Spontaneous Symmetry Breaking in Women's Genes

A spontaneous aggregation of proteins randomly determines which of the two X chromosomes in a woman's cell will remain active, and which one will stay silenced, according to a new physical model.

In all placental mammals, the females of the species have two versions of the X chromosomes while males have just one X, plus a Y chromosome. To avoid overexpression of X-chromosome genes, female cells must virtually shut down one of their X's. X chromosomes are able to wrap themselves up in a goo of RNA -- produced by one of their genes, called XIST -- inhibiting the expression of all of their genes.

But until recently, it was not known how a female's cells know that they have two X's, how they choose which one to shut down, or how they keep exactly one active. Experiments in mice -- the results presumably apply to other mammals -- have shown that during early development, each embryo cell has a 50-50 chance of shutting down one X or the other.

Recently it has been proposed that an X remains active when certain proteins aggregate at a specific spot on the chromosome, shutting down its "suicide gene" XIST. But it remained unclear why proteins floating in the nucleus would aggregate around one of the chromosome, but not around the other -- an example of what physicists call spontaneous symmetry breaking.

Now an upcoming paper in Physical Review Letters describes a statistical-mechanics model for the proteins' aggregation that would explain this phenomenon. The model relies on a key discovery published last year, namely that in females the two X chromosomes line up next to each other right at the time when one of them is due to be silenced. For a critical value of the protein's binding energies, the authors show, there is a high probability that exactly one aggregate will form in the vicinity of the two chromosomes. The aggregate will quickly bind to one of the X's, shutting down its XIST gene and thus preventing the chromosome from silencing itself.

The model also explains how cells would "count" their X's. In males, the protein complex would only have one chromosome to bind to, so it would save the single X from self-silencing. On non-sexual chromosomes, a similar mechanism could also determine which of two versions of certain genes is expressed and which one is silenced.

Nicodemi and Prisco, to appear in Physical Review Letters
Mario Nicodemi
University of Naples "Federico II"
Mario.Nicodemi@na.infn.it

Also see:
Na Xu et al., Science, 24 February 2006
Bacher et al., Nature Cell Biology, March 2006
Donohoe et al., Molecular Cell, January 12, 2007