Mutation is no fairy tale

kw: observations, natural history

From time to time science fiction will go through a wave of "Mutation" stories in which unsuspecting persons will suddenly develop new organs or limbs, gain new skills, or become superheroes. The current popularity of the Fantastic Four and the X-Men, a nostalgic relapse from the early 1960s, is a case in point. The X-Men are specifically called mutants in the Marvel comic series, while the FF superheroes are said to have experienced "changes to their DNA" due to a solar flare. In 1931, “The Man Who Evolved” by Edmond Hamilton depicts a man becoming first Homo superior, then devolving to an amoeba, from the influence of concentrated cosmic rays. Such literature goes back to about the year 1800.

Most people know innately that such sudden "evolution" doesn't happen. There is actually a greater body of literature, such as that by Olaf Stapledon, about more gradual evolutionary processes. The theory of Natural Selection proposed by Charles Darwin in 1859 is entirely gradualistic. At a time that the mechanisms of inheritance were entirely unknown, Darwin proposed that an unnamed agent of change introduces small variations in every newborn creature, that some of that generation will be more "fit" than their fellows, and thus that there will be a winnowing such that the more fit leave more progeny than the others.

The discovery of Mendelian "digital" (all-or-nothing) inheritance in the early 1900s provided the first hint that the stuff of inheritance came in discrete units. The discovery of DNA and the double helix by Watson and Crick in the 1950s gave us an actual data-recording molecule that can record and play back a creature's inherited characteristics. Tons of subsequent research have begun to show us just how it is all done.

For the purposes of this essay, only the following is needed:

• DNA consists of discrete "bases", four in number, called A, C, G, and T, that can be arranged in any order. The human genome consists of about three billion bases.
• These bases are translated by threes into amino acids. A 3-base code is called a codon.
• 4³=64, so the "genetic code" could support 62 amino acids plus "start" and "stop". In reality there are 20 amino acids that are actually used to make proteins, so the code is degenerate; each amino acid has more than one corresponding codon.
• The codons in the DNA are copied to an intermediate RNA string, from one Start to one Stop codon.
• A mechanism that is unimportant here translates the RNA codons into amino acids and strings them together into proteins.
• There is a mechanism that assures that proteins fold correctly so as to be properly active.
• And finally, all this happens in the context of a living cell, which arose by a process we have yet to discover, but which is essential for the DNA to be decoded into proteins, and for those proteins to do their work or build what they need to build.

In its raw form, a mutation is a change to the DNA. Such a change might be in the form of a change from one base to another, such as from A to G. It might be the deletion of one or more bases, or a "stutter" that inserts a new base (or more) between existing bases. It might be that a chunk of DNA of arbitrary size is duplicated and inserted into an arbitrary location.

Some of these changes will change a protein, but not all. In particular, a change of a single base has only one chance in three of making a change in the amino acid that appears, because of the degeneracy of the code, and a much smaller chance of changing an amino acid codon to a Start or Stop codon. These single-base changes, or "point" mutations, are by far the most likely, and are called Single-Nucleotide Polymorphisms, or SNPs, pronounced "snips". SNPs that don't change the amino acid are called Silent mutations.

There is a second level of silence possible. By a kind of 90-10 rule, about 90% of most proteins is scaffolding, things like alpha helices and beta sheets that hold an active site in an appropriate position, and about 10% comprises the actual active site. For structural proteins, the active site is simply a very small region that allows proteins to link up into larger structures. Most changes to the scaffolding amino acids don't cause any change in the activity of the protein, so these are also silent. A change to the active site is more likely to change the functioning of the protein.

Grosser changes, mainly insertions and deletions, are more likely to cause major disruption, because they could change the entire amino acid sequence of a protein. These are rare, and most of those that occur cause the cell to die, unless it can get along without the affected protein, or can tolerate the entirely new protein that was produced. But the production of a new protein is an opportunity for a new function to arise.

It is also necessary to consider that the 24,000 or so known genes in humans (and quite variable numbers in other organisms) take up only about 2% of the genome: 60 million out of 3 billion total bases. The other 98% has been called "junk DNA", but the term is dropping out of use. It includes about 100 total virus genomes, some of them containing sequences brought in from other animals. It includes long strings of repititious DNA (like the "TATATATATA" strings which are so hard for genome sequencing methods to figure out). It also includes areas that are thought to encode for "catalytic RNA" and "regulatory sequences" which are the subject of lots of study, but not much is yet known. This "non-gene" DNA is a vast sea of possiblities; until many of them are figured out, we won't be able to give much of an answer to, "Why is it there?".

Let us first focus on SNP mutations that are not silent. They occur in a gene, they cause a different amino acid to be strung into the protein, or they encode "Stop" and cut it short, and they change the activity of the protein or eliminate it altogether. Then we must ask, what was that protein going to do if unchanged, and what, if anything, will it do now? Here, things can get complicated.

Perhaps the protein is insulin. If it is cut short or totally disabled, the cell will die; it can't metabolize glucose. If the activity is reduced, the cell will have a lower energy level. If this is an ovum or sperm cell that gets "used" to make a baby, that person, if viable, would be less energetic. If the activity is instead increased, the energy level might be higher, though this may reduce life span due to greater levels of free radical oxidants.

Suppose the protein is only expressed when making melanin for the iris of the eye: eliminate its activity, and the eye will be blue. I once knew a blue-eyed Sioux Indian. He said he thought it was a mutation. The other Indians thought his mother had a secret. Blue eyes is a recessive trait, so there had to be at least two secrets, if that were the case!

