The Epigenetics Revolution

This can make it very difficult to unravel exactly what a miRNA is doing in a cell, as the effects will vary depending on the cell type and the other genes (protein-coding and non-protein-coding) that the cell is expressing at any one time. That can be important experimentally, but also has significant consequences for normal health and disease. In conditions where there are an abnormal number of chromosomes, for example, it won’t just be protein-coding genes that change in number. There will also be abnormal production of ncRNAs (large and small). Because miRNAs in particular can regulate lots of other genes, the effects of disrupting miRNA copy numbers may be very extensive.

Room for manoeuvre

The fact that 98 per cent of the human genome does not code for protein suggests that there has been a huge evolutionary investment in the development of complicated ncRNA-mediated regulatory processes. Some authors have even gone so far as to speculate that ncRNAs are the genetic features that have underpinned the development of Homo sapiens’ greatest distinguishing feature – our higher thought processes[141].

The chimpanzee is our closest relative and its genome was published in 2005[142]. There isn’t one simple, meaningful average figure that we can give to express how similar the human and chimp genomes are. The statistics are actually very complicated, because you have to take into account that different genomic regions (for example repetitive sections versus single copy protein-coding gene regions) affect the statistics differently. However, there are two things we can say quite firmly. One is that human and chimp proteins are incredibly similar. About a third of all proteins are exactly the same between us and our knuckle-dragging cousins, and the rest differ only by one or two amino acids. Another thing we have in common is that over 98 per cent of our genomes don’t code for protein. This suggests that both species use ncRNAs to create complex regulatory networks which govern gene and protein expression. But there is a particular difference which may be very important between chimps and humans. This lies in how ncRNA is treated in the cells of the two species.

It’s all to do with a process called editing. It seems that human cells just can’t leave well-enough alone, particularly when it comes to ncRNA[143]. Once an ncRNA has been produced, human cells use various mechanisms to modify it yet further. In particular, they will often change the base A to one called I (inosine). Base A can bind to T in DNA, or U in RNA. But base I can pair with A, C or G. This alters the sequences to which an ncRNA can bind and hence regulate.

We humans, more than any other species, edit our ncRNA molecules to a remarkable degree. Not even other primates carry out this reaction as well as we do[144]. We also edit particularly extensively in the brain. This makes editing of ncRNA an attractive candidate process to explain why we are mentally so much more sophisticated than our primate relatives, even though we share so much of our DNA template in common.

In some ways, this is the beauty of ncRNAs. They create a relatively safe method for organisms to use to alter various aspects of cellular regulation. Evolution has probably favoured this mechanism because it is simply too risky to try to improve function by changing proteins. Proteins, you see, are the Mary Poppins of the cell. They are ‘practically perfect in every way’.

Hammers always look pretty similar. Some may be big, some may be small, but in terms of basic design, there’s not much you can change that would make a hammer much better. It’s the same with proteins. The proteins in our bodies have evolved over billions of years. Let’s take just one example. Haemoglobin is the pigment that transports oxygen around our bodies, in the red blood cells. It’s beautifully adept at picking up oxygen in the lungs and releasing it where it’s needed in the tissues. Nobody working in a lab has been able to create an altered version of haemoglobin that does a better job than the natural protein.

Creating a haemoglobin molecule that’s worse than normal is surprisingly easy to do, unfortunately. In fact, that’s what happens in disorders like sickle cell disease, where mutations create poor haemoglobin proteins. A similar situation is true for most proteins. So, unless environmental conditions change dramatically, most alterations to a protein turn out to be a bad thing. Most proteins are as good as they’re going to get.

So how has evolution solved the problem of creating ever more complex and sophisticated organisms? Basically, by altering the regulation of proteins, rather than altering the proteins themselves. This is what can be achieved using complicated networks of ncRNA molecules to influence how, when and to what degree specific proteins are expressed – and there is evidence to show this actually happens.