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PubMed1983

Benzo[a]pyrene induction of extrachromosomal viral DNA synthesis in rat cells transformed by polyoma virus.

The effect of the carcinogen benzo[a]pyrene (BP) on the production of specific extrachromosomal DNAs has been studied in transformed rat cells containing integrated polyoma virus DNA. Exposure of cells previously transformed by the polyoma virus mutant ts-a, which codes for a temperature sensitive T antigen, to a non-toxic dose of BP (0.25 micrograms/ml) enhanced the production of free polyoma DNA at the population level. This occurred at 33 degrees C (the permissive temperature) but not at 39 degrees C, indicating that the BP effect was dependent on the function of the T antigen of polyoma virus. In the same cell system, BP did not induce the production of extrachromosomal copies of two endogenous rat retrovirus genomes, the 30S RNA virus and rat leukemia virus. Thus, the effects on integrated polyoma DNA are quite specific and do not reflect a generalized increase in asynchronous DNA replication and excision. Further studies utilizing a carcinogenic metabolite of BP, benzo[a]pyrene trans-7,8-dihydrodiol-9,10-epoxide (anti) (BPDE), on a rat cell line transformed by wild type (WT) polyoma virus demonstrate that the enhancement of polyoma DNA synthesis persists for at least 5 days after a single exposure to BPDE, despite the rapid decay of this compound. In addition, enhanced synthesis of polyoma DNA can be induced by fusion of normal rat fibroblasts previously exposed to BPDE with polyoma transformed rat fibroblasts not exposed to BPDE. It appears, therefore, that the effects we have observed are not due solely to direct carcinogen damage at the level of the integrated polyoma virus DNA, but may instead involve the induction of cellular factor(s) that act indirectly to enhance asynchronous replication of polyoma DNA.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed2002

A genetic screen for improved plasmid segregation reveals a role for Rep20 in the interaction of Plasmodium falciparum chromosomes.

Bacterial plasmids introduced into the human malaria parasite Plasmodium falciparum replicate well but are poorly segregated during mitosis. In this paper, we screened a random P.falciparum genomic library in order to identify sequences that overcome this segregation defect. Using this approach, we selected for parasites that harbor a unique 21 bp repeat sequence known as Rep20. Rep20 is one of six different repeats found in the subtelomeric regions of all P.falciparum chromosomes but which is not found in other eukaryotes or in other plasmodia. Using a number of approaches, we demonstrate that Rep20 sequences lead to dramatically improved episomal maintenance by promoting plasmid segregation between daughter merozoites. We show that Rep20(+), but not Rep20(-), plasmids co-localize with terminal chromosomal clusters, indicating that Rep20 mediates plasmid tethering to chromosomes, a mechanism that explains the improved segregation phenotype. This study implicates a direct role for Rep20 in the physical association of chromosome ends, which is a process that facilitates the generation of diversity in the terminally located P.falciparum virulence genes.

Animals↗
PubMed1984

Genetics of Chlamydomonas reinhardtii diploids. II. The effects of diploidy and aneuploidy on the transmission of non-Mendelian markers.

The transmission of two non-Mendelian drug resistance markers has been studied in crosses of Chlamydomonas reinhardtii involving diploids and aneuploids with different mating type genotypes. Under normal laboratory conditions for gametogenesis, mating and zygote maturation, the transmission pattern of the non-Mendelian markers sr-u-1 (resistance to streptomycin) and spr-u-1-27-3 (resistance to spectinomycin) is primarily determined by the mating type genotypes of the parental cells. Our results confirm and expand an earlier observation suggesting that an apparent codominant function of the female (mt+) allele in regulating chloroplast gene transmission in meiosis appears to be distinct and separate from its recessive function in regulating mating behavior. The chloroplast DNA complement (as indexed by the number of extranuclear DNA-containing bodies) may exert a secondary effect on the transmission of these markers. Within a mating type group (mt+/mt- or mt-/mt-) a cell line with more chloroplast DNA tended to transmit its non-Mendelian markers more frequently than a cell line with less chloroplast DNA.

Aneuploidy↗
PubMed1984

Natural selection with nuclear and cytoplasmic transmission. I. A deterministic model.

A deterministic model allowing variation at a nuclear genetic locus in a population segregating two cytoplasmic types is formulated. Additive, multiplicative and symmetric viability matrices are analyzed for existence and stability of equilibria. The protectedness of polymorphisms in both nuclear genes and cytoplasmic types is also investigated in the general model. In no case is a complete polymorphism protected with this deterministic model. Results are discussed in light of the extensive variation in mtDNA that has recently been reported.

Animals↗
PubMed1985

Genetic variation for the sex ratio in Nasonia vitripennis.