We could multiply examples, but we need to look at another level. Some genes are regulatory; they either produce proteins that regulate the expression of genes, or they produce an intermediate RNA product that does so. In multicellular creatures, there are special "homeotic" genes that control the shape of the body. In animals this is the Homeobox, in plants there is a homeotic sequence that is less specific, but equally crucial. A non-silent SNP in a homeobox gene is almost always fatal.

There are, in between the homeotic genes and the single-protein ones, several levels of regulation, perhaps as many as five or six. A non-silent SNP in any of these can cause major changes in the organism: extra or missing limbs or eyes or heads – well, suffice it to say, all kinds of things certain museums put on display as "monsters".

Now, let's step back to a high altitude. One-third, perhaps more, of fertilized human ova do not come to term. At some stage the embryo or fetus dies in utero. I don't know of anybody that has tried to do a genome sequence of an early-miscarried fetus, but it is thought that most of these are mutations that were not viable. But we all carry 50-100 SNPs that are not present in either of our parents. We, the living, were the lucky ones. Most of those SNPs are silent, and the rest at least caused little or no harm.

Let's now focus on another kind of mutation. Sometimes an entire gene is duplicated. Since only one copy is needed for the cell to function normally, a later change to one of them, no matter how disastrous, will seldom harm the cell. Let this happen to an ovum or sperm, and it frequently does, and you have an organism with a new chunk of DNA that can be changed in its descendants, perhaps into something good, but more likely into another piece of non-coding DNA (formerly "junk DNA"). Key point: we are all mutants, just not mutants "very much".

Traditional, or classic, natural selection is the name for a process that is otherwise hard to describe. It operates by the differential death between members of a population that are all mutants "not very much", but have each their 50-100 SNPs and perhaps one or two other kinds of DNA changes as compared with their parents. They all, at least, survived gestation and birth, or seed dispersal and sprouting. Some will die when very young. They will die one after another until all have died. In the meantime, some will have no offspring, some one, and some will have more.

Even having several offspring is no guarantee of anything. Abraham Lincoln had four children. He has no living offspring. In the language of evolutionary theory, his line was "selected against." In detail, some stayed single and never had children, and most of the rest died too young to have any, or their children did so. It took four generations for the family to die out.

Classic natural selection is wholly gradualistic. Changes to the way organisms grow and reproduce, however, all produced by natural selection, have led to mechanisms that increase the likelihood of less gradual changes. The homeobox in animals is a case in point. It must have arisen more than one billion years ago. It is different sizes (number of genes) in different animals, which indicates that whole sections of it were duplicated and re-spliced, many times, in the past. A worm whose "baby worms" have a double-size homeobox will simply produce longer worms with more segments. With more complex animals it gets more tricky, but it is the genes in the intermediate levels that enforce which segments become a head, or torso, or so forth.

A billion years is a long, long time. Most animals produce one or more generations per year. When times are good (lots of food, comfortable temperature and pressure, plenty of water, few or no predators), they multiply until there is no longer lots of food. Suppose you have a population of a million lemmings, and they remain rather stable for a thousand years. They reproduce twice yearly. That's two billion lemming babies, each a tiny bit different from their parents…except for the few hundred who are a lot different from their parents, due to changes in genes with more influence. How much is a lot? Not enough to change a lemming into a dog, or cat, or horse, or even mouse or vole. But enough so it can run faster, or is bigger and more aggressive, or can digest that bad-tasting flower that is taking over the over-grazed fields. There could then be a significant change in future generations.

In the literature, such mutations are called "saltations" meaning "jumps", and they are forbidden by classic theory. But they happen. The more radical a change is, the less likely it is to be helpful, so perhaps those few hundred lemmings are just not enough for any saltations to be useful in the long term. Now give those lemmings, not 1,000 years, but one million. A few hundred saltations became a quarter million. It is now much more likely that some few will be greatly beneficial, and lead to quite a shift in that population of lemmings.

Multiply by 50,000 small mammal species, and by more millions of years, and it is certain that saltation has had a lot, a LOT, to do with generating new species. We're not talking X-Men level changes, of course. That's not a saltation, that needs a new word! Compared with that, these mutated lemmings still represent a comparatively gradual change. But it is just this kind of change that can drive the "punctuated evolution" that S.J. Gould and his colleagues described just a couple of decades ago.

A mistake we all make with natural selection, is to think of it in anthropomorphic terms, as though it were intentional. Natural selection isn't a "thing", it is a term we use to describe a process which has operated since life began. Lots of babies are born, but not all grow up and have babies of their own. Combinations of factors that we describe as "fitness" are used to explain why certain individuals reproduced and certain ones did not. We can only do this after the fact, because there is no way to predict what kind of a difference leads to greater fitness.

For example, consider that lemming that is faster, a lot faster. Is that beneficial? We might think so. But consider that one defense of the lemmings against foxes is that the fox gets confused by a field full of them, and can't pick a target. Then young Speedy the Superlemming shows up, and the fox finds it easy to pick him out. "Snap!" Young Speedy is no more. He just got selected against. If only he'd been a whippet instead of a lemming; he'd be famous and make lots of little whippets. Natural selection can't tell "If only" stories. It just describes the process.

Mutations, of whatever magnitude, present numerous hostages to fortune. Some prosper and some do not. Those that prosper determine the complexion of the next generation. We can only describe what happened in hindsight.

The process of natural selection has actually resulted in a very creative tension between stasis and change. Those sections of the genome that are most strongly "conserved", that typically cannot be changed, even a little, without fatal damage to the organism, can only be changed by saltations. If Speedy the Superlemming is fast enough, he can outrun the fox. Then, as long has he can find a girl lemming that likes a fast mate, he just might sire a line of superfast lemmings, which might be enough to produce a new species. We can't predict things like this, and I don't thnk we'll ever have a theory that can, but we can say confidently that they have happened in the past, and are likely to happen again. We'll always be surprised.