Jack Schultz

Nucleic acids and their components as affected by the Y chromosome of Drosophila melanogaster: I. Constitution and amount of the ribonucleic acids in the unfertilized egg☆

Abstract 1. 1. To evaluate the relation of the heterochromatic chromosome regions to the nucleic acids, a comparison has been made of the nature and the amount of the ribonucleic acids in two types of unfertilized Drosophila melanogaster eggs; one, the normal wild type (XX), and the other containing the Y chromosome attached to one of the Xs ( X XY sc 8 ). 2. 2. The proportions of the purine and pyrimidine bases present in purified ribonucleic acids from both types of egg has been determined. 3. 3. The X XY sc 8 type RNA contains a significantly higher proportion of adenine than does the XX RNA. 4. 4. The ultraviolet absorption curves of hydrolysates of the two types of RNA correspond to those expected for a mixture of nucleotides calculated from the analysis of the respective base compositions. Both before and after hydrolysis, the X XY sc 8 RNA has a higher specific absorption than does the XX, in conformity with its higher content of adenine. 5. 5. The quantity of RNA per egg is substantially equivalent in the XX and the X XY sc 8 types. 6. 6. In the light of the new chemical data, earlier measurements of the effect of the Y chromosome on the cytoplasm of the egg are now interpreted as indicating an effect of the Y on the composition instead of the amount of RNA in the egg cytoplasm. In this way, the hypothesis of a relation between the heterochromatic regions and the nucleic acid metabolism of the cell receives new support.

Aspects of the Relation between Genes and Development in Drosophila

THE relation of genes to characters includes all the processes of development, from the gene in the chromosome to the end result. It is worth while first to consider what are the essential and what are the secondary characteristics of the problem. If we were to list what information is desirable, it would be, first of all, knowledge of the relation of the gene to the active product in the cytoplasm; of the arrangements in the cytoplasm for using the active product; of the possibilities for genic interaction within the nucleus, and afterwards, for interactions of the products in the cytoplasm; and of a number of other such properties of the system. All these are essentials of the problem of the effects of genes on development. We should subsequently turn our interest to the secondary interactions which occupy the embryologist, the relation of genes to organizers, and so on. Finally we should study the actual appearance in development of the characters differentiating, let us say, one mutant race from another. From this point of view, it is clear that the essentials are precisely the problems which are least accessible, The reason is simple: if we knew enough about developinent, and about cellular physiology in general, it would be possible to use the effects of genes on development to find out something about the nature of the gene. Contrariwise, were we familiar with the properties of the

Nucleic acids and their components as affected by the Y chromosome of Drosophila melanogaster: II. Nucleosides and related compounds in the acid soluble fraction of the unfertilized egg

Abstract 1. 1. The purine and pyrimidine-containing compounds in the cold acid-soluble fraction of the unfertilized Drosophila melanogaster egg have been investigated, in order to compare the contents of these substances in the two genetic types (XX and X XY sc 8 ) in which differences in the RNA composition have already been found. 2. 2. Identification of 14 compounds has been accomplished by determination of their Rfs on paper, ultraviolet absorption spectra at 3 pHs and by tests for deoxyribose, ribose and phosphorus. The quantities found were compared with analyses of similar extracts after hydrolysis to the free bases, to gain estimates of recoveries. Although low, these were the same for the extracts from both genetic types, permitting comparisons to be made. 3. 3. No nucleotides were recovered from these extracts, the major components being ribosides and deoxyribosides, with free bases present to a lesser degree. All the usual purine and pyrimidine bases with the exception of 5-methylcytosine have been found; in addition, some unidentified compounds having absorption maxima around 235 and 290 mμ in the ultraviolet were isolated chromatographically. 4. 4. The presence of deoxyribosides, and particularly of deoxyuridine in the extracts, is noteworthy in relation to the synthesis of DNA. 5. 5. The content of purine compounds in the extracts from X XY sc 8 eggs is more than double that of the XX type; the chief difference is due to adenine containing compounds. Although the total content of pyrimidines is the same in the two types, the proportions differ: cytosine is present in only trace amounts in the X XY sc 8 type, as compared with sizable amounts in the XX, the converse being the case for thymine. 6. 6. The existence of effects of the Y chromosome on the pool size of purine compounds, on the proportions of the pyrimidines, as well as on the base composition of the RNA, may indicate the site of action of this chiefly heterochromatic chromosome to be on the synthesis of the nucleic acid bases.

Structure of Drosophila melanogaster dAT replicated in an in vitro system.

Abstract Poly dAT found in Drosophila melanogaster has a lower density than poly dAT synthesized de novo , or than any naturally occurring poly dAT. Used as a primer in an E. coli DNA polymerase system, it proved highly efficient, and yielded a product of the same density. Nearest neighbor analysis showed this product to be composed predominantly of alternating sequences of dA and dT, with about 2% dG and dC present, but with a sufficient quantity of apposed dA-dT to account for its low density. Thus D. mel . dAT appears to have a distinctive structure differing from the other members of the group of naturally occurring poly dATs.

