Some Possible Bearings of Genetics on Pathology

Part 1

SOME POSSIBLE BEARINGS OF GENETICS ON PATHOLOGY

THOMAS HUNT MORGAN Professor of Experimental Zoology, Columbia University, New York.

Middleton Goldsmith Lecture delivered before the New York Pathological Society on February 3, 1922.

PRESS OF THE NEW ERA PRINTING COMPANY LANCASTER, PA. 1922

SOME POSSIBLE BEARINGS OF GENETICS ON PATHOLOGY

THOMAS HUNT MORGAN, PROFESSOR EXPERIMENTAL ZOOLOGY, COLUMBIA UNIVERSITY.

It has been pointed out in derision that modern genetics deals, for the most part, with the inheritance of abnormalities and disorders of various kinds—albinos, brachydactyls, cretins, dwarfs, freaks, giants, hermaphrodites, imbeciles, Jukes, Kallikaks, lunatics, morons, polydactyls, runts, simpletons, twins, and Zeros: in a word, with pathological phenomena in a very broad sense. This statement, intended as a reflection on genetics, carries with it an implication that a study dealing with such material cannot be of first rate importance. Such condemnation will probably be received by pathologists with the kind of smile it deserves, and I feel that I am not likely to be called upon here to answer such an indictment. Nevertheless, I am going to ask your indulgence, for a moment, since this slightly malicious statement should not be allowed to pass unchallenged, both because it is inaccurate, and because, even were it true, the result of such work might still be of more importance than its critics seem to realize. The source of this criticism is not without significance. It comes almost always from those whose interests lie in the field of evolution—in the old-fashioned use of that word. Now the articles of all evolutionary platforms include a plank about heredity. This plank is for the most part an ancient article that has been worn pretty thin. It is difficult to replace it (or at least it is supposed to be difficult to replace it) with the new wood of Mendelian genetics. Hence, I think, originates the criticism referred to.

It is true that the student of Mendelian heredity does not often trouble himself about the nature of the character that he studies. He is concerned rather with its mode of inheritance. But the geneticist knows that opposed to each defect-producing element in the germ-plasm there is a normal partner of that element which we call its allelomorph. We can not study the inheritance of one member of such a pair of genes without at the same time studying the other. Hence whatever we learn about those hereditary elements that stand for defects, we learn just as much about the behavior of the normal partners of those elements. In a word, heredity is not confined to a study of the shuffling of those genes that produce abnormal forms, but is equally concerned with what is going on when normal genes are redistributed. This method of pitting one gene against the other furnishes the only kind of information relating to heredity about which we have precise knowledge.

In man and in domesticated animals we find that individuals appear occasionally that are defective in one or another respect. Some of the defects are inherited. Rarely a new one appears that has not been seen before. But the majority of them are reappearances of characters that have been carried under the surface as recessive genes in the germ-plasm. Today we recognize that each of these modifications, if recessive, has first arisen as a mutational change in a single gene before it appeared on the surface as a character by the coming together of two such genes. Mendelism has furnished some information as to the way in which these hidden genes may get dispersed in the race. An example will serve to make this clear, Fig. 1.

If a fly with vestigial wings, a recessive character, is crossed to a wild fly with long wings, all the offspring (F₁’s) will have long wings. If these are bred to each other the offspring will be of two kinds, like their grandparents, in the ratio of three long winged to one vestigial fly. The extracted vestigials will breed true to vestigial. The fact that the gene for vestigial has been carried by long winged F₁ parents has not affected the gene in any way, for the second generation of vestigials has wings as short as those of their grandparents.

I have brought forward this case not so much to illustrate Mendel’s law of segregation as to use the facts for another purpose.

When the vestigial fly was crossed to normal the mutant character disappeared in the hybrid. If such a hybrid is out-bred to normal all the offspring are again normal, but half of them carry the vestigial gene. If these are out-crossed again still only normal flies appear, Fig. 2. If such out-breeding is continued the vestigial gene will become widely distributed without ever showing itself at the surface, so to speak. If, however, at any time two hybrid flies mate, then a quarter of the offspring will have vestigial wings. It might seem then that the character had appeared for the first time in the race, if one did not know its past. In reality its gene may have been there for some time. Probably many of the recessive defects and malformations that appear in the human race—at least those due to hereditary factors—have had representative genes in the germ-plasm for several generations before they have appeared on the surface.

We do not know how widespread recessive genes are in the human germ-plasm. The fact that defective individuals appear in certain communities may be safely interpreted to mean that individuals bearing the same gene have at last come together. On the other hand, the absence of such individuals from the community, at large, may only mean that the chance of suitable combinations is small, and does not mean necessarily that the gene in question is confined to the community within which the defects have been recorded.

My illustration may give, however, an entirely erroneous idea as to the chance of a recessive character contaminating the race. If one can control the matings, so that out-breeding takes place each time, the result would undoubtedly be like that in our diagram; but what chance is there for a recessive character, that is neither beneficial nor injurious, if left to itself, to contaminate widely the race with its gene? The answer is that for any one defect there is hardly any chance at all. On the other hand, there is always a possibility that a defect may become widespread despite the chances against each in turn. If a recessive character is selected against each time it appears on the surface, the chance is extraordinarily small that the gene for such a character could ever become widespread in a race. If the recessive character is advantageous, its chance is somewhat better, but still the chance that it may be lost is very great.

Let us turn for a moment to the inheritance of a Mendelian dominant character, and to simplify the situation let us first assume that the character itself is neither advantageous nor disadvantageous.

It is popularly supposed that if a trait is dominant it will be expected to spread more widely in the race than will a recessive character. This is owing largely to a verbal confusion. Colloquially we think of dominance as meaning spreading. A dominant nation, for example, is one that is spread widely over the face of the earth. But a Mendelian dominant should carry no such implications. A dominant gene, if crossed into a race, will stand the same chances of being lost as a recessive gene, Fig. 3.

The situation is similar in many ways to the inheritance of surnames in any human population. A new surname introduced is likely to disappear after a few generations. There is a bare chance, however, that it may spread.

Of course if a dominant character is advantageous in itself, it will have a better chance of spreading through the race, than will an advantageous recessive character, because every hybrid that carries one dominant gene shows also the character, which increases the chance that it will propagate and spread the genes. But, on the other hand, if a dominant character is injurious it will have a smaller chance of spreading than will an injurious recessive character; for, the recessive may be carried by the hybrid without showing itself, and therefore will not place the hybrid individual at a disadvantage.

An excellent illustration of dominance is that recently published by Mohr. He has traced, through five generations of a Norwegian family, the inheritance of a shortened first digit. In the history of this case there is one record that is extraordinarily interesting. A child was born that was so completely crippled that it died in infancy. One parent was short fingered; the other, a cousin, was probably also short fingered. It is possible that the child had a double inheritance of this character; it was a pure dominant. If this is true, then it appears that this character can survive to maturity only in the hybrid condition. As a matter of fact, in other animals there are some well-recognized cases of this sort. That of the yellow mouse is the best known. Yellow is a dominant and in double dose it kills; therefore when yellow is bred to yellow all the pure yellows die. The hybrid yellows and the pure blacks (in Fig. 4) survive. Here yellow is discriminated against in the embryo; but, being dominant, it still appears twice as frequently in each generation as does the alternate character (here black). In the fly, Drosophila, we have at least 25 dominant lethal characters, but as yet we have no knowledge as to why such a high percentage of dominant characters should be lethal when homozygous.

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