Friday, November 8, 2013

Comparison of DNA Between Single Brain Cells Reveals Surprising Variation, A Stem Cell Study Finds

“Many concepts I learned as a student are no longer true today or have drastically changed”, so said my molecular biology professor when I was an undergrad. If I met up with my prof again today I’d say, “ain’t that the truth”. A perfect example of the ever-changing nature of scientific knowledge is a report published last Friday in Science by Salk Institute researcher Fred Gage and his collaborators (visit our website to learn about Gage’s CIRM-funded research).

Their results as well as other data over the past decade muddy up a fundamental notion about our genetic makeup: that all cells of our body, with a few exceptions, have the same DNA sequence. This would seem to make sense. We were each a single-celled embryo at one point in time. As that cell divided over and over to form our bodies, each new cell received identical copies of DNA stemming from the embryo. The only difference from cell to cell, I was taught, was that specific regions of the DNA were activated in different types of cells, which contained instructions for making proteins necessary for that particular cell type. For example a hair cell would have genes active to make hair.

But this theory turns out to be too simple because Gage and collaborators show that many human neurons in the brain have significant differences in their DNA sequences. Gage summarized their result in a Salk Institute press release:
"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."
To arrive at that finding, they analyzed two cell sources: neurons from three postmortem human brains and neurons derived from the skin cells of three people. The scientists converted those skin cells into induced pluripotent stem cells and then matured those into neurons in a lab dish. Using cutting-edge instruments, they compared the DNA sequences of the single cells.

The team found large deletions and duplications of DNA within both sources of neurons. In the human brain neurons up to 41% of the neurons had at least one large rearrangement. Each cell also had a unique pattern of rearrangement, which indicates the variations occurred sporadically and weren’t just inherited from a parent. Individual neurons made from skin cells also showed large rearrangements. The skin cells used to derive the iPSCs also had rearrangements, but these were consistently smaller in size than the DNA changes that showed up in the neurons. Also, deletions of DNA were only found in the iPSC neurons and not the skin cells.

So what does all this genetic variation in the brain mean? No one really knows at this point. Perhaps the variation could be linked to neurological diseases. On the other hand some functional benefit may be gained from the genetic diversity. First author Michael McConnell added this possible explanation in the press release:
"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."
Analyzing more neurons is clearly needed to better grasp the significance of the brain’s genetic patchwork and the role the variation plays in diseases of the brain. Although CIRM didn't fund this work, as scientists learn more it may inform some of the iPSC disease-in-a-dish CIRM-funded research that Dr. Gage and others are actively pursuing as a way of developing new therapies for neurological diseases.

Whatever the case, be ready for future jolts to our understanding of human biology.

Todd Dubnicoff

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