Antigens and Antibodies as Cell Phenotypes

The paradoxical features of transplantation specificity—its strict genetic control in transfers of tissue from strain to strain as compared with its malleability on tissue passage in foreign immunological environments where the host does not reject the implant (F1 hybrid passage, tolerance actively acquired by immature hosts, and so on)—present a challenge to genetic interpretation. The attempt is made in this article to show parallels between this behavior and such changes as the transformation of serotypes in Paramecium, in which the activity of genetic units becomes fixed as a cytoplasmic state—a cellular heredity persistent under specified environmental conditions but capable of change to an alternative state—while the genetic structure of the cell remains constant. The reactions appear to differ from those in the Paramecium case in that the diverse loci control a mosaic of different specificities, which change relatively independently of each other, in contrast to mutual exclusion of cytoplasmic states influenced by the different loci in Paramecium. The process of antibody formation is considered as a change in cellular phenotype from the same point of view. The primary response in the stem cells of the lymphoid tissues is interpretable as the establishment of a new cytoplasmic state in response to a nuclear stimulus by the foreign antigen. For the secondary response, the suggestion is made that a reaction of antigen with cellular antibody at the surface of stem cells exhibiting the primary response serves as the stimulus for specific proliferation of antibody-forming clones of cells. A parallel is drawn with the fertilization reaction, specifically with regard to the initiation of cleavage in eggs by antisera to them. Finally, a general chromosomal mechanism is sought for these phenomena, on the basis of activities of specific chromosome regions in response to special developmental stimuli, such as the disproportionate local synthesis of deoxyribonucleic acid demonstrated in the giant chromosomes of the Diptera. By a correlation of such activities with the nucleocytoplasmic system of ribonucleic acid granules on membranes, a possible mechanism appears for the formation, in response to environmental stimuli, of cytoplasmic states which might supply the persistent pattern required for this type of cell heredity. The analogies made, it is believed, provide a framework for the design of test experiments.

Malignancy and the genetics of the somatic cell.

I t is a truism by now that the change from the normal to the neoplastic cell must involve a change in cellular heredity. However, this statement is now so general as to be meaningless (compare Burdette, 1955); i t demands a rephrasing in concrete terms and a more definite conceptual analysis. First, let us examine what alternatives there are to changes in cellular heredity. These alternatives are usually proposed by nongeneticists, and some of them are merely the genetic hypothesis specified in terms of a particular phenotype. For example, Warburg’s (1956) postulate of a derangement of the respiratory mechanism of the cell is a special case of hypotheses placing emphasis on cytoplasmic factors such as mitochondria and, in more general terms, plasmagenes. Again, let us consider the virus hypothesis (for example, Oberling and GuCrin, 1954; and the topic of major emphasis in Subcellular Particles i~ the Neoplastic Process, 1957). This can logically be divided into two categories, one being the case in which the frank tumor cell no longer transmits the virus; in the other case, similar to that of the lysogenic bacteria, the virus is believed to perpetuate itself within the tumor cell and somehow to be responsible for the malignant phenotype. The first case is not really to be distinguished from the mutation hypothesis: here the virus is merely a special mutagenic agent. In the second, the virus has become part of a new cellular heredity, whether by way of incorporating itself into the chromosomal mechanism, or by some less regular mechanism of multiplication in the cytoplasm. A similar confusion between genotype and phenotype exists in the discussions of an immunological theory of cancer (Green, 1957); the antigens presumably lost in the cancer cell according to this discussion, must also be genetically determined; and we are back where we started. The examples just given quickly reduce, like others (for example, Caspersson and Santesson, 1942) to special cases of a genetic interpretation of the neoplastic phenomenon. More seriously considered as an alternative concept is the view that the malignant process is an aberration of the process of differentiation (Foulds, 1954; Furth, 1953; Greene, 1955). Implicit in this formulation is a contrast between the mutational processes and those of differentiation, the essential reason for the contrast being the low frequency and the random nature of mutation versus the regular occurrence and the exquisite order of differentiation. Here again, as in the two earlier examples, we are confronted by distinctions that eventually may turn out to be artificial, since they were based on imperfections of analysis. The fact is that

Chemical determinations of the effect of the X and Y chromosomes on the nucleic acid content of the larval salivary glands of Drosophila melanogaster.

Abstract Chemical determinations of desoxypentose (DNA) and pentose (PNA) nucleic acids were carried out on mature larval salivary glands from Drosophila melanogaster which were either of normal constitution (XX or XY) or contained an extra (X XY ) or lacked a Y chromosome (XO). Both DNA and PNA contents were found to be higher in the females than the males, presumably due to the additional X chromosome of the female. On a per gland basis, neither the addition nor the deficiency of a Y chromosome influenced the content of either PNA or DNA to an extent measurable by the present methods. The results are discussed with reference to the function of the heterochromatic regions, and the relation of the DNA content of the nucleus to the PNA content of the cell.

Human values and human genetics.

Almost 25 years ago, my family and I were on a freighter bound from California to Sweden. As we made our way down the coast, through the Panama Canal, and across the Caribbean, the sun was bright on the blue sea and one looked out over the deck railing, watching the porpoises at play. I was on my way to Stockholm to find out something about the relations of the nucleic acids to the genes. But during those long pleasant days, there was time to think about other things, things one ordinarily had not much tinie for. This was, as I have said, in the late thirties, when the social uses of science were being discussed not with our present apprehension but with hope. And I began to speculate on the social uses of the understanding of gene action, my own particular field of interest. Genetics was clearly one of the outstanding applied sciences: plant breeding and animal breeding were a sufficient testimony to that. But what could be the practical use of physiological or biochemical genetics as a specialty? The concept of the genes as the controllers of enzymes affecting specific reactions in development was sufficiently advanced then to take the center of the stage in such considerations. Again, in plant and animal breeding there was an obvious point: knowledge of the physiological aspects of gene action could surely make a contribution in the selection of useful varieties. I became more interested however in another line of thought, one more unfamiliar to my usual ways, namely, the possible usefulness of the physiological genetics of man himself. I should remind you that this was in the heyday of Nazi Germany, and the perversion of genetics for evil political purposes was clear to see. Nor were the proponents of eugenics elsewhere in the world distinguished for their objectivity, as Dunn has brought out in his graphic historical account of Human Genetics or, much earlier,