Female Mosaicism: The Stronger Sex?

15 July 2020
Presented by Phil Sansom
Production by Phil Sansom.

MOSAIC

Blue and white mosaic tiles.

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The same thing that makes the patchwork colours on a tortoiseshell cat, also - according to some - is why human females live longer, see colour better, and even more often survive the coronavirus. It's all thanks to having two X chromosomes. Females compensate by switching one of them off, and the result is two distinct groups of cells in the body, each preferring one of the two X's. Welcome to the weird world of female mosaicism...

In this episode

Stylised illustration of X chromosomes.

02:01 - Females are mosaics: the silenced X

The way females deal with having two X chromosomes leads to a mosaic effect across the body...

Females are mosaics: the silenced X
Barbara Migeon, Johns Hopkins University

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.

A mosaic with a female figure.

12:60 - How females get a biological advantage

Between extra genes and two families of cells, female mammals get a leg up in many different ways...

How females get a biological advantage
Sharon Moalem

In mammals, females have two X chromosomes whereas males have one, and females compensate by ‘switching off’ one of them while still an embryo. But for each cell, the X that gets switched off is random - so an adult female is a melting pot for two different families of cells. This is the subject of a recent book by geneticist Sharon Moalem, called 'The Better Half: On the Genetic Superiority of Women'. He explained to Phil Sansom that not only does this mosaicism help females in loads of ways, but that it's more complicated: some of the genes from the ‘switched off’ X chromosome somehow survive the switching off, through a mechanism that’s not yet understood, and go on to help out even further…

Sharon - The dogma around this was, for many years, that having two X chromosomes, that they only predominantly use one, that one was shut down early on in development. What we're discovering right now is not only that females are made up of two populations of cells that are cooperating, but actually within the individual cells, females have access to about 25% of the so-called silenced X. So what that actually means is another 250 genes. It's much more genetic horsepower, so to speak, in every female cell compared to male cells. And many of those genes are involved in the prevention of cancer, in immunological function, in the building and maintaining of a human brain. So although having an extra 1000 genes overall to use might not sound that significant, because we have about 20,000 genes, these genes are crucial.

Phil - So what you're saying is that for all the cells in a woman's body... they all have two X chromosomes and where previously everyone thought, "oh, one of those X chromosomes just isn't doing anything," now you're saying actually some of that X chromosome is doing stuff, and that's adding extra genetic material. But not only that - of all the cells in that woman's body, some of them are oriented such that they use one of the X chromosomes and a little bit of the other, and some of them are oriented that they use that other X chromosome and a little bit of the first one. Is that right?

Sharon - Yeah, exactly. And so having those two populations of cells, the other thing that's happening is they're not actually just behaving independently. They're sharing genetic information and proteins and tools across populations. If a baby's born and their brain doesn't receive enough oxygen, if certain cells in the brain are using the X from the mother that have genes that are better suited for low oxygen conditions, those cells then can take over and start dividing in the brain, and then provide the necessary genetic and cellular material to help the baby grow to survive. And that's actually what we're seeing. We're seeing that whatever the insult that's experienced throughout life, females really are able to overcome and survive. Until very recently we viewed this as females just having a 'spare', almost like a spare tire that they can swap in. The example that most people may be familiar with is colourblindness. The three genes for colour vision - two of them are on the X chromosome. In males, if one of those two genes has a mutation on it, they drop down from being able to differentiate between 1 million colours to about 30,000. Females then - their rate of colourblindness is only 0.1%. But because females have these two populations of cells working in the back of the retina, the cells are cooperating. So it's not just that females have a backup; females, we've just discovered, have the ability for something called tetrachromatic vision. And so instead of having just normal vision, these women are thought to be able to see 100 million colours instead of the normal 1 million.

Phil - That's unbelievable! How recently known about is this science? How recently discovered is this?

Sharon - Really just in the last handful of years. Once you understand the implications it really becomes mind blowing, because what we're saying is then that everywhere you look in a female - be it her heart, her skin, her immune system - there's really two populations of cells that are cooperating. And it really also helps to explain why males have this biological fragility. Because unfortunately, even though myself as a genetic male, I may be physically strong, I may have more physical power, but biologically I am more fragile because every one of my cells has only one X. Wherever you look in my body, every one of cells has to rely on that one X. If there's any issue with any of those genes that I've inherited, I'm going to be in trouble when it comes to survival.

Phil - What about the Y chromosome though? Doesn't that help to have that extra little bit of genetic material?

Sharon - It does. Again, it gives me my upper body strength. But when it comes to survival the Y is a very slim addition to our genome. It has around 70 genes on it; of those, many are involved in sex development, and some of the other genes are involved in the making of sperm. And so it becomes apparent why males are the weaker sex. Although we've ascribed female surviving into old age... I was taught in grad school and in medical school that the reason really is behavioural. Women don't take risks; they don't smoke or drink. And yet when you look at early on in life - and this is what happened to me when professionally I switched to taking care of babies that are born premature in the neonatal intensive care unit - I saw the same survival advantage. And of course it's not behaviour; baby girls or baby boys sitting in the incubator are not taking up smoking or drinking, or riding a motorcycle without a helmet. What's driving that survival advantage? And when it comes down to it, having an extra 1000 genes really makes that difference. These are fundamental differences at the biological level. And so when we look at data regarding the coronavirus and the sex mortality, again, we see men dying at the rate of two to one.

