There have been claims that assisted reproductive technologies may result in higher levels of imprinting disorders, especially Beckwith-Wiedemann, Silver-Russell and Angelman syndromes. The concerns arise because the embryos are being cultured in the laboratory during the critical period when imprinting gets established. It may seem strange that we don’t know if there really is a problem or not. Surely with 5 million children to analyse it should be quite straightforward to perform the calculations? But the problem is that imprinting disorders are rare, only occurring naturally at rates of one in several or even tens of thousands. When you are analysing events that are so rare, the statistics can be skewed really easily.
Remember Concorde, one of only two supersonic plane models that ever entered commercial service? For decades it was the safest passenger plane in the world, because there had never been a fatal crash. But following the tragic accident at Paris Charles de Gaulle airport in 2000 in which 109 passengers and crew were killed, it became one of the most unsafe planes, statistically speaking. Of course, this was simply because there were relatively few Concorde flights compared with most airliners and the passenger numbers were small (it was a surprisingly bijou plane inside). Therefore, one event could have a major effect on the statistics if these were calculated in a fairly simplistic fashion.
It’s just the same with imprinting disorders. If you would normally expect to see 50 cases for every 5 million children born, how do you interpret it if you detect 55 among the children born via assisted reproductive technologies? Has the medical intervention led to a 10 per cent increase in imprinting disorders, or is this just statistical noise?[27] We also have to bear in mind that infertility itself may lead to a slight increase in imprinting problems, which is simply unmasked by the assisted reproductive techniques. It’s possible that sperm or eggs from people with low fertility are more likely to carry imprinting defects, but these only become apparent because they are able to have children thanks to medical technology. In the past, they wouldn’t have been able to reproduce so we wouldn’t have seen the effects of the imprinting defect.{212} It’s one of those confusing situations in biology where what we think we see is possibly distorted because of what’s out of sight.
11. Junk with a Mission
It’s quite possible that the most wonderful and compelling aspect of biology is its glorious inconsistency. Biological systems have evolved in magnificently creative ways, usurping and repurposing processes for completely new uses wherever possible. It means that almost every time we think a theme is emerging, we find exceptions. And sometimes it can be very difficult to unravel which is the norm and which the exception.
Let’s take junk DNA and non-protein-coding RNAs. Based on pretty much everything we have seen so far, it would be perfectly reasonable to develop a hypothesis along the following lines:
When junk DNA encodes a non-protein-coding RNA (junk RNA), the function of the RNA is to act as a kind of scaffold, directing the activity of proteins to particular regions of the genome.
This hypothesis would certainly be consistent with the roles of long non-coding RNAs. They act as the Velcro between epigenetic proteins and DNA or histones. The proteins frequently operate in a complex, and at least one member of the complex is often an enzyme, i.e. a protein that can bring about a chemical reaction. This can be the reaction that adds or removes epigenetic modifications on DNA or histone proteins, or that adds another base to a growing messenger RNA molecule.
In all these situations, the protein is the verb in the molecular sentence. It’s the ‘doing’ or action molecule.
Attractive as this model sounds, it has one unfortunate flaw. There is a situation where the roles are entirely reversed. In this reversed situation, the proteins are relatively silent, but the junk RNA acts as an enzyme, causing a chemical change to another molecule.
This sounds so peculiar that it is tempting to assume that it’s a one-off quirky exception. But if that’s the case, it’s a really quite remarkable exception because the junk RNA molecules that have this function account for about 80 per cent of the RNA molecules present in a human cell at any given time.{213} We’ve actually known about these peculiar RNA molecules for decades, making it yet more surprising that we have maintained such a protein-centric vision of our genomic landscape.
The RNA molecules with this odd function are called ribosomal RNA molecules, or rRNA for short. Logically enough, they are mainly found at structures in the cell called ribosomes. These structures are not in the nucleus but in the cytoplasm, which we first encountered in Chapter 2 and which was shown in Figure 2.3 (see page 16). The ribosomes are the structures where the information in the messenger RNA molecules is converted into strings of amino acids joined together, creating protein molecules. Using our analogy of the knitting pattern from Chapters 1 and 2, the ribosomes are all the ladies knitting away and turning the information on the printed page into warm socks and gloves for the overseas soldiers.{214}
If analysed by weight, the rRNA makes up about 60 per cent of the structure of a ribosome, and proteins make up the other 40 per cent. The rRNA molecules cluster into two major sub-structures. One contains three types of rRNA and around 50 different proteins. The other sub-structure contains just one type of rRNA and around 30 proteins. The ribosome is sometimes referred to as a macromolecular complex as it is a really big, structured conglomeration of many different components. We can think of it as a large protein-synthesis robot.
When messenger RNA molecules are produced for protein-coding genes, these messenger RNAs are transported out of the nucleus and over to the region of the cell where the ribosome robots are located. Messenger RNA molecules are fed through the ribosome and the genetic instructions carried on the messenger RNA are ‘read’ by the ribosomes. This results in amino acids being connected together in the correct sequence. It’s the ribosomal RNA that carries out the reaction by which an amino acid is joined to its adjacent neighbour. This creates the long, stable protein molecule.
As the messenger RNA is fed through the ribosome, another ribosome may bind at the start of the same message. It too will create protein chains. This is why one messenger RNA molecule can be used as the template for multiple copies of the same protein. The process is shown in Figure 11.1.
Figure 11.1 A messenger RNA molecule moves through a ribosome, travelling from left to right. The ribosome builds the protein chain. As the beginning of the messenger RNA emerges from the processing ribosome, it can engage another ribosome. As a consequence, there may be multiple ribosomes on a single messenger RNA molecule, all building full-length proteins.
The amino acids are brought to the ribosomes by another type of junk RNA called transfer RNA, or tRNA. These are quite small non-coding RNAs, only about 75 to 95 bases in length.{215} But they are able to fold back on themselves creating an intricate three-dimensional structure usually referred to as a clover leaf. A specific amino acid is attached to one end of the tRNA. At the far end, on a loop, is a sequence of three bases. This base triplet can bind to the correct matching sequence on a messenger RNA molecule. It does this by using essentially the same rules as the base pairing in DNA.