We detected genetic variation for the sex ratio in the parasitoid wasp Nasonia vitripennis by analysis of inbred lines and with an artificial selection experiment. Sex ratios differed significantly among five independently isolated lines. Furthermore, sex ratio in broods produced by single females in single hosts shifted from 80-90% female to 50-55% female in 13 to 15 generations in each of two replicate selection lines. The final sex ratios of both selection lines were significantly lower than any of the inbred line sex ratios. Backcrosses revealed that the selection response was due to nuclear genes acting through the female parent. In light of known facultative sex ratio behavior and major genes affecting sex ratio in Nasonia, our results suggest that population and individual sex ratios in this species are molded by processes at both genetic and behavioral levels.

Animals↗
PubMed1988

Amplification of KP elements associated with the repression of hybrid dysgenesis in Drosophila melanogaster.

Mobile P elements in Drosophila melanogaster cause hybrid dysgenesis if their mobility is not repressed. One type of repression, termed P cytotype, is a complex interaction between chromosomes carrying P elements and cytoplasm and is transmitted through the cytoplasm only of females. Another type of repression is found in worldwide M' strains that contain approximately 30 copies per individual of one particular P element deletion-derivative termed the KP element. This repression is transmitted equally through both sexes. In the present study we show that biparentally transmitted repression increases in magnitude together with a rapid increase in KP copy-number in genotypes starting with one or a few KP elements and no other deletion-derivatives. Such correlated increases in repression and KP number per genome occur only in the presence of complete P elements, supporting the interpretation that they are probably a consequence of the selective advantage enjoyed by flies carrying the highest numbers of KP elements. Analysis of Q strains also reveals the presence of qualitative differences in the way the repression of dysgenesis is transmitted. In general, Q strains not containing KP elements have the P cytotype mode of repression, whereas Q strains with KP elements transmit repression through both sexes. This difference among Q strains further supports the existence of at least two types of repression of P-induced hybrid dysgenesis in natural populations of D. melanogaster.

Animals↗
PubMed1992

Tandem repeats in extrachromosomal ribosomal DNA of Dictyostelium discoideum, resulting from chromosomal mutations.

Extrachromosomal ribosomal DNA in the simple eukaryote Dictyostelium discoideum is readily separated from chromosomal DNA by orthogonal field electrophoresis (OFAGE), forming a prominent band in the 110-kb region of the gel. Here we show that mutations in at least two chromosomal genes give rise to a ladder of rDNA bands increasing in size up to about 300 kb. One of these mutations, the rrcA350 allele, which is recessive to wild type and maps to the centromere-proximal region of linkage group II, has an unstable phenotype; spontaneous revertants, which no longer exhibit the rDNA ladder, have been recovered. Another mutation rrc-351, provisionally mapped to linkage group IV, is dominant to wild type. The rDNA ladder is caused by concatamerization of a 34-kb fragment in the nontranscribed central spacer region of the 88-kb linear rDNA palindrome. Restriction enzyme analysis has revealed that each concatamer is generated by crossovers between two rDNA molecules.

Animals↗
PubMed1994

The search for homology does not limit the rate of extrachromosomal homologous recombination in mammalian cells.

Mouse LTK- cells were transfected with a pair of defective Herpes simplex virus thymidine kinase (tk) genes. One tk gene had an 8-bp insertion mutation while the second gene had a 100-bp inversion. Extrachromosomal homologous recombination leading to the reconstruction of a functional tk gene was monitored by selecting for tk positive cells using medium supplemented with hypoxanthine/aminopterin/thymidine. To assess whether the search for homology may be a rate-limiting step of recombination, we asked whether the presence of an excess number of copies of a tk gene possessing both the insertion and inversion mutations could inhibit recombination between the singly mutated tk genes. Effective competitive inhibition would require that homology searching (homologous pairing) occur rapidly and efficiently. We cotransfected plasmid constructs containing the singly mutated genes in the presence or absence of competitor sequences in various combinations of linear or circular forms. We observed effective inhibition by the competitor DNA in six of the seven combinations studied. A lack of inhibition was observed only when the insertion mutant gene was cleaved within the insertion mutation and cotransfected with the two other molecules in circular form. Additional experiments suggested that homologous interactions between two DNA sequences may compete in trans with recombination between two other sequences. We conclude that homology searching is not a rate-limiting step of extrachromosomal recombination in mammalian cells. Additionally, we speculate that a limiting factor is involved in a recombination step following homologous pairing and has a high affinity for DNA termini.

Animals↗
PubMed1994

The SUP35 omnipotent suppressor gene is involved in the maintenance of the non-Mendelian determinant [psi+] in the yeast Saccharomyces cerevisiae.

