The Molecular Clock

Now, while we are talking molecules, we have some unfinished business left over from the chapter on evolutionary clocks. There, we looked at tree rings, and at various kinds of radioactive clocks, but we deferred consideration of the so-called molecular clock until we had learned about some other aspects of molecular genetics. The time has now come. Think of this section as an appendix to the chapter on clocks.

The molecular clock assumes that evolution is true, and that it proceeds at a sufficiently constant rate through geological time to be used as a clock in its own right, provided that it can be calibrated using fossils, which are in turn calibrated with radioactive clocks. Just as a candle clock assumes that candles burn at a fixed and known rate, and a water clock assumes that water drains from a bucket at a rate that can be calibrated, and a grandfather clock assumes that a pendulum swings at a fixed rate, so the molecular clock assumes that there are certain aspects of evolution itself that proceed at a fixed rate. That fixed rate can be calibrated against those parts of the evolutionary record that are well documented with (radioactively datable) fossils. Once calibrated, the molecular clock can then be used for other parts of evolution that are not well documented by fossils. For example, it can be used for animals that don't have hard skeletons and seldom fossilize.

Nice idea, but what gives us the right to hope that we can find evolutionary processes that go at a fixed rate? Indeed, much evidence suggests that evolutionary rates are highly variable. Long before the modern era of molecular biology, J. B. S. Haldane proposed the darwin as a measure of evolutionary rates. Suppose that, over evolutionary time, some measured characteristic of an animal is changing in a consistent direction. For example, suppose the mean leg length is increasing. If, over a period of a million years, leg length increases by a factor of e (2.718 . . ., a number chosen for reasons of mathematical convenience, which we needn't go into),* the rate of evolutionary change is said to be one darwin. Haldane himself assessed the rate of evolution of the horse as approximately 40 millidarwins, while it has been suggested that the evolution of domestic animals under artificial selection should be measured in kilodarwins. The rate of evolution of guppies transplanted to a predator-free stream, as described in Chapter 5, has been estimated as 45 kilodarwins. The evolution of 'living fossils' such as Lingula (page 140) is probably to be measured in microdarwins. You get the point: rates of evolution of things that you can see and measure, like legs and beaks, are hugely variable.

If rates of evolution are so variable, how can we hope to use them as a clock? This is where molecular genetics comes to the rescue. At first sight, it will not be clear how this can be so. When measurable characteristics like leg length evolve, what we are seeing is the outward and visible manifestation of an underlying genetic change. How, then, can it be the case that rates of change at the molecular level provide a good clock while rates of leg or wing evolution don't? If legs and beaks undergo change at rates ranging from microdarwins to kilodarwins, why should molecules be any more reliable as clocks? The answer is that the genetic changes that manifest themselves in outward and visible evolution - of things like legs and arms - are a very small tip of the iceberg, and they are the tip that is heavily influenced by varying natural selection. The majority of genetic change at the molecular level is neutral, and can therefore be expected to proceed at a rate that is independent of usefulness and might even be approximately constant within any one gene. A neutral genetic change has no effect on the survival of the animal, and this is a helpful credential for a clock. This is because genes that affect survival, positively or negatively, would be expected to evolve at a changed rate, reflecting this.

When the neutral theory of molecular evolution was first proposed by, among others, the great Japanese geneticist Motoo Kimura, it was controversial. Some version of it is now widely accepted and, without going into the detailed evidence here, I am going to accept it in this book. Since I have a reputation as an arch-'adaptationist' (allegedly obsessed with natural selection as the major or even only driving force of evolution) you can have some confidence that if even I support the neutral theory it is unlikely that many other biologists will oppose it!*

A neutral mutation is one that, although easily measurable by molecular genetic techniques, is not subject to natural selection, either positive or negative. 'Pseudogenes' are neutral for one kind of reason. They are genes that once did something useful but have now been sidelined and are never transcribed or translated. They might as well not exist, as far as the animal's welfare is concerned. But as far as the scientist is concerned they very much exist, and they are exactly what we need for an evolutionary clock. Pseudogenes are only one class of those genes that are never translated in embryology. There are other classes which are preferred by scientists for molecular clocks, but I won't go into detail. What pseudogenes are useful for is embarrassing creationists. It stretches even their creative ingenuity to make up a convincing reason why an intelligent designer should have created a pseudogene - a gene that does absolutely nothing and gives every appearance of being a superannuated version of a gene that used to do something - unless he was deliberately setting out to fool us.

Leaving pseudogenes aside, it is a remarkable fact that the greater part (95 per cent in the case of humans) of the genome might as well not be there, for all the difference it makes. The neutral theory applies even to many of the genes in the remaining 5 per cent - the genes that are read and used. It applies even to genes that are totally vital for survival. I must be clear here. We are not saying that a gene to which the neutral theory applies has no effect on the body. What we are saying is that a mutant version of the gene has exactly the same effect as the unmutated version. However important or unimportant the gene itself may be, the mutated version has the same effect as the unmutated version. Unlike pseudogenes, where the gene itself can properly be described as neutral, we are now talking about cases where it is only mutations (i.e. changes in genes) that can strictly be described as neutral, not genes themselves.

