It’s worth looking at where the expansion occurs in the myotonic dystrophy gene. It’s right at the far end, after the last amino acid-coding region. In Figure 2.5, this would be on the horizontal line to the right of box ‘G’. This means that the entire amino acid-coding region can be copied into RNA before the copying machinery encounters the expansion.
It’s now clear that the expansion itself gets copied into RNA. It is even retained when the long RNA is processed to form the messenger RNA. The myotonic dystrophy messenger RNA does something unusual. It binds lots of protein molecules that are present in the cell. The bigger the expansion, the more protein molecules that get bound. The mutant myotonic dystrophy messenger RNA acts like a kind of sponge, mopping up more and more of these proteins. The proteins that bind to the expansion in the myotonic dystrophy messenger RNA are normally involved in regulating lots of other messenger RNA molecules. They influence how well messenger RNA molecules are transported in the cell, how long the messenger RNA molecules survive in the cell and how efficiently they encode proteins. But if all these regulators are mopped up by the expansion in the myotonic dystrophy gene messenger RNA, they aren’t available to do their normal job.{13} This is shown in Figure 2.6.
Again an analogy may help. Imagine a city where every member of the police force is engaged in controlling a riot in a single location. There will be no officers left for normal policing, and burglars and car thieves may run amok elsewhere in the city. It’s the same principle in the cells of people with the myotonic dystrophy mutation. The CTG repeat sequence expansion in a single gene — the myotonic dystrophy gene — ultimately leads to mis-regulation of a whole number of other genes in the cell.
Figure 2.6 The upper panel shows the normal situation. Specific proteins, represented by the chevron, bind to the CTG repeat region on the myotonic dystrophy messenger RNA. There are plenty of these protein molecules available to bind to other messenger RNAs to regulate them. In the lower panel, the CTG sequence is repeated many times on the mutated myotonic dystrophy messenger RNA. This mops up the specific proteins, and there aren’t enough left to regulate other messenger RNAs. For clarity, only a small number of repeats have been represented. In severely affected patients, they may number in the thousands.
This is because the expansion mops up more and more of the binding proteins as it gets larger. This leads to disruption of a greater quantity of other messenger RNAs, causing problems for increasing numbers of cellular functions. This eventually results in the wide range of symptoms found in patients carrying the myotonic dystrophy mutation, and explains why the patients with the largest repeats have the most severe clinical problems.
Just as we saw in Friedreich’s ataxia and Fragile X syndrome, the normal CTG repeat sequences in the myotonic dystrophy gene have been highly conserved in human evolution. This is consistent with them having a healthy and important functional role. We are even more convinced this is the case for the myotonic dystrophy gene because of the proteins that bind to the repeat in the messenger RNA. These also bind to shorter repeat lengths, of the size that are present in normal genes. They just don’t bind in the same abundance as they do when the repeat has expanded.
It’s clear from the myotonic dystrophy example that there is a reason why messenger RNA molecules contain regions that don’t code for proteins. These regions are critical for regulating how the messenger RNAs are used by the cells, and create yet another level of control, fine-tuning the amount of protein ultimately produced from a DNA gene template. But what no one appreciated when the myotonic dystrophy mutation was identified, almost ten years before the release of the human genome sequence, was just how extraordinarily complex and variable this fine-tuning would turn out to be.
3. Where Did All the Genes Go?
On 26 June 2000, it was announced that the initial draft of the sequence of the human genome had been completed. In February 2001, the first papers describing this draft sequence in detail were released. It was the culmination of years of work and technological breakthroughs, and more than a little rivalry. The National Institutes of Health in the USA and the Wellcome Trust in the UK had poured in the majority of the approximately $2.7 billion{14} required to fund the research. This was carried out by an international consortium, and the first batch of papers detailing the findings included over 2,500 authors from more than 20 laboratories worldwide. The bulk of the sequencing was carried out by five laboratories, four of them in the US and one in the UK. Simultaneously, a private company called Celera Genomics was attempting to sequence and commercialise the human genome. But by releasing their data on a daily basis as soon as it was generated, the publicly funded consortium was able to ensure that the sequence of the human genome entered the public domain.{15}
An enormous hoopla accompanied the declaration that the draft human genome had been completed. Perhaps the most flamboyant statement was from US President Bill Clinton, who declared that ‘Today we are learning the language in which God created life’.{16} We can only speculate on the inner feelings of some of the scientists who had played such a major role in the project as a politician invoked a deity at the moment of technological triumph. Luckily, researchers tend to be a shy lot, especially when confronted by celebrities and TV cameras, so few expressed any disquiet publicly.
Michael Dexter was the Director of the Wellcome Trust, which had poured enormous sums of money into the Human Genome Project. He was not much less fulsome, albeit somewhat less theistic, when he defined the completion of the draft sequence as ‘The outstanding achievement not only of our lifetime, but in terms of human history’.{17} You might not be alone in thinking that perhaps other discoveries have given the Human Genome Project a run for its money in terms of impact. Fire, the wheel, the number zero and the written alphabet spring to mind, and you probably have others on your own list. It could also be claimed that the human genome sequence has not yet delivered on some of the claims that were made about how quickly it would impact on human disease. For instance, David Sainsbury, the then UK Science Minister, stated that ‘We now have the possibility of achieving all we ever hoped for from medicine’.{18}
Most scientists knew, however, that these claims should be taken with whole shovelfuls of salt, because we have been taught this by the history of genetics. Consider a couple of relatively well-known genetic diseases. Duchenne muscular dystrophy is a desperately sad disorder in which affected boys gradually lose muscle mass, degenerate physically, lose mobility and typically die in adolescence. Cystic fibrosis is a genetic condition in which the lungs can’t clear mucus, and the sufferers are prone to severe life-threatening infections. Although some cystic fibrosis patients now make it to the age of about 40, this is only with intensive physical therapy to clear their lungs every day, plus industrial levels of antibiotics.