Stability Of Naturally Selected Genes

Having discovered the increase of the natural mutation rate by any kind of ionizing rays, one might think of attributing the natural rate to the radio-activity of the soil and air and to cosmic radiation. But a quantitative comparison with the X-ray results shows that the ’natural radiation’ is much too weak and could account only for a small fraction of the natural rate.

Granted that we have to account for the rare natural mutations by chance fluctuations of the heat motion, we must not be very much astonished that Nature has succeeded in making such a subtle choice of threshold values as is necessary to make mutation rare.

I have concluded that frequent mutations are detrimental to evolution.

Individuals which, by mutation, acquire a gene configuration of insufficient stability, will have little chance of seeing their ‘ultra-radical’, rapidly mutating descendancy survive long.

The species will be freed of them and will thus collect stable genes by natural selection.

But, of course, as regards the mutants which occur in our breeding experiments and which we select, qua mutants, for studying their offspring, there is no reason to expect that they should all show that very high stability.

For they have not yet been ’tried out’ - or, if they have, they have been ‘rejected’ in the wild breeds - possibly for too high mutability. At any rate, we are not at all astonished to learn that actually some of these mutants do show a much higher mutability than the normal ‘wild’ genes.

Temperature Influences Unstable Genes Less Than Stable Ones

This enables us to test our mutability formula, which was t == re WlkT .

(It will be remembered that t is the time of expectation for a mutation with threshold energy W.) We ask: How does t change with the temperature? We easily find from the preceding formula in good approximation the ratio of the value oft at temperature T + 10 to that at temperature T

tT+ 10 - IoWlkT 2 ==e . tT

The exponent being now negative, the ratio is, naturally, smaller than I. The time of expectation is diminished by raising the temperature, the mutability is increased.

That can be tested and has been tested with the fly Drosophila in the range of temperature which the insects will stand.

The result was, at first sight, surprising.

The low mutability of wild genes was distinctly increased, but the comparatively high mutability occurring with some of the already mutated genes was not, or at any rate was much less, increased. That is just what we expect on comparing our two formulae.

A large value of W/kT, which according to the first formula is required to make t large (stable gene), will, according to the second one, make for a small value of the ratio computed there, that is to say for a considerable increase of mutability with temperature.

The actual values of the ratio seem to lie between about! and 1.

The reciprocal, 2·5, is what in an ordinary chemical reaction we call the van’t Hofffactor.

How X-Rays Produce Mutation

The X-ray-induced mutation rate from the breeding experiments reveals:

1. From the proportionality of mutation rate, and dosage that some single event produces the mutation

2. From quantitative results and from the fact that the mutation rate is determined by the integrated ionization density and independent of the wave-length), that this single event must be an ionization, or similar process.

This has to take place inside a certain volume of only about 10 atomic-distances-cubed, in order to produce a specified mutation. According to our picture, the energy for overcoming the threshold must obviously be furnished by that explosion-like process, ionization or excitation.

I call it explosion-like because the energy spent in one ionization (spent, incidentally, not by the X-ray itself, but by a secondary electron it produces) is well known and has the comparatively enormous amount of 30 electron-volts.

It is bound to be turned into enormously increased heat motion around the point where it is discharged and to spread from there in the form of a ‘heat wave’, a wave of intense oscillations of the atoms.

This heat wave should still be able to furnish the required threshold energy of I or 2 electron-volts at an average ‘range of action’ of about ten atomic distances, is not inconceivable, though it may well be that an unprejudiced physicist might have anticipated a slightly lower range of action.

That in many cases the effect of the explosion will not be an orderly isomeric transition but a lesion of the chromosome, a lesion that becomes lethal when, by ingenious crossings, the uninjured partner (the corres- ponding chromosome of the second set) is removed and replaced by a partner whose corresponding gene is known to be itself morbid - all that is absolutely to be expected and it is exactly what is observed.

Their Efficiency Does Not Depend On Spontaneous Mutability

Quite a few other features are, if not predictable from the picture, easily understood from it. For example, an unstable mutant does not on the average show a much higher X-ray mutation rate than a stable one.

With an explosion furnishing an energy of 30 electron-volts you would certainly not expect that it makes a lot of difference whether the req uired threshold energy is a little larger or a little smaller, say I or 1·3 volts.

REVERSIBLE MUTATIONS

In some cases a transition was studied in both directions, say from a certain ‘wild’ gene to a specified mutant and back from that mutant to the wild gene.

In such cases the natural mutation rate is sometimes nearly the same, sometimes very different.

At first sight, one is puzzled, because the threshold to be overcome seems to be the same in both cases.

But, of course, it need not be, because it has to be measured from the energy level of the starting configuration, and that may be different for the wild and the mutated gene. (See Fig. 12 on p. 54, where’ I’ might refer to the wild allele, ‘2’ to the mutant, whose lower stability would be indicated by the shorter arrow.)

On the whole, I think, Delbriick’s ‘model’ stands the tests fairly well and we are justified in using it in further considerations.