Mutations can be neutral for various reasons. The DNA code is a 'degenerate code'. This is a technical term meaning that some code 'words' are exact synonyms of each other.* When a gene mutates into one of its synonyms, you might as well not bother to call it a mutation at all. Indeed, it isn't a mutation, as far as consequences on the body are concerned. And for the same reason it isn't a mutation at all as far as natural selection is concerned. But it is a mutation as far as molecular geneticists are concerned, for they can see it using their methods. It is as though I were to change the font in which I write a word, say kangaroo to kangaroo. You can still read the word, and it still means the same Australian hopping animal. The change of typeface from Minion to Helvetica is detectable but irrelevant to the meaning.

Not all neutral mutations are quite so neutral as that. Sometimes the new gene translates into a different protein, but the 'active site' (remember the carefully shaped 'dents' that we met in Chapter 8) of the new protein remains the same as the old one. Consequently, there is literally no effect on the embryonic development of the body. The unmutated and the mutated form of the gene are still synonyms as far as their effects on bodies are concerned. It is also possible (although 'ultra-Darwinists' like me incline against the idea) that some mutations really do change the body, but in such a way as to have no effect on survival, one way or the other.

So, to sum up on the neutral theory, to say that a gene, or a mutation, is 'neutral' doesn't necessarily mean that the gene itself is useless. It could be vitally important to the animal's survival. What it means is that the mutated form of a gene - which might or might not be important for survival - is no different from the unmutated form with respect to its effects (which might be very important) on survival. As it happens, it is probably true to say that most mutations are neutral. They are undetectable by natural selection, but detectable by molecular geneticists; and that is an ideal combination for an evolutionary clock.

None of this is to downgrade the all-important tip of the iceberg - the minority of mutations that are not neutral. It is they that are selected, positively or negatively, in the evolution of improvements. They are the ones whose effects we actually see - and natural selection 'sees' too. They are the ones whose selection gives living things their breathtaking illusion of design. But it is the rest of the iceberg - the neutral mutations, which are in the majority - that concern us when we are talking about the molecular clock.

As geological time goes by, the genome is subjected to a rain of attrition in the form of mutations. In that small portion of the genome where the mutations really matter for survival, natural selection soon gets rid of the bad ones and favours the good ones. The neutral mutations, on the other hand, simply pile up, unpunished and unnoticed - except by molecular geneticists. And now we need a new technical term: fixation. A new mutation, if it is genuinely new, will have a low frequency in the gene pool. If you revisit the gene pool a million years later, it is possible that the mutation will have increased in frequency to 100 per cent or something close to it. If that happens, the mutation is said to have 'gone to fixation'. We shall no longer think of it as a mutation. It has become the norm. The obvious way for a mutation to go to fixation is for natural selection to favour it. But there is another way. It can go to fixation by chance. Just as a once proud surname can die out for lack of male heirs, so the alternatives to the mutation we are talking about can just happen to disappear from the gene pool. The mutation itself can become frequent in the gene pool, by the same luck as has led 'Smith' to emerge as the commonest surname in England. Of course it is much more interesting if the gene goes to fixation for a good reason - that's natural selection - but it can also happen by chance, given a large enough number of generations. And geological time is vast enough for neutral mutations to go to fixation at a predictable rate. The rate at which they do so varies, but it is characteristic of particular genes, and, given that most mutations are neutral, this is precisely what makes the molecular clock possible.

It's fixation that matters for the molecular clock, because 'fixed' genes are the ones that we look at when we compare two modern animals to try to estimate how long ago their ancestors split apart. Fixed genes are the genes that characterize a species. They are the ones that are all but universal in the gene pool. And we can compare the genes that have become fixed in one species with the genes that have become fixed in another, in order to estimate how recently the two species split apart. There are complications, which I won't go into because Yan Wong and I discussed them fully in 'The Epilogue to the Velvet Worm's Tale'. With reservations, and with various important correction factors, the molecular clock works.

Just as radioactive clocks tick at hugely variable speeds, with half-lives ranging from fractions of a second through to tens of billions of years, so different genes provide a marvellous spread of molecular clocks, suitable for timing evolutionary change on scales ranging from a million to a billion years, and all stages in between. Just as each radioactive isotope has its characteristic half-life, so each gene has a characteristic turnover rate - the rate at which new mutations typically go to fixation by random chance. Histone genes characteristically turn over at a rate of one mutation per billion years. Fibrinopeptide genes are a thousand times faster, with a turnover of one new mutation fixed per million years. Cytochrome-C and the suite of haemoglobin genes have intermediate turnovers, with times to fixation measured in millions to tens of millions of years.

Neither radioactive clocks nor molecular clocks tick in a regular fashion like a pendulum clock or a watch. If you could hear them ticking, they'd sound like a Geiger counter, the radioactive clocks literally so since a Geiger counter is precisely what you would use to listen to them. A Geiger counter doesn't tick regularly, like a watch; it ticks at random, the ticks coming in strange, stuttering bursts. That's how mutations, and fixations, would sound, if we could hear them on the immensely long timescale of geology. But, whether stuttering like a Geiger counter or ticking metronomically like a watch, the important thing about a timekeeper is that it should tick at a known average rate. That's what radioactive clocks do, and that's what molecular clocks do.

I introduced the molecular clock by saying that it assumes the fact of evolution and therefore can't be used in evidence of it. But now, having understood how the clock works, we can see that I was too pessimistic. The very existence of pseudogenes - useless, untranscribed genes that bear a marked resemblance to useful genes - is a perfect example of the way animals and plants have their history written all over them. But that is a topic that must wait for the next chapter.

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