The SUP35 gene of yeast Saccharomyces cerevisiae encodes a 76.5-kD ribosome-associated protein (Sup35p), the C-terminal part of which exhibits a high degree of similarity to EF-1 alpha elongation factor, while its N-terminal region is unique. Mutations in or overexpression of the SUP35 gene can generate an omnipotent suppressor effect. In the present study the SUP35 wild-type gene was replaced with deletion alleles generated in vitro that encode Sup35p lacking all or a part of the unique N-terminal region. These 5'-deletion alleles lead, in a haploid strain, simultaneously to an antisuppressor effect and to loss of the non-Mendelian determinant [psi+]. The antisuppressor effect is dominant while the elimination of the [psi+] determinant is a recessive trait. A set of the plasmid-borne deletion alleles of the SUP35 gene was tested for the ability to maintain [psi+]. It was shown that the first 114 amino acids of Sup35p are sufficient to maintain the [psi+] determinant. We propose that the Sup35p serves as a trans-acting factor required for the maintenance of [psi+].

Amino Acid Sequence↗
PubMed1995

Quantitative genetics of response to competitors in Nemophila menziesii: a field experiment.

Recent investigations of evolution in heterogeneous environments have begun to accommodate genetic and environmental complexity typical of natural populations. Theoretical studies demonstrate that evolution of polygenic characters depends heavily on the genetic interdependence of the expression of traits in the different environments in which selection occurs, but information concerning this issue is scarce. We conducted a field experiment to assess the genetic variability of the annual plant Nemophila menziesii in five biotic regimes differing in plant density and composition. Significant, though modest, additive genetic variance in plant size was expressed in particular treatments. Evidence of additive genetic tradeoffs between interspecific and intraspecific competitive performance was found, but this result was not consistent throughout the experiment. Two aspects of experimental design may tend to obscure genetically based tradeoffs across environments in many previously published experiments: (1) inability to isolate additive genetic from other sources of variation and (2) use of novel (e.g., laboratory) environments.

Analysis of Variance↗
PubMed1995

Variability within the Seychelles cytoplasmic incompatibility system in Drosophila simulans.

In Drosophila simulans, we described a cytoplasmic incompatibility (CI) system (Seychelles) restricted to insular populations that harbor the mitochondrial type SiI. Since then, these populations have been shown to be heterogeneous, some being infected by one Wolbachia genetic variant only (wHa), while others are infected simultaneously by wHa and by another variant (wNo) always found in association with wHa. We have experimentally obtained two D. simulans strains only infected by the wNo variant. This variant determines its own cytoplasmic incompatibility type. In particular, the cross between wNo-bearing flies and wHa-bearing ones is bidirectionally incompatible. The Seychelles CI type, stricto sensu, is distinguished by being determined by the simultaneous presence of two Wolbachia variants that we found to be mutually incompatible. In addition, we observed incomplete maternal transmission of the Wolbachia.

Animals↗
PubMed1995

Evolutionary consequences of mutation and selection within an individual.

Whether in sexual or asexual organisms, selection among cell lineages during development is an effective way of eliminating deleterious mutations. Using a mathematical analysis, we find that relatively small differences in cell replication rates during development can translate into large differences in the proportion of mutant cells within the adult, especially when development involves a large number of cell divisions. Consequently, intraorganismal selection can substantially reduce the deleterious mutation rate observed among offspring as well as the mutation load within a population, because cells rather than individuals provide the selective "deaths" necessary to stem the tide of deleterious mutations. The reduction in mutation rate among offspring is more pronounced in organisms with plastic development than in those with structured development. It is also more pronounced in asexual organisms that produce multicellular rather than unicellular offspring. By effecting the mutation rate, intraorganismal selection may have broad evolutionary implications; as an example, we consider its influence on the evolution of ploidy levels, finding that cell-lineage selection is more effective in haploids and tends to favor their evolution.

Biological Evolution↗
PubMed1996

Mosaic analysis using a ncl-1 (+) extrachromosomal array reveals that lin-31 acts in the Pn.p cells during Caenorhabditis elegans vulval development.

We describe a genetic mosaic analysis procedure in which Caenorhabditis elegans mosaics are generated by spontaneous loss of an extrachromosomal array. This technique allows almost any C. elegans gene that can be used in germline transformation experiments to be used in mosaic analysis experiments. We identified a cosmid clone that rescues the mutant phenotype of ncl-1, so that this cell-autonomous marker could be used to analyze mosaic animals. To determine the sites of action for unc-29 and lin-31, an extrachromosomal array was constructed containing the ncl-1(+) cosmid linked to lin-31(+) and unc-29(+) cosmids. This array is mitotically unstable and can be lost to produce a clone of mutant cells. The specific cell division at which the extrachromosomal array had been lost was deduced by scoring the Ncl phenotypes of individual cells in genetic mosaics. The Unc-29 and Lin-31 phenotypes were then scored in these animals to determine in which cells these genes are required. This analysis showed that unc-29, which encodes a subunit of the acetylcholine receptor, acts in the body muscle cells. Furthermore, lin-31, which specifies cell fates during vulval induction and encodes a putative transcription factor similar to HNF-3/fork head, acts in the Pn.p cells.

