Fight Aging!

Researchers are now able to compare the mutational damage to nuclear DNA in individual long-lived cells such as neurons, which is a step towards measuring how much of this damage there is and how it varies over time and from cell to cell. That in turn is a step towards getting a handle on whether or not this damage has any meaningful effect over the course of a human life span beyond raising the risk of cancer. For example is the presence of stochastic mutational damage causing large enough alterations in the day to day operation of metabolism across enough cells to matter? There is some debate on this issue, and certainly a lack of good enough data to nail down a proof one way or another.

A single neuron in a normal adult brain likely has more than a thousand genetic mutations that are not present in the cells that surround it, according to new research. The majority of these mutations appear to arise while genes are in active use, after brain development is complete. "We found that the genes that the brain uses most of all are the genes that are most fragile and most likely to be mutated." It's not yet clear how these naturally occurring mutations impact the function of a normal brain, or to what extent they contribute to disease.

Cells of many shapes, sizes, and function are intimately intertwined inside the brain, and scientists have wondered for centuries how that diversity is generated. Scientists are further interested in genome variability between neurons due to evidence that mutations that affect only a small fraction of cells in the brain can cause serious neurological disease. Until recently, however, scientists who wanted to explore that diversity were stymied by the scant amount of DNA inside neurons: Although researchers could isolate the genetic material from an individual neuron, there was simply not enough DNA to sequence, so cell-to-cell comparisons were impossible. However, technology has become available in the last few years for amplifying the full genomes of individual cells. With plenty of DNA now available, the scientists could fully sequence an individual neuron's genome and scour it for places where that cell's genetic code differed from that of other cells.

The scientists isolated and sequenced the genomes of 36 neurons from healthy brains donated by three adults after their deaths. For comparison, the scientists also sequenced DNA that they isolated from cells in each individual's heart. What they found was that every neuron's genome was unique. Each had more than 1,000 point mutations (mutations that alter a single letter of the genetic code), and only a few mutations appeared in more than one cell. What's more, the nature of the variation was not quite what the scientists had expected. "We expected these mutations to look like cancer mutations, in that cancer mutations tend to arise when DNA is imperfectly copied in preparation for cell division, but in fact they have a unique signature all their own. The mutations that occur in the brain mostly seem to occur when the cells are expressing their genes. To what extent do these mutations normally shape the development of the brain, in a negative way or a positive way? To what extent do we have a patch of brain that doesn't work quite right, but not so much that we would call it a disease? That's a big open question."

Link: http://www.hhmi.org/news/study-examines-scale-gene-mutations-human-neurons