Fig. 14.Diagram showing inheritance of a sex-linked recessive lethal (“tumor”) factor inDrosophila melanogaster. Here, in the center of the diagram, the sex-chromosome that carries the lethal factor is represented by the black rod. A female with the tumor-factor, normal wings and red eyes, in one of her sex-chromosomes and with the factors for yellow wings and eosin eyes in the other is bred in each generation to a male with yellow wings and eosin eyes. In the next generation there are twice as many daughters as sons, since all the sons that carry the black chromosome die. The half of the daughters (i.e., those not yellow eosin) that carry the black chromosome repeat the same history. The linkage of yellow and eosin enables one to pick out in each generation those daughters that carry the tumor-factor.
Fig. 14.Diagram showing inheritance of a sex-linked recessive lethal (“tumor”) factor inDrosophila melanogaster. Here, in the center of the diagram, the sex-chromosome that carries the lethal factor is represented by the black rod. A female with the tumor-factor, normal wings and red eyes, in one of her sex-chromosomes and with the factors for yellow wings and eosin eyes in the other is bred in each generation to a male with yellow wings and eosin eyes. In the next generation there are twice as many daughters as sons, since all the sons that carry the black chromosome die. The half of the daughters (i.e., those not yellow eosin) that carry the black chromosome repeat the same history. The linkage of yellow and eosin enables one to pick out in each generation those daughters that carry the tumor-factor.
Fig. 14.Diagram showing inheritance of a sex-linked recessive lethal (“tumor”) factor inDrosophila melanogaster. Here, in the center of the diagram, the sex-chromosome that carries the lethal factor is represented by the black rod. A female with the tumor-factor, normal wings and red eyes, in one of her sex-chromosomes and with the factors for yellow wings and eosin eyes in the other is bred in each generation to a male with yellow wings and eosin eyes. In the next generation there are twice as many daughters as sons, since all the sons that carry the black chromosome die. The half of the daughters (i.e., those not yellow eosin) that carry the black chromosome repeat the same history. The linkage of yellow and eosin enables one to pick out in each generation those daughters that carry the tumor-factor.
All males that get their single X with this tumor-gene will die; therefore, since no adult males carry it, normal males must be used for mating in each generation. They are mated to females that are heterozygous for the chromosome carrying the tumor genes. Such matings as I have said always give two daughters to one son. But since half the daughters are normal and half carry the gene for tumor it is desirable to be able to pick out the latter from the stock. Therefore we have made use of a trick we call “marking the chromosome,” which means that we use a male whose sex chromosome carries a known gene near the tumor locus. By using this type of male in successive generations we get two types of daughters: one type like their surviving brothers in eye color that do not carry the tumor-gene and the other daughter with normal eyes that carries it. We use only the latter to continue the stock, but we could eliminate the tumor from the stock at once by using the other kind of daughters.
Curiously enough the tumor no longer appears in the inbred stock but reappears again on out-breeding. Nevertheless the sex-ratio in the inbred stock continues as before, and since the missing males are those with red eyes we know that the tumor-gene is still present and doing its deadly work—only now the young male larvæ die even before they reach the age at which the tumor is due to appear.
So far I have spoken of heredity as though that term had become synonymous with Mendelian heredity. Those of as who are at work on Mendelian inheritance are often criticized as too narrow. It is said that we do not recognize that any other kind of inheritance takes place. I do not think the criticism is quite fair, because, in the first place, the very great number of variations studied has been shown to conform to the Mendelian principles or at least to be capable of such interpretation. There are, however, a few exceptional cases. In certain albino plants it has been shown that the inheritance of albinism can be traced to the behavior of the chlorophyll bodies in the cytoplasm. Thechlorophyll bodies are known to divide and to be distributed to the two daughter cells at each division independently of the nuclear division and of the maturation process in the egg.
