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Brain cell genomes show their individuality


If the human brain — with 100 billion neurons forging trillions of connections — were not complicated enough, research now suggests that every neuron may have its very own genome.

A study of the genomes of individual human neurons created from reprogrammed stem cells reveals huge variability between neurons from the same person. Such variation could explain differences in behaviour and susceptibility to mental illness, says Mike McConnell, a stem-cell biologist at the Salk Institute in La Jolla, California. He presented the work on 13 November at the Society for Neuroscience conference in Washington DC.

“Monozygotic twins can, from time to time, be discordant for things like schizophrenia, for things like autism. They grew up together. They have the same genome, why are they different,” he says.

McConnell has been exploring this phenomenon for more than a decade. In a 2001 paper, he and his colleagues found that individual mouse cells destined to develop into neurons contain substantial chromosomal changes called aneuploidy. A few years later, he showed that neurons with these changes are active in the mouse brain.

Because humans are born with most of the neurons they will use throughout life, genetic variability among them could have a long-lasting effect on how people behave, McConnell says.

To see whether human brain cells are genetic mosaics, McConnell turned to induced pluripotent stem (iPS) cells. They are created by treating adult cells with a suite of reprogramming factors that transform the cells into an embryonic-like state in which they can form other tissues. His team transformed iPS cells from two people into neuron cells and then examined the genomes of individual neurons, looking for places where a huge chunk of the genome is missing or duplicated.

No brain cell’s genome looked the same. They all contained numerous duplications and deletions, but never in the same pattern. The team also examined the genomes of the adult cells that were reprogrammed into iPS cells and then neurons, and these cells contained numerous insertions and deletions, but not the same ones as the neurons. McConnell says that this suggests that cells acquire their own genomes as they turn into neurons.

Right now, McConnell can only speculate on whether these changes might influence behaviour. But he is eager to go looking for signs of genetic mosaicism in real human brains, as well as reprogrammed neurons from people with conditions such as schizophrenia.

The sorts of genetic changes he found in the mosaic neurons — deletions and duplications — have been linked, in rare cases, to neuropsychiatric and neurodevelopmental diseases such as schizophrenia, bipolar syndrome and autism. Geneticists discovered these mutations in the germ lines of people with these conditions, meaning that every cell in their bodies contains the mutations. But McConnell hypothesizes that these mutations could also form in individual neurons in the developing brain.

Meanwhile, a paper published last month in Nature helps to explain how human neurons might develop their own genomes. Researchers discovered that the genomes of human brain cells are rife with genetic sequences called transposons that ferry themselves around the genome, sometimes interrupting genes. McConnell says that one kind of transposon, called LINE, is activated by a pathway important in neuron development.

Add to these observations the overwhelming evidence that epigenetic modifications influence traits such as obesity, or the suggestion that the sequences of many genes are subtly altered after being transcribed, and you get the sense that organisms are not content to stick with the genome they were born with.

Image courtesy of ethermoon under Creative Commons


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    Michael Chisnall said:

    One of the conclusions of studies like this – and the Bruder et al study a few years ago on somatic copy number mosaicism – is that twin studies are not an accurate measure of the geneticness of any given disorder or trait. Nature recently published a set of features on autism for example which repeated the well known claim that twin studies show that autism has an environmental component. They don’t. What they show is that there is a component that isn’t inherited. That component could be environmental but as this result and others show it could also be genetic. Indeed some studies have suggested that as much as 90% of autism may be genetic and yet, many years ago, Nature had a feature quoting Susan Folstein as claiming that roughly 10% of people with autism showed evidence for mosaicism, which wouldn’t be picked up in a twin study despite being genetic. Its possible therefore that autism may be much more strongly genetic that hinted at by twin studies.

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