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PubMed1995

Evolution of Mhc class II polymorphism: the rise and fall of class II gene function in primates.

The substitution rate at the codons implicated at ARS of Mhc class II genes has previously been shown to be heavily biased towards nonsynonymous substitutions, indicative of positive selection for polymorphism. Based on our analysis of the number of synonymous changes at codons outside putative ARS in primates, the average age of the polymorphism at class II loci was found to increase in the following order: DPB1, DRB3, DRB5, DRB1, DRB4, DQB1, DQA1. For DRB loci, nonsynonymous changes were found to exceed synonymous changes at HLA-DRB1, DRB3 and DRB5, while no evidence of deviations from equal rates of synonymous and nonsynonymous substitutions were found for DRB6. The pattern of substitutions at the DRB loci of most Catarrhini species indicates constant positive selection at ARS codons over the evolutionary period examined. An exception to the relatively stable selection pattern between species exhibited by most loci is the appearance of polymorphism under positive selection at DRB4 only in the regular chimpanzee. The ds/dn ratios for DQA1 and DQB1 alleles are lower than for the most polymorphic DRB genes. Since the dn/ds ratio of ARS codons may be positively correlated to the ds for non-ARS codons, at least for DQB1, caution must be exercised in interpreting the low ratio for the DQ genes as an indication of weaker selection. The DQA1 allelic lineages show different dn/ds ratios, consistent with the hypothesis that the lineages are constrained from evolving in relation to the diversity of the interacting DQB1 alleles. In contrast to all other class II loci, DPB1 appears to have been subjected to strong positive selection only in the human lineage, and may represent the most conspicuous example of an Mhc locus acquiring an altered function in antigen presentation.

Animals↗
PubMed2005

Genes and homology in nervous system evolution: comparing gene functions, expression patterns, and cell type molecular fingerprints.

The evolution of the nervous system is one of the most fascinating, but also most nebulous fields of homology research. We do not know for example whether the last common ancestors of human, squid, and fly already possessed an elaborate brain and eyes, or rather had a simple, diffuse nervous system. Nevertheless, in the past decade molecular data has greatly advanced our understanding of bilaterian nervous system evolution. In this methodological review, I explain the four levels on which molecular genetic studies advance the quest for homologies between animal nervous systems. (I) Bioinformatic homology research elucidates the evolutionary history of gene families relevant for nervous system evolution such as the opsin superfamily. It tells us when and in what order genes and their functions have emerged. Based on this, we can (II) infer the organismal complexity of some remote ancestor from the functional diversity of its reconstructed proteome. (III) Most common in molecular homology research has been the comparison of expression patterns of developmental control genes. This approach matches and aligns embryonic regions along the body axes, between remote bilaterians. It does not tell us much, however, about the complexity of structures that developed from these regions in Urbilateria. (IV) This is overcome by a novel variant of molecular homology research, the comparison of cell types. Here, a similar "molecular fingerprint" of cells is taken as indication of cross-bilaterian homology. This approach makes it possible to reconstruct the cell-type repertoire of the urbilaterian nervous system.

Animals↗
PubMed2006

Primary cilium formation requires von hippel-lindau gene function in renal-derived cells.

Biallelic inactivation of the von Hippel-Lindau tumor suppressor gene, VHL, occurs in the majority of renal clear cell carcinomas (RCC). VHL's function, regulating the degradation of hypoxia-inducible factor alpha (HIFalpha) subunits, explains the angiogenic nature of these tumors, but not tumor initiation. Because the development of renal cysts precedes tumor formation, and because the dysfunction of primary cilium is a common pathogenic mechanism in polycystic kidney diseases, we determined whether kidney-derived VHL- cells required VHL for the generation of cilium. Ectopic expression of VHL in RCC(VHL-) cells induced increased polarization and primary cilium formation. Cilium formation correlated directly with the expression of both wild-type VHL isoforms and a VHL mutant not associated with RCC development, whereas expression of RCC-associated VHL mutants did not support ciliogenesis. Requirement of VHL for ciliogenesis was independent of HIFalpha abundance. These data indicate separable independent functions for VHL (HIFalpha degradation and differentiation) and suggest a mechanism whereby disruption of both functions is required for renal carcinogenesis.