Phil - This all sounds just mad and bizarre though - to imagine that someone has two symbiotic types of cells in every part of their body. How can you even tell?

Sharon - That actually, interestingly enough, has been some of the challenges in doing this work. Because to find out what percentage the populations of cells are, you actually need to sample the tissue. So if you're looking in the blood and you're looking at immune cells, that's more accessible because you can just take a blood sample. The challenge of course is that you can't access the brain that easily - I can't go around sticking a biopsy needle into people's brains to try to get out samples - but what we know at least from animal models, and also from tissue samples from people when we do have access to them, is that the population of cells and females that are using one X over the other is dynamic, meaning it actually changes over time. In the book I give this example of an unfortunate incident that my wife and I experienced. We were in a pretty horrific car accident where we were really lucky to be alive. And we ended up with very similar injuries, and she did actually much better than I did when it came to infections and her wounds healing. And that's because when it comes to the skin, for example; again, the skin starts out, on a woman's body, 50% of skin cells are using the X from the mother, and on average 50% are using the X from the father. But when an injury happens and wound healing needs to take place, it seems that the one cell population that's using the X that can heal much faster, that cell population starts dividing a little faster. And so in the wound area, you might end up with 90% of the cells using the X predominantly from the mother, which say was better for wound healing. And the same thing is happening in the immune system. If one population of cells in a female is better at fighting a certain pathogen, bacterial or viral, that will take over and be the predominant cell at 80 or 90%. And this happens within minutes or hours of the initiation of an infection. And this dynamic mosaic of these different groups of cells and females could be different in every organ in her body.

Phil - Is that what's going on in the context of something you mentioned earlier, with the coronavirus, the fact that men seem to be hit much harder than women?

Sharon - Yes. The current pandemic is an unfortunate example. This is a prediction that I made in my book; I wrote it long before the pandemic happened, and I predicted the next time that we would see a microbe unfortunately take its toll on human populations, we'd see increased male mortality. And the reason is actually multifactorial. One that you mentioned is the immune system. So we know that females have a much more aggressive immune system. It's not only the fact that they have two populations of cells; female sex hormones, oestrogen, stimulate the immune system, it makes it their immune cells much more aggressive. Testosterone, for example, inhibits the immune system, it does the exact opposite. Then we look at the immune cells and we say, all these extra genes that females can bring into play is another example. And even if we look at the gate or the lock on our cells that the coronavirus unlocks -ACE2, it's a protein that sits on the cell surface - that gene is found on the X chromosome. So that means that both your and my cells are all using the identical ACE2 from the X that you inherited from your mother and that I inherited from my mother as well. If we encounter a coronavirus that has a spike protein that can unlock that ACE2, all our cells will unlock equally and we'll be in trouble. And yet when you look at females, 50% of their cells will be using one version of ACE2 and 50% will be using another. So the coronavirus has to have a key that can pick both locks, ACE2, equally in females. And that's an advantage that then females have over men as well. Females are doing better in the ICU as well, post infection. And again, having those two populations of cells, having all that extra genetic material coming to bear is what's allowing females to walk out and recover from the ICU. And unfortunately males, not having those genetic options, are succumbing in such higher numbers.

Phil - It's not a hundred percent good though, right? Because there are some disorders that are linked specifically to the X chromosome. I'm thinking Fragile X syndrome, I'm thinking Rett syndrome...

Sharon - Yes. Rett syndrome is actually a really good example. Some people have given Rett syndrome the moniker of like a female autism, because it's a genetic syndrome that's linked to a gene on the X chromosome, and so we thought that it only happens in females because we only saw females that were affected. And yet, as it turns out, that's not the case. The reason that we don't see any males is because for the most part, Rett is actually lethal to males in utero! So the males aren't even strong enough to make it to birth with Rett syndrome. And yet we thought of this as a female-only condition because we only really saw females with Rett syndrome. But when you talk about, what are the costs of having two populations of cells; what is the big cost of having an aggressive immune system and these violent immune cells that females have; the cost really is an increased risk of auto-immunity for almost every autoimmune condition that we know of. And so if it's lupus, it's nine females for every male; multiple sclerosis, rheumatoid arthritis, pretty much right across the board. Again, this makes sense. It's not just because female cells are more aggressive - that plays a role - but one of the driving forces, I believe, behind it comes back again to the reason that females have a survival advantage of the first place. And that's because females are made up of two populations of cells that are using different X chromosomes. So if an immune cell is looking to see if cells are infected with viruses, or perhaps have they become malignant; and let's just say that immune cell encounters a cell in the joint that is predominantly using the X from the other parent. It might think that that joint cell is foreign and unfortunately attack it. And when that process begins, you get so-called friendly fire, you get the immune system attacking itself. And unfortunately that's why women really bear the brunt of autoimmunity. And yet even when you look at autoimmune conditions, when you compare men and women, say, who have multiple sclerosis, women have elevated risk for it, but they have better outcomes in these autoimmune conditions predominantly over men. And that's because generally women having two populations of cells can deal with challenges, even if those challenges were self-induced through autoimmunity.

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