In a search for embryonic lethal mutants on the second chromosome ofDrosophila melanogaster, 5764 balanced lines isogenic for an ethyl methane sulfonate (EMS)-treatedcn bw sp chromosome were established. Of these lines, 4217 carried one or more newly induced lethal mutations corresponding to a total of 7600 lethal hits. Eggs were collected from lethal-bearing lines and unhatched embryos from the lines in which 25% or more of the embryos did not hatch (2843 lines) were dechorionated, fixed, cleared and scored under the compound microscope for abnormalities of the larval cuticle. A total of 272 mutants were isolated with phenotypes unequivocally distinguishable from wild-type embryos on the basis of the cuticular pattern. In complementation tests performed between mutants with similar phenotype, 48 loci were identified by more than one allele, the average being 5.4 alleles per locus. Complementation of all other mutants was shown by 13 mutants. Members of the complementation groups were mapped by recombination analysis. No clustering of loci with similar phenotypes was apparent. From the distribution of the allele frequencies and the rate of discovery of new loci, it was estimated that the 61 loci represent the majority of embryonic lethal loci on the second chromosome yielding phenotypes recognizable in the larval cuticle.

Mutations affecting the pattern of the larval cuticle inDrosophila melanogaster : I. Zygotic loci on the second chromosome.

MicroRNAs (miRNAs) are integral elements in the post-transcriptional control of gene expression. After the identification of hundreds of miRNAs, the challenge is now to understand their specific biological function. Signalling pathways are ideal candidates for miRNA-mediated regulation owing to the sharp dose-sensitive nature of their effects. Indeed, emerging evidence suggests that miRNAs affect the responsiveness of cells to signalling molecules such as transforming growth factor-beta, WNT, Notch and epidermal growth factor. As such, miRNAs serve as nodes of signalling networks that ensure homeostasis and regulate cancer, metastasis, fibrosis and stem cell biology.

MicroRNA control of signal transduction.

Inversions, deletions and insertions are important mediators of disease and disease susceptibility. We systematically compared the human genome reference sequence with a second genome (represented by fosmid paired-end sequences) to detect intermediate-sized structural variants >8 kb in length. We identified 297 sites of structural variation: 139 insertions, 102 deletions and 56 inversion breakpoints. Using combined literature, sequence and experimental analyses, we validated 112 of the structural variants, including several that are of biomedical relevance. These data provide a fine-scale structural variation map of the human genome and the requisite sequence precision for subsequent genetic studies of human disease.

Fine-scale structural variation of the human genome.

All animal embryos pass through a stage during which developmental control is handed from maternally provided gene products to those synthesized from the zygotic genome. This maternal-to-zygotic transition (MZT) has been extensively studied in model organisms, including echinoderms, nematodes, insects, fish, amphibians and mammals. In all cases, the MZT can be subdivided into two interrelated processes: first, a subset of maternal mRNAs and proteins is eliminated; second, zygotic transcription is initiated. The timing and scale of these two events differ across species, as do the cellular and morphogenetic processes that sculpt their embryos. In this article, we discuss conserved and distinct features within the two component processes of the MZT.

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The maternal-to-zygotic transition: a play in two acts

The best known genes of microbes, mice and men are those that specify enzymes. Wild type, mutant and heterozygote for variants of such genes differ in the catalytic activity at the step in the enzyme network specified by the gene in question. The effect on the respective phenotypes of such changes in catalytic activity, however, is not defined by the enzymes change as estimated by in vitro determination of the activities obtained from the extracts of the three groups. In vivo enzymes do not act in isolation, but are kinetically linked to other enzymes via their substrates and products. These interactions modify the effect of enzyme variation on the phenotype, depending on the nature and quantity of the other enzymes present. An output of such a system, say a flux, is therefore a systemic property, and its response to variation at one locus must be measured in the whole system. This response is best described by the sensitivity coefficient, Z, while is defined by the fractional change in flux over the fractional change in enzyme activity. (formula: see text). Its magnitude determines the extent to which a particular enzyme "controls" a particular flux or phenotype and, implicitly, determines the values that the three phenotypes will have. There are as many sensitivity coefficients for a given flux as there are enzymes in the system. It can be shown that the sum of all such coefficients equals unity. (formula: see text). Since n, the number of enzymes, is large, this summation property results in the individual coefficients being small. The effect of making a large change in enzyme activity therefore usually results in only a negligible change in flux. A reduction to 50% activity in the heterozygote, a common feature for many mutants, is therefore not expected to be detectable in the phenotype. The mutant would therefore be described as "recessive". The widespread occurrence of recessive mutants is thus seen to be the inevitable consequence of the kinetic structure of enzyme networks. The ad hoc hypothesis of "modifiers" selected to maximize the fitness of the heterozygote, as proposed by Fisher, is therefore unnecessary. It is based on the false general expectation of an intermediate phenotype in the heterozygote. Wright's analysis, substantially sound in its approach, proposed selection of a "safety factor" in enzyme activity. The derivation of the summation property explains why such safety factors are automatically present in almost all enzymes without selection.