Adenocarcinoma, Clear Cell↗
PubMed1989

A cytopathological investigation of Autographa californica nuclear polyhedrosis virus p10 gene function using insertion/deletion mutants.

The role of the Autographa californica nuclear polyhedrosis virus p10 gene in viral cytopathology and morphogenesis was examined using classes of p10 deletion mutants with and without lacZ (beta-galactosidase) gene fusion. Mutant-infected cells did not form the fibrillar cytoplasmic and nuclear structures normally observed late in infection with wild-type (wt) virus, and the cells failed to lyse even at 2 weeks post-infection. Based on wt and mutant cytopathology, we suggest lysis may be facilitated by stepwise exhaustion of the host nuclear membrane, and may require a function resident in the carboxy region of p10; this portion of the molecule is also essential for formation of the p10-rich fibrillar bodies. Additional changes in cytopathology were correlated with the level of p10/LacZ fusion protein expression. The insertional mutant designated Ac229, which encodes 51 N-terminal amino acids of p10 fused to LacZ, caused intranuclear accumulation of granular structures at sites corresponding to the fibrillar bodies of wt viral infections. Occlusion body membranes, which associate with the fibrillar bodies in wt infections, were also formed in mutant virus-infected cells. However, membranes did not associate with occlusion bodies in Ac229 infections, and were aberrantly attached to occlusion bodies in cells infected with mutants having simple p10 deletions (represented by Ac231). Loss of the outer membrane increased sensitivity of the occlusion bodies to disruption by physical stress; a partially attached membrane afforded some protection from disruption.

Animals↗
PubMed1999

Isolation and characterization of Synechococcus PCC7942 promoters: tRNApro gene functions as a promoter.

Promoter-active fragments of Synechococcus PCC7942 were isolated by transcriptional gene fusion to the promoterless beta-glucuronidase (GUS) gene of E. coli, which was used as a reporter gene. Several of the isolated promoter-active fragments expressed GUS activity in Synechococcus comparable to that of the lambdaPR promoter. Only 10% of the isolated promoter-active fragments also functioned in E. coli. The transcription initiation sites of the two promoter-active fragments, D13 and E3, were identified. The major transcription initiation sites of D13 and E3 in Synechococcus were located within the nucleotides TTTG and TTG respectively, which were identical to those corresponding to E. coli. The inferred -10 and -35 regions of D13 were TAAACT and TTGTAG respectively, which conformed to the E. coli sigma70 promoter. Immediately upstream of the E3 transcription initiation sites was the tRNApro (GGG) gene, which contained two regions exhibiting strong homology to the major promoter elements in eukaryotic tRNA genes, but did not contain the E. coli promoter element. Thus, the tRNApro gene can act as a promoter.

Amino Acid Sequence↗
PubMed2005

A maize resistance gene functions against bacterial streak disease in rice.

Although cereal crops all belong to the grass family (Poacea), most of their diseases are specific to a particular species. Thus, a given cereal species is typically resistant to diseases of other grasses, and this nonhost resistance is generally stable. To determine the feasibility of transferring nonhost resistance genes (R genes) between distantly related grasses to control specific diseases, we identified a maize R gene that recognizes a rice pathogen, Xanthomonas oryzae pv. oryzicola, which causes bacterial streak disease. Bacterial streak is an important disease of rice in Asia, and no simply inherited sources of resistance have been identified in rice. Although X. o. pv. oryzicola does not cause disease on maize, we identified a maize gene, Rxo1, that conditions a resistance reaction to a diverse collection of pathogen strains. Surprisingly, Rxo1 also controls resistance to the unrelated pathogen Burkholderia andropogonis, which causes bacterial stripe of sorghum and maize. The same gene thus controls resistance reactions to both pathogens and nonpathogens of maize. Rxo1 has a nucleotide-binding site-leucine-rich repeat structure, similar to many previously identified R genes. Most importantly, Rxo1 functions after transfer as a transgene to rice, demonstrating the feasibility of nonhost R gene transfer between cereals and providing a valuable tool for controlling bacterial streak disease.

Amino Acid Sequence↗
PubMed1990

Wing formation in Drosophila melanogaster requires decapentaplegic gene function along the anterior-posterior compartment boundary.

