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Size Isn’t All That Matters

July 23, 2013

Stressed people can lose a marble or two, stressed cells lose a chromosome instead.

Sometimes the pressures and stresses of everyday life can make some people go a little crazy…they lose a few of their marbles.  The same thing can happen to a cell too.  The only difference is that instead of losing their marbles, cells can lose their chromosomes!

There are all sorts of mechanisms in place to make sure that a cell has just the right number of chromosomes.  Still, sometimes all these systems fail and a chromosome is lost.  This can be catastrophic for a cell and, as an important part of cancer, catastrophic for the whole body too.

Given how important having the right number of chromosomes is, it is surprising how little we know about what makes a particular chromosome more likely to fly the coop.  Kumaran and coworkers set out to change this in their new study in PLOS ONE.

First off, they showed that some chromosomes in S. cerevisiae are indeed more likely to be lost than other ones and that there was a surprisingly wide range of stabilities.  For example, chromosomes XIII and XIV were thousands of times more stable than chromosome III.

One key factor in stability was chromosome size—the smaller the chromosome the more likely it was to be lost.  But chromosome III showed that size was not the whole story.  It was five times more likely to be lost than the smallest chromosome.

The authors next set out to determine what about chromosome III made it so flighty.  By creating a hybrid of chromosomes III and IX, they were able to show that there was no single site that made chromosome III so unstable.  They were also able to rule out the idea that HML, HMR, and the MAT locus made chromosome III more likely to be lost.

They next focused on the centromere because it is such an important player in chromosome segregation.  They created a series of plasmids using the centromeres from chromosomes III, IX, XII, XIV, and XV and found that the ones from chromosome III and chromosome XV were around 5-fold less stable than the other chromosomes. While they do not have a good explanation for why chromosome III and XV fared the same in their assay, the result did suggest that at least part of the instability of chromosome III could be explained by its centromere.

As a final experiment, they determined the frequency of chromosome loss in mad2 deletion mutants.  They did this because MAD2 is involved in the spindle checkpoint and so is a key mediator of chromosome stability.  They found that deleting this gene significantly increased the loss of other chromosomes, but chromosome III was 3-6 fold less affected by the loss of MAD2.  It was almost as if the centromere of chromosome III was already somewhat compromised for its interaction with the spindle.

The authors aren’t sure yet how chromosome III got to be so unstable. It could be that random mutations just made its centromere less effective. But another interesting possibility is that it might be under selective pressure. Carrying the mating type loci, chromosome III could be considered to be equivalent to a sex chromosome in larger eukaryotes, and we know that those chromosomes are under different evolutionary constraints from other chromosomes. Maybe S. cerevisiae just can’t take the pressure!