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At least 19 recordsLinked to original sources
PubMed2009

Multipotent genetic suppression of retrotransposon-induced mutations by Nxf1 through fine-tuning of alternative splicing.

Cellular gene expression machinery has coevolved with molecular parasites, such as viruses and transposons, which rely on host cells for their expression and reproduction. We previously reported that a wild-derived allele of mouse Nxf1 (Tap), a key component of the host mRNA nuclear export machinery, suppresses two endogenous retrovirus-induced mutations and shows suggestive evidence of positive selection. Here we show that Nxf1(CAST) suppresses a specific and frequent class of intracisternal A particle (IAP)-induced mutations, including Ap3d1(mh2J), a model for Hermansky-Pudlak syndrome, and Atcay(hes), an orthologous gene model for Cayman ataxia, among others. The molecular phenotype of suppression includes approximately two-fold increase in the level of correctly-spliced mRNA and a decrease in mutant-specific, alternatively-processed RNA accumulating from the inserted allele. Insertional mutations involving ETn and LINE elements are not suppressed, demonstrating a high degree of specificity to this suppression mechanism. These results implicate Nxf1 in some instances of pre-mRNA processing, demonstrate the useful range of Nxf1(CAST) alleles for manipulating existing mouse models of disease, and specifically imply a low functional threshold for therapeutic benefit in Cayman ataxia.

Alternative Splicing↗
PubMed1975

Conditional-lethal mutations that suppress genetic defects in morphogenesis by altering structural proteins.

An analysis of revertants of missense mutants in phage P22 has shown: (i) New temperature-sensitive (TS) and cold-sensitive (CS) phenotypes are often acquired concomitant with reversion. (ii) In many cases, these new phenotypes are due to second-site mutations (suppressors) that correct the original defect. (iii) Sometimes the suppressor mutation is not in the same gene as the original mutation. (iv) Extragenic suppressors are almost always in genes whose products are known to interact physically with the original gene products. (v) The suppressor mutations typically retain their TS or CS phenotypes when crossed into wild-type genetic backgrounds. (vi) Some TS and CS mutants derived by reversion can themselves be reverted to produce additional mutations. We have shown that genetic reversion of missense mutants can be of value in producing new temperature-sensitive and cold-sensitive mutations affecting related functions. We suggest that our approach can be extended to organisms with large genomes.

Chromosome Mapping↗
PubMed2025

Extensive Recombination Suppression and Genetic Degeneration of a Young ZW Sex Chromosome System in Halfbeak Fish.

Sex chromosome systems have evolved independently across the tree of life, at different times in the past, and the evolutionary consequences of lacking recombination in sex-linked regions have been characterized in many old-established systems. However, empirical studies of young sex chromosomes are still scarce, especially in vertebrates. Integrating whole-genome sequencing data of two species of halfbeak fish, Hyporhamphus sajori and Hyporhamphus intermedius, we identified the sex-determining system in H. sajori as female heterogamety, involving a large fully sex-linked ZW region (∼26 Mb) on chromosome 5. The closest relative, H. intermedius, has a small sex-linked region on a different chromosome and shows male heterogamety, suggesting at least one turnover in this fish genus. The H. sajori sex-linked region includes two evolutionary strata, but the estimated Z-W divergence times are small, less than 3 million years for the older stratum, which is less than between the two species. Nevertheless, this evolutionarily young W-linked region is enriched with repetitive sequences, differs from the ancestral state by five inversions, and about one-third of its protein-coding genes have already become nonfunctional. Transcriptomic analysis suggests that some form of dosage compensation may already be evolving for some sex-linked genes.

Animals↗
PubMed1975

Genetic control of specific immune suppression. II. H-2-linked dominant genetic control of immune suppression by the random copolymer L-glutamic acid50-L-tyrosine50 (GT).

Several inbred as well as congenic resistant strains of mice, which fail to respond to the random copolymer of L-glutamic acid50-L-tyrosine50 (GT), were shown to develop specific PFC responses when stimulated by GT complexed to an immunogenic carrier such as methylated bovine serum albumin (MBSA). In these studies we have found that GT preimmunization has a tolerogenic effect on the response to GT-MBSA in some mouse strains; whereas in other strains of mice, GT fails to inhibit the GT-MBSA response. We may, therefore, conclude that immune suppression cannot account for nonresponsiveness in all cases. The development of specific immune suppression in response to GT was shown to be inherited as a dominant trait in F1 hybrids resulting from the mating of suppressor with nonsuppressor strains. This trait is, therefore, under the control of a gene or genes that we have designated as specific immune suppression gene(s) Is genes. The strain distribution of GT induced suppression demonstrates that Is genes are coded for in the H-2 complex. Furthermore, immune suppression by the two related copolymers, GT and GAT, are distinct in different strains of mice. The significance of these data for our understanding of the regulation of the immune response is discussed.

