X Chromosomes and Choices

The crux of the matter.

Humans have two versions of each chromosome — one inherited from each parent — with one exception: Men don’t have two X chromosomes. Instead, they have an X and a Y. The (few) genes on the Y chromosome are what make a man develop into a man.

But what makes a woman a woman, rather than the presence of two X’s, is the lack of a Y. A woman’s cells don’t need the extra X, and in fact, if the genes on both X chromosomes of a woman’s cell were just as active as those on a man’s single X, the cell would probably die.

This presents women — in fact, females in all placental mammals — with a problem: to be healthy, their cells must completely shut down one, and only one, of their X chromosomes. Geneticists have discovered in recent years that the shut-down happens in the early-embryo stage, and that when cells duplicate, the daughter cells will keep the same version of the X shut down.

Also recently, geneticists have noticed that the choice of which chromosome to shut down is entirely random. The shut-down however happens several duplications after the egg is fertilized, so that not all cells in the developed organism will silence the same X. If you are a woman, some of your cells express your father’s X genes, while some express your mother’s.

The easy way of doing this could be to make each X chromosome shut itself down with 50 percent probability. If you do the math, though, you quickly realize that this is a pretty dumb solution. If each chromosome in each cell has a 50 percent chance of shutting down, the results are similar to what you get from tossing two coins simultaneously: you have a 25 percent chance of both shutting down, a 25 percent chance of both staying active, and only a 50 percent chance of achieving your objective — one shut down, one active. Trouble is, in this way 50 percent of cells would quickly die during the embryo’s development, either because they have two active X’s or because they have none. That would be very inefficient. It doesn’t seem likely that embryos need to toss out half of their cells.

But how does a female embryo know that it has two X’s, and that it needs to shut down exactly one of them? And how does a male embryo, for that matter, know that it is a male, so that it won’t end up shutting down its only X? This problem has puzzled geneticists for a while. According to a paper to appear in next week’s Physical Review Letters, nature may have found an elegant solution.

According to Mario Nicodemi and Antonella Prisco, the two Italian biophysicists authors of the research, a random process leads certain proteins to spontaneously aggregate and determine which of the two X chromosomes in a cell will remain active, and which one will stay completely shut down.

An X chromosome silences itself by wrapping itself up in a goo of an otherwise useless kind of RNA (“non-coding” RNA, i.e., which doesn’t translate into any protein), inhibiting the expression of all of its genes. A “suicide gene” located on the X itself, called XIST, is what produces the RNA goo.

A recent paper has proposed that an X remains active when certain proteins aggregate at a specific spot on the chromosome, forming a complex that latches onto the “suicide gene” XIST and prevents it from doing its job.

But it remained unclear how such proteins would aggregate around one of the chromosomes, but not around the other — an example of what physicists call spontaneous symmetry breaking. In general, if you produce proteins that tend to bind to each other into complexes, it’s hard to control exactly how many complexes will form.

The Italians describe how this could be physically possible, using the mathematics of randomness and Brownian motion. Their model relies on a key discovery published last March in Nature Cell Biology, 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, Nicodemi and Prisco show, there is a high probability — more than 90 percent, Nicodemi says — that exactly one protein complex would form in the vicinity of the two chromosomes. “If the binding energy is high enough, only one complex will form instead of several,” Nicodemi says.

The complex will quickly bind to one of the X’s, the model predicts, shutting down the XIST gene and thus saving the chromosome from being silenced.

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. In females with more than two X’s — a rare genetic syndrome — the process would still allow for a single X to stay active.

A similar mechanism could also be at play in a phenomenon called random monoallelic expression. Apart from the case of the X and Y, both males and females have two versions of each chromosome, one from each parent. The corresponding genes, known as alleles, may both be active or inactive, depending on the tissue and the stage of development. However, in recent years geneticists have discovered numerous cases in which exactly one of the alleles is chosen randomly to be kept active, while the other one is shut down. Nicodemi says that their model could potentially explain also this type of spontaneous symmetry breaking.

Read my article in Physics News Update


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