Women with just one X chromosome are shorter than average, and have underdeveloped ovaries.{262} Women with three X chromosomes are taller than average and at increased risk of learning disabilities and developmental delay as children.{263} Males with two X chromosomes (plus a Y of course) are taller than average, and may have relatively small testicles, leading to problems caused by low production of the male hormone, testosterone. They are also at increased risk of learning disabilities.{264}
Although potentially distressing for the patients and their families, the symptoms are milder than we see for patients with abnormal numbers of autosomal chromosomes (remember Down’s, Edward’s and Patau sydromes — see pages 76–7). That’s because although the X chromosome is large, most of the genes on it are appropriately inactivated, no matter how many copies of this chromosome are present. But there are some that aren’t.
To understand what is happening, we need to think back to what happens when eggs or sperm are created. At a certain stage, the chromosomes line up in pairs and then one of each pair is pulled to opposite ends of the cell. The cell divides and its daughter cells contain one of each pair. In a female cell this is easy to visualise. The two X chromosomes pair up and then can be separated, in exactly the same way as any other pair of chromosomes from number 1 to number 22. But when males are creating sperm, there is a problem. Males contain one large X chromosome and one tiny Y chromosome. These are very different from each other. Yet somehow, during the creation of sperm, the X and the Y must find each other and pair up, despite being so different.
The reason they can do this is because there is a small region at the ends of the X and Y chromosomes where they are very similar to each other. This allows them to recognise each other and to associate during cell division, holding hands until they need to move to opposite ends of the dance floor.
These stretches are known as pseudoautosomal regions. They contain protein-coding genes, and they are protected from silencing during X inactivation. The genes in the pseudoautosomal region are treated very differently from most of the other genes on the X chromosome. This pattern of activated and inactivated genes, which leads to detectable symptoms in males and females with the wrong number of X chromosomes, was a clear sign from biology that cells contain very fundamental ways of functionally separating different blocks of DNA.
X inactivation is critically dependent on the Xist long non-coding RNA spreading along the chromosome on which it is expressed. But Xist doesn’t spread into the pseudoautosomal regions. The protection from this in the pseudoautosomal region shows us that our genomes have evolved in such a way that at key positions, they can draw a line in the sand. As Jean-Luc Picard declared, in reference to Borg incursions into Federation space, ‘The line must be drawn here! This far, no farther!’{265} Junk insulator regions prevent the creeping genomic paralysis that spreads out from the Xist locus.
Figure 13.3 The effects of different numbers of X chromosomes in male and female cells. Because of X inactivation, there is only one active X chromosome in each cell. But because the pseudoautosomal regions at the ends of the X and Y chromosomes escape X inactivation, their numbers increase or decrease pathologically with changes in X chromosome number.
Figure 13.3 shows how these non-silenced regions result in changes in people who have the wrong numbers of X chromosomes. A woman who only has one X chromosome expresses 50 per cent of the normal amounts of gene products from the pseudo-autosomal regions as a typical XX woman. A woman with three X chromosomes produces 50 per cent more of these gene products than normal, as does a male with two X chromosomes and a Y.
It’s no coincidence that both males and females with an extra X chromosome are taller than average, and women lacking an X tend to be on the short side. The pseudoautosomal region contains a particular protein-coding gene[38]{266} which controls the expression of other genes and is important for development of the skeleton, especially the long bones of the arms and legs. Men and women with extra X chromosomes express more of this protein than normal, which tends to increase leg length and hence height. The opposite is true for women lacking an X chromosome. It’s one of the few examples in the human genome where we can really identify a single region which has a significant impact on the normal range of human height. Outside of this region, height is influenced by multiple sites in the genome,{267} and many of these are regions of junk DNA, where we don’t yet know how they individually contribute to making you a Harlem Globetrotter, or someone who is always overlooked in a bar.
14. Project ENCODE — Big Science Comes to Junk DNA
If you ever find yourself far from city lights, on a cloudless night with no moon, grab a blanket and lie on the ground and look up at the stars. It’s one of the most wonderful sights imaginable, and quite breathtaking for anyone who spends their life in a city. The glints of silver in the dark blanket of the heavens seem too many to count.
But — if you have access to a telescope, you realise that there is so much more in the firmament than you can detect with the naked eye. There are details like the rings of Saturn, and there are vastly more stars than we could ever imagine. There is so much more in the apparent darkness of the universe than can be seen just with our limited unaided vision. This becomes even more obvious if we use equipment that can detect the energy in the other parts of the electromagnetic spectrum, beyond just the visible wavelengths. More information keeps pouring in, from gamma waves to the microwave background. Those details and those stars have always been there, we just couldn’t detect them when we relied only on eyesight.
In 2012, a whole slew of papers was published that attempted to turn a telescope onto the furthest reaches of the human genome. This was the work of the ENCODE consortium, a collaborative effort involving hundreds of scientists from multiple different institutions. ENCODE is an acronym derived from Encyclopaedia Of DNA Elements.{268} Using the most sensitive techniques available, the researchers probed multiple features of the human genome, analysing nearly 150 different cell types. They integrated the data in a consistent way, so that they could compare the outputs from the different techniques. This was important because it’s very difficult to make comparisons between data sets that have been generated and analysed differently from each other. Such piecemeal data were what we had previously relied on.
When the ENCODE data were published, there was an enormous amount of attention from the media, and from other researchers. Press coverage included headlines such as ‘Breakthrough study overturns theory of “junk DNA” in genome’;{269} ‘DNA project interprets “Book of Life”’{270} and ‘Worldwide army of scientists cracks the “junk DNA” code’.{271} We might imagine that other scientists would all be congratulatory, and even grateful for all the additional data. And a lot were really fascinated, and are using the data every day in their labs. But the acclaim has been far from universal. Criticism has come mainly from two camps. The first is the junk sceptics. The second is the evolutionary theorists.