Sex Chromosomes And X-linked Diseases
Chris - Now can we just orientate people a bit first because the whole point of molecular biology and genetics to many people is a little bit overwhelming. So first of all, DNA, gene, chromosome, genome: what do these words mean and how do they all relate? How does it all build up to make the genome of a person or an animal?
Mark - To take the genome first of all, all the people in this room are recognisably human because we have a human genome. So the human genome is the complete collection of all our genes and a complete set of all of our chromosomes. The genome is packaged in the cell. The genome comprises of long linear threads of DNA and these are packaged into the cell in the chromosomes. Chromosomes are a mixture of the genetic material that are DNA and the proteins that package that DNA into the cell. The genes are what are generally considered to be the functional components in the genome. There are other functional components as well but the genes are the focus of much interest. They're the parts of the genome that contain instructions to build protein molecules. It's the proteins then that go on to carry out the functions in the cell, in the tissue and in the body.
Chris - So the gene is the bit you inherit; it's the functional unit. In other words, there are a certain number of DNA letters that make up a gene and the gene tells the cell how to make a particular recipe.
Mark - That's right. We inherit our DNA in general and only a tiny fraction of that actually contains instructions to make a protein. It's about 2% of the total genetic material. So we've inheriting other genetic material as well. Some of that has function, so for example, pieces of our DNA control genes and tell then when to be switched on or switched off in a particular tissue.
Chris - But 2% seems a tiny amount. 98% not turning into something physical in the body seems like a big waste.
Mark - Well there is a large fraction of our genome that is often described as junk DNA. That would be considered to be a wasteful fraction of our genome. However, I think it's actually too early to conclude that this repetitive DNA that is particularly good at getting itself copied throughout our genome lacks a function. Perhaps we'll get a chance later to talk about the phenomenon of X-chromosome deactivation, and that's a possible area where this so-called junk DNA could have a role and something that we're interested in.
Chris - Well lets get down to what you work on, which is the X-chromosome. You actually led the Human Genome Project to sequence that chromosome.
Mark - Yes, that's right. The idea of that project was to determine the so-called DNA sequence of the X-chromosome. So looking in more detail at the DNA, the long molecules of the DNA are made up of four basic sub-units. It's the order of these sub-units in the DNA and in the genes in particular that determine what the structure of a protein will be. So the sequence of that DNA is very interesting to us and once we have the sequence it allows us to do a large amount both studying the function of the genes and also we can look at the evolution of our genome and that's something I'm particularly interested in.
Chris - As in, how we come from chimpanzees.
Mark - That would be one example, but I'm more interested in looking back at marsupials and looking at the other mammalian group too; the monotremes. These are egg-laying mammals and include things like the duck-billed platypus. We look at the sex chromosomes and how they've evolved in the mammals. If you go further back, these same sex chromosomes don't exist in birds for example.
Chris - Because women have two X-chromosomes. As men, we have one and a Y chromosome. So just talk about that a little bit and how it actually works.
Mark - The reason that the sex chromosomes are called sex chromosomes is because they are inherited differently between males and females. Females have two X-chromosomes whereas males have one X-chromosome and a much smaller Y - chromosome. The interesting thing is that we know that these chromosomes, although they look very different from each other, have actually evolved from a normal pair of chromosomes: a non-sex chromosome pair if you like. The reason is that they have become involved in sex determination. That's the trigger to either sexual differentiation into a male or sexual differentiation into a female.
Chris - So when a baby is first conceived in an early embryo, it's neither male nor female. Genetically speaking it is, but from a developmental point of view it is neither male nor female to start with.
Mark - That's right. It's the development of the gonads down one of two possible pathways that determines our phenotypic sex, or the way we look.
Chris - And the Y-chromosome does that.
Mark, Yes, the Y-chromosome contains SRY, the sex determining region of the Y. If we inherit the Y-chromosome and we inherit that gene, then the gonad develops into a testis and all male characteristics develop from hormones produced in the testes.
Chris - But what's really interesting is that I've got one X-chromosome, but the ladies we work with here have got two. What do they do with the extra one? Is there a problem having more genetic material than you should do? If you look at people who have Down's Syndrome, they've got an extra copy of chromosome 21, and that obviously creates some problems for them. But with the X - chromosome, women can have an extra copy and there doesn't seem to be a major issue.
Mark - That's right. As you've pointed out, in general, having an extra copy of a chromosome causes very severe problems. In the case of having an extra X, this doesn't happen. The reason is that female mammals, including the females in the studio silence one of their X-chromosomes. They switch one of their X-chromosomes off in each of their cells and so the genes are no longer active on that X-chromosome. In that way, males and females have a single active copy of their X-chromosome.
Chris - Doesn't that cause interesting things with relations to certain diseases? So if there's a certain gene that's abnormal on the X-chromosome, men will get it. But because women have two X-chromosomes, if one has a faulty gene but the other has a healthy gene, the women don't succumb to the disorder.
Mark - There's a very characteristic pattern of inheritance of so-called X-linked conditions, where males are generally affected and women are either affected or have mild symptoms of the condition. These kinds of inheritance patterns have been described going back thousands of years, particularly for things like haemophilia. In some instances, because this process of switching off one of the X-chromosomes in females is a random process, that would mean that on the whole, half of the cells in the female body would have switched off the undamamged X - chromosome and the other half will have switched of the damaged X-chromosome. That could account for why some of these symptoms are visible in females. In some extreme cases this X-inactivation can skew in one direction, presumably the cells that have switched off the undamaged X - chromosome. They don't thrive while the other cells do.