Alanine↗
PubMed1975

A genetic analysis of phototactic behavior in Drosophila melanogaster. II. Hybridization of divergent populations.

Artificial selection has produced populations of Drosophila melanogaster which show either positive or negative phototactic behavior. Selection was carried out in the presence of various marked multiple inversions used to suppress genetic recombination. Reciprocal hybridizations between photopositive and photonegative populations of flies have revealed the X chromosome of D. melanogaster to be important in phototactic behavior regardless of conditions which restricted genetic recombination during selection.

Animals↗
PubMed2026

The mechanism of malignant progression in extramammary Paget's disease (EMPD): hallmarks of EMPD.

The pathogenesis of cancer is characterized by the acceleration of tumor growth, inhibition of tumor suppression, genetic and epigenetic alteration, lubricative transformation and tumor microenvironment. Extramammary Paget's disease (EMPD) is a rare skin cancer that originates from apocrine glands in genital and axillary area. Although the pathogenesis of EMPD is still poorly understood, increasing evidence reveals that the mechanism of EMPD progression is regulated by the acquired ability of EMPD cells and tumor microenvironment. HER2/PI3K/AKT signaling and hormone receptor pathways are activated. Whereas tumor mutation burden is low, numerous driver genes such as ERBB2 and PIK3CA are detected. Tumor evolution in EMPD is characterized by high genetic intratumor heterogeneity with shared background factors. Tumor microenvironment in EMPD promotes immune evasion through the reduction of reduced CD4 + and CD8 + T cells and the increase of Treg cells and CD163 + macrophages. Enhanced Warburg effect and S. aureus contribute to the suppression of antitumor immunity. This review focuses on the mechanism of malignant progression in EMPD (hallmarks of EMPD).

Genome mutation↗
PubMed1975

Autoradiographic studies of nicotinic acid utilization in human-mouse heterokaryons and inhibition of utilization in newly-formed hybrid cells.

Although most mammalian cell lines can utilize either nicotinic acid or nicotinamide for the biosynthesis of nicotinamide adenine dinucleotide (NAD), thymidine kinase-deficient, mouse 3T3-4F cells are unable to utilize nicotinic acid. When 3T3-4E cells were fused with human D98/AH2 cells, autoradiography showed that the resultant heterokaryons synthesized NAD from nicotinic acid at rates comparable to the human parental cell. The rate of nicotinic acid utilization in heterokaryons remained unchanged over the four-day period of study following cell fusion. In contrast to the results observed with heterokaryons, nicotinic acid utilization was markedly reduced in hybrid cells. Of 100 hybrid clones examined at four or five days following cell fusion, 60 utilized nicotinic acid at rates less than one tenth that of the parental human cell. Similar results were observed in hybrid clones at nine or ten days following fusion. Uniformly high rates of NAD biosynthesis were observed in hybrid clones with nicotinamide as the precursor. This excludes the possibility that the reduction in nicotinic acid utilization in hybrid cells is due to a general metabolic dysfunction. The biochemical mechanism by which nicotinic acid utilization is markedly reduced has not been determined with certainty, however, several observations suggest genetic suppression.

Aminopterin↗
PubMed1976

Mutagenesis in bacteriophage T7. I. Chemically induced mutagenesis.

The mutagenesis in phage T7 after MMS-, HNO2-, hydroxylamine-, 5-BUdR-, and 2-AP-treatment in relation to host controlled functions is investigated. There was no dependence of the induction of mutations on the character of the host strains (rec, hcr). A back mutation system (amber system) and a forward mutation system (host range system) have been used. Substances which cause mainly transitions from GC to AT do not lead or only rarely lead to reversions of the amber system; but chemicals producing transitions from AT to GC do so.

2-Aminopurine↗
PubMed1979

Isolation and properties of a plasmid which expresses the E. coli Su+7 amber suppressor tRNA gene.

