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.
miRNAs play major roles in control of pluripotency and control of cellular differentiation. ES cells can be encouraged to differentiate into other cell types by changing the culture conditions in which they’re grown. When they begin to differentiate, it’s essential that ES cells switch off the gene expression pathways that normally allow them to keep producing additional ES cells (self-renewal). There is a miRNA family called let-7 which is essential for this switch-off process[145].
One of the mechanisms the let-7 family uses is the down-regulation of a protein called Lin28. This implies that Lin28 is a pro-pluripotency protein. It’s therefore not that surprising to discover that Lin28 can act as a Yamanaka factor. Over-expression of Lin28 protein in somatic cells increases the chances of reprogramming them to iPS cells[146].
Conversely, there are other miRNA families that help ES cells to stay pluripotent and self-renewing. Unlike let-7, these miRNAs promote the pluripotent state. In ES cells, the key pluripotency factors such as Oct4 and Sox2 are bound to the promoters of these miRNAs, activating their expression. As the ES cells start to differentiate, these factors fall off the miRNA promoters, and stop driving their expression[147]. Just like the Lin28 protein, these miRNAs also improve reprogramming of somatic cells into iPS cells[148].
When we compare stem cells with their differentiated descendants, we find that they express very different populations of mRNA molecules. This seems reasonable, as the stem and differentiated cells express different proteins. But some mRNAs can take a long time to break down in a cell. This means that when a stem cell starts to differentiate, there will be a period when it still contains many of the stem cell mRNAs. Happily, when the stem cell starts differentiating, it switches on a new set of miRNAs. These target the residual stem cell mRNAs and accelerate their destruction. This rapid degradation of the pre-existing mRNAs ensures that the cell moves into a differentiated state as quickly and irreversibly as possible[149].
This is an important safety feature. It’s not good for cells to retain inappropriate stem cell characteristics – it increases the chance they will move down a cancer cell pathway. This mechanism is used even more dramatically in species where embryonic development is very rapid, such as fruit flies or zebrafish. In these species this process ensures that maternally-inherited mRNA transcripts supplied by the egg are rapidly degraded as the fertilised egg turns into a pluripotent zygote[150].
miRNAs are also vital for that all-important phase in imprinting control, the formation of primordial germ cells. A key stage in creation of primordial germ cells is the activation of the Blimp1 protein that we met in Chapter 8. Blimp1 expression is controlled by a complex interplay between Lin28 and let-7 activity[151]. Blimp1 also regulates an enzyme that methylates histones, and a class of proteins known as PIWI proteins. PIWI proteins in turn bind to another type of small ncRNAs known as PIWI RNAs[152]. PIWI ncRNAs and proteins don’t seem to play much of a role in the somatic cells but are required for generation of the male germline[153]. PIWI actually stands for P element-induced wimpy testis. If the PIWI ncRNAs and PIWI proteins don’t interact properly, the testes in a male foetus don’t form normally.
We are finding more and more instances of cross-talk and interactions between ncRNAs and epigenetic events. Remember that the genetic interlopers, the retrotransposons, are normally methylated in the germline, to prevent their activation. The PIWI pathway is involved in targeting this DNA methylation[154][155]. A substantial number of epigenetic proteins are able to interact with RNA. Binding of non-coding RNAs to the genome may act as the general mechanism by which epigenetic modifications are targeted to the correct chromatin region in a specific cell type[156].