The human body is made up of trillions of cells. Every one of them has genetic information stored in packages known as chromosomes, explaining to our bodies how to build themselves up from the subtlest hormones all the way up to skin and bone. We have forty-six chromosomes in total, split into twenty-three pairs, and the roots of the genetic differences between men and women lie in our twenty-third pair, known as the sex chromosomes. In women, they’re called XX, with one X chromosome inherited from each parent. Men’s sex chromosomes are called XY, with the X coming from the mother and the Y from the father. For a long time it was assumed that these sex chromosomes were mainly concerned with reproduction and not much else. Today some scientists, including Arnold, believe that the consequences of this seemingly tiny genetic difference may stretch much further.
Every chromosome in a pair carries the same genes in the same locations, known as alleles. The one for eye colour from a person’s father, for example, will be matched by another one for eye colour in the same place from the mother. That’s true of a female’s two X chromosomes too. For males with XY sex chromosomes, however, a matching allele isn’t always there. X and Y don’t have the same genes in the same locations. In fact, the Y is far smaller than the X.
Having just one copy of the genes on the X chromosome can have repercussions for a man’s body. ‘It’s long been thought, and there is good evidence for this, that having two versions of the gene buffers women against certain diseases or environmental changes,’ says Arnold. If a man happens to have a genetic mutation on one of his X chromosomes that causes an illness or disability, he has no way of avoiding it. A woman, on the other hand, will have an extra X chromosome to counteract it, unless she’s unlucky enough to have the same genetic mutation on both of her X chromosomes, one from each parent. ‘The simple case would be if one gene works better when it’s cold and another works better when it’s hot. A woman with both of those alleles can be healthy when it’s hot and cold. The male only gets one shot. He only has one copy. So his body either works better when it’s hot or works better when it’s cold, but not both.’
There are some well-known genetic traits to which men are more susceptible than women simply because they have one X chromosome. These X-linked disorders include red-green colour blindness, haemophilia, muscular dystrophy and IPEX syndrome, which affects immune function. Mental retardation, which affects 2 to 3 per cent of people in developed countries, and significantly more men than women, also has a strong link to the X chromosome.
This is a reason why, in the effort to understand sex differences in health, Arthur Arnold has chosen to zero in on chromosomes. ‘We went back to the most fundamental biological differences between males and females. From the time of the fertilisation of the egg, the only one thing that we know is different between males and females is sex chromosomes. So everything has got to come from that … everything’s downstream of the sex chromosomes.’
‘What we know of X-linked diseases is that they’re pretty rare,’ says Steven Austad. ‘But I think there are a lot more X-linked diseases than we think about. I think this probably underlies a considerable proportion of the sex difference.’ One example is respiratory syncytial virus, which infects the lungs and breathing passages and is one of the biggest causes of bronchitis in children under the age of one in Britain and the United States. Researchers have found that the virus tends to hit boys far more than girls, and that something inside one particular gene on the X chromosome might be responsible.
Sabine Oertelt-Prigione agrees that there may be genes linked to resilience, immunity and disease susceptibility on the human X chromosome that haven’t yet been discovered or understood. ‘In my school we were taught that the X and Y are basically related to sexual function. That’s it. Nobody was thinking beyond that really at the time, and I’m talking about twenty years ago. Then things slowly started to change.’
In 1961 English geneticist Mary Frances Lyon found that, even though women have two X chromosomes, one is randomly inactivated in every cell. In other words, only one of them shows up for work. Women are therefore a genetic mosaic in which some cells have genes from one X chromosome, and other cells have genes from the other. Researchers have more recently discovered that some of the genes on the second X chromosome aren’t actually inactivated at all. Christine Disteche, a professor of pathology at the University of Washington, Seattle, and one of the world’s leading researchers on X inactivation, describes them as ‘little islands of escape’. In 2009 researchers at Penn State College of Medicine totted up these un-inactivated genes to discover that they comprise 15 per cent of genes on the second X. ‘We are now looking at huge datasets on gene expression between males and females, in humans and mice, to really try to see what is the extent of these differences,’ says Disteche.
‘Finding out that one of the two is not completely inactivated, it leads to speculation about lots of interesting aspects of life for women. It may be the reason we live longer,’ suggests Oertelt-Prigione.
The problem for all researchers in this area is that it’s not easy to distil the impact of the X chromosome from all the other factors that can cause a person to get sick or die. Most diseases don’t appear to be linked to one or even a few genes, in the way that X-linked genetic disorders such as haemophilia and muscular dystrophy are. The things that kill many of us, such as cardiovascular disease, are more complicated than that. Could genes from a second X chromosome have consequences for how the heart works, for instance?
To answer this question, Arthur Arnold and his team have used a special kind of laboratory animal, one with absolutely no difference between its males and females except for the number of X chromosomes they have. In nature, these creatures don’t exist. But by using genetic modification, scientists can come close to building them. Since sex hormones have the most obvious impact on male and female bodies before birth (without androgens a male wouldn’t develop male gonads, for instance), researchers have created laboratory mice for Arnold that don’t produce these hormones. The resulting mice have XY chromosomes, like a male, but also ovaries, like a female. This has allowed Arnold to compare genetically altered XY female mice to normal XX female mice. The only difference between them should be in their chromosomes. If their health differs, it’s purely because of the effects of their genes.
The results have indeed shown a link between the number of X chromosomes a mouse has and its health. Arnold describes ‘three dramatic cases’. When he and his team looked at body weight, they found that mice get fat if you remove their gonads. But animals with two X chromosomes get a lot fatter than those with just one. This mirrors something we see in human adults – women tend to have a higher percentage of fat mass in their bodies than men. ‘A second example is that if we give the mouse a heart attack, the animals with two X chromosomes do worse than the animals with one X chromosome,’ says Arnold. ‘And the third example in the mouse model is with multiple sclerosis, where we induced a multiple sclerosis-like disease in the mouse, and the animals that are XX do worse than the animals that are XY.’ Multiple sclerosis in humans, being an autoimmune disease, affects more women than men.
The take-home message from this research is that many of the sex differences we see in health are rooted deep down in genetics. ‘The study of mouse models has provided convincing evidence that cells with two X chromosomes are intrinsically different from those with one X chromosome. Sex differences caused by the number of X chromosomes can have a profound effect on disease,’ Arnold and his colleagues wrote in their paper about the experiment, published in 2016 in the journal Philosophical Transactions of the Royal Society of London Series B.
But not everyone is convinced. Some are dubious as to whether rodents can provide quite as much insight as Arnold believes they can. ‘Personally, I’m not a mouse fan,’ says Sabine Oertelt-Prigione. ‘I don’t know how translatable findings in mice are to humans … I think they have given us a lot of information, but I just wonder at this point how far we should pursue that.’
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