Animals↗
PubMed1998

Mitochondrial genotype segregation during preimplantation development in mouse heteroplasmic embryos.

Mitochondrial DNA content remains constant between the mature egg and the blastocyst stage in mammals, making this the only period in development when genotypes segregate to daughter cells without the confounding effect of genotype replication. To analyze the segregation patterns of mitochondrial DNA during preimplantation development, we introduced polymorphic mitochondria either peripherally (cytoplast transplantation) or in the perinuclear vicinity (karyplast transplantation) into zygotes. Genotype ratios were significantly more variable among blastomeres from cytoplast (coefficient of variation = 83.8%) than karyoplast (coefficient of variation = 34.7%) reconstructed zygotes. These results suggest that heteroplasmy caused by polymorphic mitochondria positioned in the periphery of oocytes at the time of fertilization shows a more stringent segregation pattern than when the organelle is in the vicinity of the nucleus. Moreover, donor-to-host mitochondrial genotype ratios in karyoplast-derived groups increased significantly during development, particularly in the C57BL/6 group, where the ratio practically doubled between the four-cell (17.3%) and the blastocyst stage (29.6%). Although the mechanisms controlling this preferential replication of nuclear-type mitochondrial DNA are unknown, it is suggested that access to nuclear-derived transcription and replication factors could lead to the preferential replication of perinuclear mitochondrial genotypes during morula and blastocyst formation.

Animals↗
PubMed1999

The Drosophila pumilio gene encodes two functional protein isoforms that play multiple roles in germline development, gonadogenesis, oogenesis and embryogenesis.

The pumilio (pum) gene plays an essential role in embryonic patterning and germline stem cell (GSC) maintenance during oogenesis in Drosophila. Here we report on a phenotypic analysis using pum(ovarette) mutations, which reveals multiple functions of pum in primordial germ cell proliferation, larval ovary formation, GSC division, and subsequent oogenic processes, as well as in oviposition. Specifically, by inducing pum(-) GSC clones at the onset of oogenesis, we show that pum is directly involved in GSC division, a function that is distinct from its requirement in primordial germ cells. Furthermore, we show that pum encodes 156- and 130-kD proteins, both of which are functional isoforms. Among pum(ovarette) mutations, pum(1688) specifically eliminates the 156-kD isoform but not the 130-kD isoform, while pum(2003) and pum(4277) specifically affect the 130-kD isoform but not the 156-kD isoform. Normal doses of both isoforms are required for the zygotic function of pum, yet either isoform alone at a normal dose is sufficient for the maternal effect function of pum. A pum cDNA transgene that contains the known open reading frame encodes only the 156-kD isoform and rescues the phenotype of both pum(1688) and pum(2003) mutants. These observations suggest that the 156- and 130-kD isoforms can compensate for each other's function in a dosage-dependent manner. Finally, we present molecular evidence suggesting that the two PUM isoforms share some of their primary structures.

Animals↗
PubMed1999

Roles of the C terminus of Armadillo in Wingless signaling in Drosophila.

Drosophila melanogaster Armadillo and its vertebrate homolog beta-catenin play multiple roles during development. Both are components of cell-cell adherens junctions and both transduce Wingless (Wg)/Wnt intercellular signals. The current model for Wingless signaling proposes that Armadillo binds the DNA-binding protein dTCF, forming a bipartite transcription factor that activates Wingless-responsive genes. In this model, Armadillo's C-terminal domain is proposed to serve an essential role as a transcriptional activation domain. In Xenopus, however, overexpression of C-terminally truncated beta-catenin activates Wnt signaling, suggesting that the C-terminal domain might not be essential. We reexamined the function of Armadillo's C terminus in Wingless signaling. We found that C-terminally truncated mutant Armadillo has a deficit in Wg-signaling activity, even when corrected for reduced protein levels. However, we also found that Armadillo proteins lacking all or part of the C terminus retain some signaling ability if overexpressed, and that mutants lacking different portions of the C-terminal domain differ in their level of signaling ability. Finally, we found that the C terminus plays a role in Armadillo protein stability in response to Wingless signal and that the C-terminal domain can physically interact with the Arm repeat region. These data suggest that the C-terminal domain plays a complex role in Wingless signaling and that Armadillo recruits the transcriptional machinery via multiple contact sites, which act in an additive fashion.

Amino Acid Sequence↗