Genetic Variations Found In The Brain
November 4, 2013

Genetic Variations Discovered In Different Neurons Originating From Same Brain

redOrbit Staff & Wire Reports - Your Universe Online

While it was once believed that every cell in a person’s body contains the same DNA code, new research, led by experts at the Salk Institute, has found an unexpected level of variation among the genomes of different neurons originating from the same person’s brain.

Previously, it was assumed that the way in which a genome is read imparts cell function and ultimately defines the individual, but the authors of the new study report that this is an oversimplification when it comes to many different types of human cells. Many of the neuronal genome studies published over the past several years have discovered additional or missing chromosomes, DNA fragments that can be copied and pasted throughout a genome.

“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,” the Institute explained in a recent statement. Now, Mike McConnell, a former junior fellow in the Salk Crick-Jacobs Center for Theoretical and Computational Biology, and his colleagues used single-cell DNA sequencing to demonstrate that there is more variation in the genomic structure of individual neurons than previously believed.

As part of their study, which appears in the latest edition of the journal Science, McConnell’s team isolated approximately 100 neurons posthumously from three different individuals. They conducted a high-level view of the entire genome, looking for duplications and large-scale deletions of DNA known as copy number variations (CNVs). They found that up to 41 percent of neurons possessed at least one unique, massive CNV that had not been passed down from a parent, and that those variations were spread throughout the genome.

“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,” the Institute explained, adding that the researchers “found a similar amount of variability in CNVs within individual neurons derived from the skin cells of three healthy people.”

“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,” explained corresponding author Fred Gage, the Vi and John Adler Chair for Research on Age-Related Neurodegenerative Disease at the Institute. “A good bit of our study was doing control experiments to show that this is not an artifact. We had to do that because this was such a surprise – finding out that individual neurons in your brain have different DNA content.”

Generally, researchers use induced pluripotent stem cells (iPSCs) to study living neurons in a culture dish. Since these types of step cells are derived from a single skin cell, one might assume that their genomes would be identical, but the researchers discovered that they are not. In fact, according to Gage, there are multiple unique deletions and amplifications in the genomes of neurons derived from a single iPSC line.

Furthermore, the study authors found that the skin cells themselves have genetic differences, though they aren’t as exaggerated as the neurons. This discovery, when paired with the discovery that the neurons had unique CNVs, leads the investigators to conclude that genetic changes happen later in a person’s development and are not actually passed from parent to offspring.

McConnell, who is currently an assistant biochemistry and molecular genetics professor at the University of Virginia School of Medicine, said that it makes sense for neurons to have more genome diversity than skin cells because “unlike skin cells, they don't turn over, and they interact with each other. 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.”