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Nov 4, 2013

Brain Cells a Mixed Bag, Genetically

  • Scientists using single-cell genomics have found that human neurons display a surprising degree of genetic diversity. This finding reinforces recent studies of neuronal genomes that have revealed extra or missing chromosomes, or pieces of DNA that can copy and paste themselves throughout the genomes. Moreover, it suggests that a simplified view of a cell’s individuality—the idea that each cell has the same DNA as other cells but differs because of how its DNA is read—exaggerates the degree of perfection attained by our genes.

    The finding that somatic mutations are abundant in the human brain was made after researchers at the Salk Institute 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% 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.

    “Contrary to what we once thought, the genetic makeups of neurons in the brain aren’t identical, but are made up of a patchwork of DNA,” said Fred Gage, Salk's Vi and John Adler Chair for Research on Age-Related Neurodegenerative Disease.

    Gage is corresponding author of a November 1 paper in Science, “Mosaic Copy Number Variation in Human Neurons.” Besides obtaining neurons from postmortem human brains, the authors of this paper looked at neurons derived from human induced pluripotent stem cell (iPSC) lines.

    The investigators found a similar amount of variability in CNVs within individual neurons derived from the skin cells of three healthy people, even though the skin cells themselves did not show nearly as much variability 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,” said research collaborator Michael McConnell, who is now an assistant professor of biochemistry and molecular genetics at the University of Virginia School of Medicine. “The thing about neurons is that, 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.”

    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.

    Speculating on the effects of somatic genome diversification on neuronal function, the authors suggested a straightforward hypothesis: Neurons with different genomes will have distinct molecular phenotypes because of altered transcriptional or epigenetic landscapes. The authors expect that ongoing development of single-cell technologies will allow for this hypothesis to be tested by measuring multiple states of the same neuron (for example, the genome and the epigenome, transcriptome, or proteome).



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