How many chromosomes does it take to make a functioning cell?

Apparently, that's a more flexible number than one might suspect. In two recent papers, researchers from The Scripps Research Institute in La Jolla, Calif., and their colleagues at the University of California at San Diego, came to some surprising conclusions about the prevalence and functional consequences of mosaicism and aneuploidy.

Mosaicism is the existence of cell populations, each having different genotypes, in the same individual. It is most commonly caused by a snafu in cell division during development, which leads to a population of daughter cells with an extra copy of one chromosome or another, for a total of 47 instead of the usual 46.

Mosaicism of the X chromosome is a normal feature of female cells. In that case, the number of chromosomes is normal, but either the paternal or maternal X chromosome randomly is inactivated in each cell to prevent overexpression of proteins. But other than that, the prevailing wisdom is that mosaicism, when it does not cause the outright death of the affected cells, usually spells disease.

Regardless of the cell population, an individual cell that has the wrong number of chromosomes - in humans, anything other than 46 - is known as aneuploid. Systemic aneuploidy, or having the wrong number of chromosomes in every cell, most often leads to embryonic death early in development. But in those cases in which it is not fatal, such as Down and Turner's syndrome "systemic aneuploidies have a broad spectrum of outcomes," Jerold Chun, professor of neuroscience at Scripps, told BioWorld Today.

Chun said those differences might be due to mosaicism, or differences in the extent to which the extra chromosome copies are inactivated. His research also suggested that in the nervous system, both aneuploidy and mosaicism might be normal and fairly frequent occurrences.

In a recent anatomical paper, which appeared in the March 2, 2005, issue of the Journal of Neuroscience, Chun and his colleagues at Scripps investigated the frequency of neuronal aneuploidy in humans via fluorescent in situ hybridization, or FISH. The scientists studied samples of normal postmortem brains and analyzed the frequency of trisomy 21 cells. Chun and his colleagues chose to focus on trisomy 21 because it has a good control group available: samples from Down syndrome patients. Roughly 4 percent of the cells Chun and his colleagues studied showed aneuploidy. Trisomy was the most frequent form of aneuploidy, but they also found cells with either one or four copies of chromosome 21. The authors concluded that several types of human brain cells can be aneuploid and that the resulting mosaicism is a normal feature of the human brain.

A second paper appeared in the April 26, 2005, issue of the Proceedings of the National Academy of Sciences. The Journal of Neuroscience paper, which was based on analysis of postmortem human brain samples, could not determine whether the aneuploidy they observed had been in functional neurons. In the PNAS paper, Chun and his colleagues used a combination of anatomical studies, connection tracing and activation markers to determine in greater detail what sort of cells show one particular kind of aneuploidy - extra copies of male sex chromosomes - in mice.

The authors found strong evidence that aneuploidy is not limited to what Chun called "garbagy" cells; instead, they found about 0.2 percent of the cells they studied were both hyperploid for either the X or the Y chromosome, and active neurons that were part of functional circuits in multiple brain areas. The authors noted that even though that likely is a conservative estimate of the actual number of such cells, it is already substantially higher than the number of cells undergoing other "neurobiologically relevant phenomena," such as neurogenesis.

What's It Good For?

The functional consequences of aneuploidy are still completely uncharted territory, but Chun suggested a few logical possibilities that stem from the characteristics of neurons. "Neurons don't proliferate, so what else might they do? They could die, or they could become hyperactive," he said, noting that neurodegenerative diseases and epilepsy, respectively, would be consistent with such neural malfunctioning.

"If you look at the major neuropsychiatric diseases, they are all sporadic, and they are broad in presentation. You can't peg them to a specific gene, and even when you can identify genes and familial cases, those only account for a small percentage of cases - maybe 5 percent in ALS and 10 percent in Alzheimer's. So 90 percent or more of the cases are sporadic - why is that? Perhaps mosaicism is part of those diseases," Chun said.

He suggested that an increase in the number of neurons that are aneuploid for specific chromosomes in a given disease could give valuable clues to the underlying biological mechanisms behind it.

Chun also pointed out that depending on just how wildly one is willing to speculate, differences in aneuploidy could be one mechanism for individual differences in health, as well as disease. "If you look at the population, we are not identical," Chun said. "So where does that come from? The standard answer is that it's in the environment and the genes. Well, maybe this is another mechanism."