/pdf/the-molecular-basis-of-dominance-3lvmp4jcph.pdf

The Molecular Basis of Dominance

By combining elements of two Y-autosome translocations with displaced autosomal breakpoints, it is possible to produce zygotes heterozygous for a deficiency for the region between the breakpoints, and also, as a complementary product, zygotes carrying a duplication for precisely the same region. A set of Y-autosome translocations with appropriately positioned breakpoints, therefore, can in principle be used to generate a non-overlapping set of deficiencies and duplications for the entire autosomal complement.-Using this method, we have succeeded in examining segmental aneuploids for 85% of chromosomes 2 and 3 in order to assess the effects of aneuploidy and to determine the number and location of dosage-sensitive loci in the Drosophila genome (Figure 5). Combining our data with previously reported results on the synthesis of Drosophila aneuploids (see Lindsley and Grell 1968), the following generalities emerge.-1. The X chromosome contains no triplo-lethal loci, few or no haplo-lethal loci, at least seven Minute loci, one hyperploid-sensitive locus, and one locus that is both triplo-abnormal and haplo-abnormal. 2. Chromosome 2 contains no triplo-lethal loci, few or no haplo-lethal loci, at least 17 Minute loci, and at least four other haplo-abnormal loci. 3. Chromosome 3 contains one triplo-lethal locus that is also haplo-lethal, few or no other haplo-lethal loci, at least 16 Minute loci, and at least six other haplo-abnormal loci. 4. Chromosome 4 contains no triplo-lethal loci, no haplo-lethal loci, one Minute locus, and no other haplo-abnormal loci.-Thus, the Drosophila genome contains 57 loci, aneuploidy for which leads to a recognizable effect on the organism: one of these is triplo-lethal and haplo-lethal, one is triplo-abnormal and haplo-abnormal, one is hyperploid-sensitive, ten are haplo-abnormal, 41 are Minutes, and three are either haplo-lethals or Minutes. Because of the paucity of aneuploid-lethal loci, it may be concluded that the deleterious effects of aneuploidy are mostly the consequence of the additive effects of genes that are slightly sensitive to abnormal dosage. Moreover, except for the single triplo-lethal locus, the effects of hyperploidy are much less pronounced than those of the corresponding hypoploidy.

/pdf/segmental-aneuploidy-and-the-genetic-gross-structure-of-the-56ek8kudqc.pdf

Segmental aneuploidy and the genetic gross structure of the drosophila genome

The presence of supercoiled deoxyribonucleic acid in the form of a relaxation complex is described for the antibiotic resistance plasmids R64, R28K, and R6K. The properties of these relaxation complexes indicate that they consist of a covalently closed circular deoxyribonucleic acid molecule associated with an activable, single strand-specific endonuclease.

Properties of the Relaxation Complexes of Supercoiled Deoxyribonucleic Acid and Protein of the R Plasmids R64, R28K, and R6K