Why, then, it is asked, may not there be present in the cytoplasm of the cell other self-perpetuating bodies that are responsible for certain kinds of inheritance? Why not go further and ask, why, since the cytoplasm appears to be handed down from cell to cell, may it not furnish also a different medium for inheritance of characters? Theoretically such an argument is logical. No student of Mendelism would I think deny such a possibility. But, as a matter of fact, it is not going too far to say that, at present, there is little evidence that such inheritance takes place, except in a few special cases, like that of the chlorophyll bodies. It is safe, I think, to say that if cytoplasmic inheritance played any important rôle in heredity in the higher animals and plants, we should expect, by now, to have found many cases of it. None are known to us.
Whether Mendel’s laws of heredity apply to unicellular animals, to bacteria and to similar types, in which the mechanism for this type of inheritance has not been shown to exist, can not be affirmed or denied from the evidence at hand.
There are at present three outstanding cases in the higher animals, in which an induced variation is said to be inherited afterwards. These cases are of great interest to pathology. We can not afford to pass them over. First, there is Brown-Sequard’s claim that injuries to the nerve cord or to the cervical or sciatic nerves of guinea pigs produce effects that are transmitted.
Second, there are the cases of the inherited effects caused by alcohol in guinea pigs discovered by Stockard.
Third, there is Guyer’s evidence that an effect on the eye, caused by foreign serum, is transmitted.
Brown-Sequard’s experiments have been repeated several times; almost always with negative results. Today his claims are practically forgotten.
Stockard’s results with guinea pigs, unlike those of Brown-Sequard, have been done under carefully controlled conditions.He has guarded against abnormalities in his stock by using pedigreed material. The malformations that reappear in successive generations are general rather than specific. Such organs as the eye are those hardest hit, but this is supposed to be rather a by-product of the general debility of the individual. Stockard points out that the alcohol has affected the germ cells, and it is through these that the effects are transmitted. Now if one or more genes had been permanently changed we should expect to have evidence of Mendelian inheritance. The results do not show convincingly that the inheritance is not Mendelian, but it does not appear to be so. There is another possibility. Recent results have shown that rarely entire blocks of genes—pieces of the chromosomes—may be duplicated (owing to imperfect separation) or pieces may be lost. Here the effects on the organism are more far-reaching than when a single gene is changed. It remains to be discovered whether, in some such way as this, Stockard’s remarkable results may be brought into line.
Guyer injected the crushed lens of rabbits into fowls. From the blood of the fowl he obtained serum that was injected into pregnant rabbits. The offspring of these rabbits whether male or female often had defective eyes and lenses. The defect was even transmitted to later generations. Here also the germ cells of the embryo may be changed by serum that at the same time affects the development of the eyes of the embryo in utero.
If this is the case we should expect, as Guyer pointed out, that the germ cells of the pregnant mother (into which the serum was injected) would also show effects. It should have been a simple matter to show this by a proper test. The test that Guyer made, namely by out-breeding the mother and finding no defective F₁ young, was quite inadequate if, as appears to be the case, the character is a recessive.
It is important to keep clearly in mind that there are two distinct questions involved in these three cases. Genetics has to deal with only one of them. There is first the question of the action of environment on the germ cells. Genetics has nothing to do with this question. There is then to be determined whether,if variations may be induced in these ways, they fall into one or another of the Mendelian moulds. This is for the geneticist to determine, but he finds himself in a curious predicament, for it can not be claimed that any of these three cases have been shown to give a direct Mendelian result—but neither can it be denied that they may possibly come under the scheme, or some modification of it. There we must leave the matter at present.
If I have appeared at times overcritical concerning the application of genetics to pathology, it is not because I do not sympathize with the attempts that have been made to apply genetics to pathology. I realize, of course, that from the nature of the case much of this work is pioneer work, where rough and ready methods have often to be resorted to. So long as this is kept in view, no harm can be done in attempting to find how far Mendel’s principles can apply to heredity in man. But I want to enter a protest against the danger of premature conclusions drawn from insufficient evidence. In our enthusiasm in applying Mendel’s laws, we should be careful not to compromise them.