistlines expand in middle age
Advancements in muon detection: Taishan Antineutrino Observatory's innovative top veto tracker
Chips off the old block
Microvascular decompression combined with nerve combing for atypical trigeminal neuralgia
Cutting the complexity from digital carpentry
Lung immune cell type “quietly” controls inflammation in COVID-19
Fiscal impact of expanded Medicare coverage for GLP-1 receptor agonists to treat obesity
State and sociodemographic trends in US cigarette smoking with future projections
Young adults drive historic decline in smoking
NFCR congratulates Dr. Robert C. Bast, Jr. on receiving the AACR-Daniel D. Von Hoff Award for Outstanding Contributions to Education and Training in Cancer Research
Chimpanzee stem cells offer new insights into early embryonic development
This injected protein-like polymer helps tissues heal after a heart attack
FlexTech inaugural issue launches, pioneering interdisciplinary innovation in flexible technology
In Down syndrome mice, 40Hz light and sound improve cognition, neurogenesis, connectivity
Methyl eugenol: potential to inhibit oxidative stress, address related diseases, and its toxicological effects
A vascularized multilayer chip reveals shear stress-induced angiogenesis in diverse fluid conditions
AI helps unravel a cause of Alzheimer's disease and identify a therapeutic candidate
Coalition of Autism Scientists critiques US Department of Health and Human Services Autism Research Initiative
Structure dictates effectiveness, safety in nanomedicine
Mission accomplished for the “T2T” Hong Kong Bauhinia Genome Project
[Press-News.org] Study finds a patchwork of genetic variation in the brainSalk scientists find a surprising degree of variation among genomes of individual neurons from the same brain