The gene of the amber suppressor tRNA derived from tRNATry, Su+7, has been inserted into a col E1-derived vehicle by selecting for its expression. Despite selection for a suppressor phenotype, and the plasmid's stable presence at ca. 180 copies cell during balanced growth, the level mature tRNA maintained by the gene is less than that of the normal haploid tRNATry locus in the bacterial chromosome. Transfer RNA genes, both the plasmid Su+7 gene and chromosomal tRNA's are expressed during inhibition of protein synthesis. During, e.g. chloramphenicol inhibition, Su-7 and Su+7 tRNA can be elevated similarly in the plasmid-containing cell; Su+7 reaches levels of molecules/cell which ordinarily characterize a major tRNA. The recombinant plasmid, but not the cloning vehicle alone, has a more general effect on tRNA levels; accumulation of tRNA from three chromosomal tRNA loci including tRNATry, continues during extensive isoleucine limitation. The plasmid therefore contains a locus which probably alters the relaxed-stringent circuit, whose effect is disseminated to at least 3 widely separated loci.

Chromosome Mapping↗
PubMed1975

Reversions of the two missense and one nonsense trp-mutations induced by UV-light or methyl methanesulfonate in E. coli wild type and its polAi and uvrE502 mutants.

Two missense mutations, trpA58 and trpA78, and one nonsense mutation-trp-ochre, were used to determine the types of base-pair substitution caused by ultra, violet irradiation and methyl methanesulfonate (MMS) in Escherichia coli. UV irradiation of the wild-type bacteria led to the formation of revertants mainly arising as a result of GC yields AT transitions (suppressor revertants of the trpA58 mutant). True revertants of the trp- mutant (arising via transitions of AT pairs) and 5-methyl tryptophan-sensitive (MT-s) Trp+ of the trpA78 mutant (arising via unidentified transversions) occurred at a lower frequency. The polAI mutation did not change the frequency of the UV-induced transitions GC yields AT or that of the substitutions of the AT pairs. The uvrE502 mutation significantly increased the frequency of the UV-induced revertants arising via the transition GC yields AT. Treatment of the wild-type bacteria with MMS resulted in the formation of revertants mainly due to the GC yields AT substitution, and with a lower frequency to the AT yields GC transitions. MMS also induced, with a low frequency, some transversions. The frequency of the MMS-induced GC yields AT transitions was enhanced in the uvrE502 mutant. On the other hand, the uvrE502 mutation eliminated or significantly lowered MMS-induced revertants arising as a result of AT yields GC transitions or transversions.

Adenine Nucleotides↗
PubMed1975

Radiation-sensitive pyrimidine auxotrophs of Ustilago maydis. I. Isolation and characterization of mutants.

The relationship between UV sensitivity and pyrimidine auxotrophy has been examined. Fourteen pyrimidine-requiring mutants have been classified on the basis of genetic complementation and utilization of biosynthetic intermediates and have been assigned to at least four loci. All the mutants studied were sensitive to UV, although the degree of sensitivity varied both between loci and amongst alleles at the same locus. A double mutant strain carrying pyrimidine mutants at two loci was only as sensitive to UV as the more sensitive of the singles. This suggests that both mutants are deficient in the same repair mechanism. Suppressor mutations which restored endogenous pyrimidine biosynthesis were isolated. These suppressors restored UV resistance in the presence of the original mutation. The results indicate that the UV sensitivity of these mutants is a direct result of pyrimidine auxotrophy and not to any secondary properties of the mutants.

Alleles↗
PubMed1975

Recombination-deficient deletions in bacteriophage lambda and their interaction with chi mutations.

We have isolated a new class of deletion mutants of phage lambda that extend from the prophage attachment site, att, into the gam and cIII genes. In this respect they are similar to certain of the lambda pbio transducing phage, but they differ in having a low burst size and in forming minute plaques. Lytically grown stocks of the deletions contain a variable proportion of phage that produce large plaques. These have been shown to carry an additional point mutation. Similar mutations, called chi, have been described by Lam et al. (1974), who showed that they result in a hot-spot for recombination produced by the host recombination system (Rec). We show that chi mutations can occurat several sites in the lambda genome and produce a Rec-dependent increase in the burst size of the one deletion tested.---In addition to reducing burst size, the one deletion tested reduces synthesis of DNA and emdolysin but increases production of serum blocking protein. A chi mutation partially restores DNA synthesis and endolysin production and reduces serum blocking protein to normal levels. Our results are consistent with the hypothesis put forward by Lam et al., that chi enhances the frequency of Rec-promoted recombination, which provides the only pathway for production of maturable DNAin a red gam infection. The mechanism of the differential effect on protein production is, however, unclear.---Chi mutations are found to occur in DNA other than that of lambda. We show that, as has been suggested elsewhere (McMilin, Stahl and Stahy 1974), the lambda pbio transducing phages carry a chi mutation within the E. coli DNA substitution. A chi mutation also arose in a new substitution of unknown origin isolated in the course of this work.

Chromosome Aberrations↗