Major Structural Rearrangements Research Articles

Cytogenetic analysis of the action of carcinogens and tumour inhibitors inDrosophila melanogaster V. Differential genetic response to the alkylating mutagens and x-radiation

1. Chemical mutagens have been shown to act on gene loci which are apparently stable to X-radiation. By the use of a group of alkylating compounds it was possible to induce nearly 200 ‘new’ sex-linked recessive visibles (ranks 1 and 2), different in phenotype and genetic position from those induced by the physical agent. 2. The ratio of sex-linked recessive visibles/lethals in the same sample of treated chromosornes is exceptionally high for a particular amino-acid mustard (p-N-di(chloroethyl)phenylalanine); which mutates 2–3 times as many morphogenesis loci (relative to lethals) as X-rays or any other alkylating compound. 3. The distribution of the loci of recessive lethals along the X-chromosome is the same for three representative alkylating mutagens, and is significantly different from that for X-rays. A significant difference also occurs in the distribution of theF 1 viable breaks induced by an imine (tri(ethyleneimino)triazine) as compared to X-radiation. 4. The rate of induction of small deficiencies by the alkylating compounds is nearly twice that produced by mutagenically equivalent doses of X-rays. Evidence is available that chemically induced deficiencies result from errors in gene reproduction rather than chromosome breaks. 5. There is a shortage in major structural rearrangements in viable sperm, as well as among the sex-linked recessive lethals, under the effect of the alkylating agents compared with mutagenically equivalent doses of X-rays. This shortage, in the case of the tri(ethyleneimino)triazine rearrangement lethals, has been shown to be due to differences in the properties of the chromosome breaks induced by the imine and X-rays, rather than a lower efficiency in the induction of the primary chromosome breaks by the chemical agent. 6. The dose effects as regards the induction of sex-linked recessive lethals, dominant lethals and viable chromosome breaks, are identical for tri(ethyleneirnmo)triazne and X-rays. This suggests that the hypothesis of direct action of radiations on the genetic material is not conclusively proved by evidence based solely on dose relations. 7. Among the sex-linked recessive lethals induced by various closes of tri(ethyleneimiao)triazine there is a fixed proportion showing cytoiogically detectable chromosome aberrations: major rearrangements and deficiencies. Within this fixed proportion, the fraction with rearrangements increases and that with deficiencies decreases with increase in dose. The bearing of this observation on the mechanism of induction of chromosome breaks by chemical means has been outlined.

Cytogenetic analysis of the action of carcinogens and tumour inhibitors in Drosophila melanogaster. I. 1:2, 3:4-diepoxybutane.

This analysis is part of an investigation designed for the elucidation of the correlation between mutagenesis and carcinogenesis. Diepoxybutane was found to be a strong mutagen when injected into the haemocoel of adultDrosophilamales, producing lethal, semi-lethal and ‘visible’ mutations. One of the ‘visible’ mutations produced resulted in the appearance of neoplastic melanotic ‘tumours’ in the offspring of the treated flies. This is most significant in relation to the mutation theory of cancer causation. The successive stages of the male germ line manifest a varied susceptibility to mutagenic action, there being a certain stage among the earlier germ cells which is the most sensitive. The proportion of major structural rearrangements among the sex-linked recessive lethals produced by chemical agents (diepoxybutane and mustard gas) is far lower than that produced by mutagenically equivalent doses of X-rays. Small deficiencies, on the other hand, are twice as frequent among diepoxybutane lethals as among the same type of mutation induced by mustard gas or X -rays. The quality of the bands involved in the deficiencies is also different, diepoxybutane affecting the darker bands of the salivary glandX-chromosome preferentially, mustard gas the lighter ones. This might indicate that diepoxybutane has a preferential action on the gene loci with a higher charge of nucleic acid. A ‘coarse’ specificity for chromosome segments, however, does not seem to occur. The distributions of recessive lethals and loci of damage, induced by the diepoxide and mustard gas in the successive segments of theX-chromosome, are not significantly different. Mosaics for visible mutations and chromosomal changes occur more frequently after treatment with chemical mutagens than after X-radiation. This mosaicism has been explained on the basis of the multiple-strand structure of the mitotic chromosome and partial damage to some of its subunits.