Females are mosaics: the silenced X

The science discussed in this programme was first hypothesised by English geneticist Mary Lyon. The idea is, that the way females deal with having two X chromosomes leads to this mosaic effect; that one cell in one part of the body might be relying on one of the Xs, but its neighbour might be relying on the other, and so on repeated across every part of the body. It’s a baffling subject, and one whose consequences have fascinated geneticist Barbara Migeon . She’s author of the book ‘Females are Mosaics’, and she took Phil Sansom through what that phrase actually means....

Barbara - Women have two X chromosomes, whereas males have only one, because of the way we determine sex. And for reasons understood only because we never see anybody who has two functional X chromosomes, it has to be compensated for in some way.

Phil - You're saying two X chromosomes is sort of too much X chromosome?

Barbara - It is. I can't tell you why, but empirically we know that it is. And individuals who express too much of the X chromosome have congenital abnormalities. And so we know that it's an abnormal situation.

Phil - So what happens? How does the body compensate?

Barbara - During embryonic development, very, very early, one of the X chromosomes in every one of her cells is turned off, is silenced. It stays there, but it doesn't work. Chromosomes are transcribed into RNA and into protein, and it doesn't get transcribed at all.

Phil - How does that happen then? How does the cell decide "I'm going to shut this one off and keep this one running"?

Barbara - We don't know all the answers to that question yet. We do know a lot about how to turn off a chromosome. There is a gene on the X chromosome that encodes an RNA, not a protein like most genes encode, that stays with the chromosome. It spreads up and down the chromosome, and then it attracts all kinds of factors that will tend to turn the genes off.

Phil - Almost like a chromosome self-destruct button!

Barbara - It is like that.

Phil - But without the destruction...

Barbara - Yes, but it is a very potent gene. If you take that gene and put it into any other chromosome, it will inactivate that chromosome as well. So it's a very potent chromosome inactivator. It's called Xist, which is an X inactivation specific transcript.

Phil - If it's that powerful, how come both the Xs don't immediately get shut down?

Barbara - Well, that's the question I have. I think it's a terribly important question. It seems that there has to be some way to repress that particular gene Xist. Studies are in progress to try to identify how that happens.

Phil - Now, I want to talk about the consequences of one X being silenced, because I know Barbara you've written this book, Females are Mosaics. Can you talk on that please?

Barbara - Well a mosaic is pieces of glass together and you create a mosaic individual. Biologists use it to mean a mixture of cells. And females are mosaics because they have a mixture of cells, each expressing a different X chromosome. Some of the cells express the chromosome from the mother, other cells express the chromosome that comes from the father. And the genes on the father's X differ sometimes considerably from those on the mother's X.

Phil - Are females really then made up of two groups of cells, which can do different things, in a way that males just aren't?

Barbara - Yes, that's true. The only males that do the same thing are those that have an extra X chromosome like those with Klinefelter syndrome.

Phil - What's Klinefelter syndrome?

Barbara - Klinefelter syndrome is a syndrome of generally infertile, tall men who have two X chromosomes and a Y chromosome. Because they have two Xs, only one of them is expressed exactly like in women.

Phil - So like females, the Klinefelter males, they also have a bit of a lucky break in case there's some sort of defective mutation?

Barbara - Yes, exactly. Equally well as human females do in that regard.

Phil - Can you give me an example? Cause I'm just struggling to get my head around how something that broad can have like a specific effect on something like a disease.

Barbara - I think muscular dystrophy, that's an easy one because there are genes on the X chromosome that cause muscular dystrophy. Very few females have muscular dystrophy because they have a second X chromosome that can provide the gene product that is missing from the other.

Phil - What if though, the cells that get the muscular dystrophy, cause you said one of the Xs got silenced, but the other was still active. What if they accidentally have the active bad version of the gene?

Barbara - Well, 50% of normal product seems to be enough in many cases to protect the female from a problem. In other cases, the cells don't do as well as the normal cell and so that they will grow more slowly and they eventually get overgrown by normal cells.

Phil - So one population of cells can really protect the other in a bunch of different ways. They can either provide enough of a missing protein, or just overpower the defective cells in certain places?

Barbara - It's exactly right. Yes. I think it's marvelous that that kind of therapeutic effect occurs in females when they're not aware of it at all.

Phil - Normally for someone female, is it like some kind of modern art painting where there's great big swabs of colour, all in groups alongside each other? Or is it more like some sort of Jackson Pollock where there's a lot of tiny little dots nestled alongside each other?

Barbara - Well, it depends on the tissue you look at. If you look at brain, it's more like tiny little dots next to one another. But if you look at placenta, for instance, it's big patches of colour.

Phil - And we've talked about muscular dystrophy. In the grand scheme of all the health problems that a person can have, how big a role does this mosaicism play? How broad are the effects?

Barbara - Well, there are something like a thousand genes on the X chromosome. The effect of these genes on women's health is fairly tremendous, I think. Most people attribute differences in expression of disease to either the hormone differences between males and females, or life experiences. Males tend to be more dangerous and often get into situations that women would not. However, I think that the X chromosome inactivation plays a more important role than any of those. The fact that women are mosaic is very protective. And we know that because from the time of implantation, when the foetus is implanted in the uterus, to the end of life, 20% more males die at every stage. And in the end, we end up with many more females by the age of 75 to 80, more females start to die, because they're the only ones that are left. The variety of cells gives us a variety of gene products that can interact and help. Even when both genes are not defective. Women need to realise that they do have a biologic advantage that enables them to do even better than males do under certain circumstances.

Phil - You know what? You've convinced me, Barbara. Sign me up for an extra X chromosome. It sounds great!

Barbara - Yeah. So if you can get one I would try to! But you don't want Klinefelter syndrome.