I N 1959 SANDLER, HIRAIZUMI and SANDLER reported the discovery of the Segregation-Distorter locus ( S D ) in Drosophila melanogaster. In subsequent papers SANDLER and HIRAIZUMI described a number of puzzling properties of the SD system, including translocal modification and instability. An understanding of the problems of segregation distortion has been hampered by the lack of a suitable method for the analysis of experimental data. The present paper offers such a method; it does not attempt to develop causal explanations. SANDLER and HIRAIZUMI (1960) reported the phenomenon of instability. When original SD chromosomes were examined by crossing SD/SD+ males with homozygous SD+ females, the ratio of SD to total gametes recovered (which is defined as the k value) was in excess of 0.95. However, when recombinant SD chromosomes were obtained from SD/SD+ females, there was an increased maleto-male variation in k value, and stocks were defined as being stable, semistable, or unstable, according to the degree of this variation. A stabilizing modifier gene, St, was postulated, and located on the right arm of chromosome 2. When St was lost from an original SD chromosome as a consequence of crossing over, the recombinant chromosome yielded less stable k distributions. The hypothesis was examined by introducing St into both semistable and unstable lines; it was found that unstable lines were only partially stabilized, whereas semistable ones were rendered fully stable. The mechanism of instability was envisaged as involving two or more “SD states” either at the organisma1 or cellular Ievels. It was argued that each male in an unstable line has its own k value or SD state, and that there is a high mutability from one SD state to another, since the sons of males with both high and low k values yield similar unstable distributions. Alternatively, it was thought that an SD state characterizes each cell, and the k value of a male is determined by the proportions of meiocytes in each of several available states. The SANDLER and HIRAIZUMI hypothesis involves the introduction of new concepts; of SD states, SD-state mutation, and a stabilizer which controls this mutation. Our analysis dispenses with these assumptions and allows predictions on the relationship of the value of k and its variability.

An analysis of the instability of segregation-distorter in Drosophila melanogaster.

The problems of the Segregation-Distorter system are approached and unified in terms of an orthodox quantitative genetic system. It is shown that the SD system involves positive and negative modifier genes of varying strengths, that there is no major Stabiliser gene, and that the Activator gene is not unique. It is further argued that the SD phenomenon is mainly male limited, with "female effects" being of small magnitude.

https://www.genetics.org/content/genetics/70/3/405.full.pdf

An investigation of the components of segregation-distorter systems in drosophila melanogaster

The behaviour of two “meiotic drive” systems, Segregation-Distorter (SD) and the sex chromosome SC~SC* has been examined in the same meiocyte. It has been found that the two systems interact in a specific way. When the distorting effects of SD and sc4sc8 are against each other, there is no detectable interaction. Each system is apparently oblivious to the presence of the other, gametes being produced according to independence expectations. However when the affected chromosomes are at the same meiotic pole an interaction occurs; the survival probability of the gamete containing both distorted chromosomal products is increased, rather than being decreased by the combined action of two systems. HE Segregation-Distorter (SD) “meiotic drive” system in the Drosophila Tmale, discovered originally by SANDLER, HIRAIZUMI and SANDLER (1959), has been extensively studied and recently reviewed ( ZIMMERING, SANDLER and NICOLETTI 1970). HARTL, HIRAIZUMI and CROW (1967) demonstrated genetically that the SD/SD+ genotype operates by “gamete dysfunction,” so that the SD+ chromosome is generally recovered in very low frequency in the offspring of an SD/SD+ male, and the SD homologue appears among the progeny in excess of 99%. Other lines of inquiry have further specified the mechanism of the SD system. By means of electron microscope studies, NICOLETTI (1968), as well as TOKUYAW, PEACOCK and HARDY (1972), have provided cytological insights into the dysfunction hypothesis. The latter authors have shown that a maximum of half of the sperm of SD/SD+ males can exhibit developmental abnormalities, and they have inferred that the irregularities in sperm development are confined to the SD+ class. The statistical approach of MIKLOS and SMITH-WHITE (1971) has been generalised to provide a framework in which the SD system can be visualized in standard quantitative genetic terms (MIKLOS 1971,1972). Many previous problems in the genetic interpretation of SD data have stemmed from the way in which the observed progeny classes have been analysed. The use of k value (the ratio of SD gametes to the total recovered) has introduced complexities which have been avoided by MIKLOS and SMITH-WHITE (1971), who used the

/pdf/multiple-meiotic-drive-systems-in-the-drosophila-2g9dbaapco.pdf

George L. Gabor Miklos

Papers

Segmental aneuploidy and the genetic gross structure of the drosophila genome

Properties of the Relaxation Complexes of Supercoiled Deoxyribonucleic Acid and Protein of the R Plasmids R64, R28K, and R6K

An analysis of the instability of segregation-distorter in Drosophila melanogaster.

An investigation of the components of segregation-distorter systems in drosophila melanogaster

Multiple meiotic drive systems in the Drosophila melanogaster male.