Previous analyses of the decapentaplegic (dpp) gene in Drosophila melanogaster have suggested that its product, a polypeptide of the transforming growth factor-beta family of secreted factors, acts at the level of intercellular communication to control several events in spatial pattern formation. In this report, we use clonal analysis to demonstrate a localized requirement for wild-type dpp expression along the anterior-posterior (A/P) compartment boundary of the developing wing primordium. Clonal analysis reveals that normal wing blade development is solely dependent on dpp+ function in those anterior compartment cells that border the anterior-posterior (A/P) compartment boundary of the wing imaginal disk. Conversely, the wing blade will not develop if these boundary cells lack dpp activity. The localized requirement for dpp coincides with the spatial distribution of dpp transcripts, which accumulate in a stripe of cells at or near the known A/P compartment boundary of the wing imaginal disk. Thus, only a small subset of the cells that normally comprise the wing must express dpp to permit development of the entire structure. We propose that this localized expression of dpp is essential to proximal-distal appendage development. We discuss the possibility that dpp expression serves as a landmark for establishing and/or maintaining positional information in imaginal disks.

Animals↗
PubMed2003

Major histocompatibility lineages and immune gene function in teleost fishes: the road not taken.

It has become increasingly clear over the course of the past decade that the immune system genes of teleosts and tetrapods are plainly derived from common ancestral genes. The last 5 years, however, have also made it abundantly clear that in the teleost genome some of these genes are organized in a manner very different from that seen in mammals. These differences are probably the result of differences in life history traits, such as fecundancy, within each group of species when faced with an evolutionary fork in the road shortly after their divergence from each other. One group, the tetrapods, including mammals, chose a highly organized linked major histocompatibility complex, while in teleosts the major histocompatibility genes remained unlinked. In this review we will discuss the structural and functional implications of this different organization, particularly for major histocompatibility genes, but drawing on the current knowledge of some other genes for further support for the hypothesis that each group took a different road, one more traveled and one less taken.

Alleles↗
PubMed2005

A gymnosperm ABI3 gene functions in a severe abscisic acid-insensitive mutant of Arabidopsis (abi3-6) to restore the wild-type phenotype and demonstrates a strong synergistic effect with sugar in the inhibition of post-germinative growth.

The CnABI3 gene of yellow-cedar is an orthologue of the ABI3/VP1 gene of angiosperms; it shares many common characteristics with other ABI3/VP1 genes, yet has unique characteristics as well. We examined whether this gymnosperm transcription factor can functionally complement an angiosperm species with a defective ABI3 gene. A severe Arabidopsis abi3 null mutant abi3-6 was stably transformed with the CnABI3 gene coding-region driven by a modified CaMV 35S promoter. Several of the visible mutant phenotypes (e.g., production of green seeds due to a lack of chlorophyll breakdown) were fully restored to those of the wild-type and the transformed seeds acquired desiccation tolerance. The functional complementation of the mutant also extended to the accumulation of several seed proteins (including seed-storage-proteins, alpha-tonoplast intrinsic protein, dehydrin-related polypeptides and oleosin), which were restored to wild-type levels. However, not all phenotypes were fully restored; sensitivities of transgenic seeds to exogenous ABA (as far as germination is concerned) were lower than that of the wild-type seeds, and flowering times were intermediate of those characteristic of wild-type and abi3-6 plants. A novel function for CnABI3, potentially related to a direct or indirect role in ER homeostasis was revealed. Two proteins with a molecular chaperone function in the ER (BiP and protein disulphide isomerase) were elevated in mutant seeds (indicative of ER stress); expression of the CnABI3 gene decreased the accumulation of these proteins to levels characteristic of the wild-type. These studies reveal the degree of conservation of ABI3 functions between gymnosperms and angiosperms as well as some novel functions of ABI3-related genes.

Abscisic Acid↗
PubMed1978

Construction and characterization of an Escherichia coli plasmid bearing a functional gene G of bacteriophage phiX174.

In order to study the mutagenic effects of site-specific, covalent modifications of biologically active DNA, we need host cells that are permissive for any type of mutation that might be produced in vivo from the modified DNA. Specifically, we require a general, in vivo complementation system for the bacteriophage phiX174 gene G, an essential gene that we have chosen for our initial studies of chemical mutagenesis. Toward this end, we have constructed a plasmid (pphiXG) that carries a functional copy of phiX174 gene G. Three different bacterial strains that are nonpermissive for am9, a gene G amber mutant, have been transformed with pphiXG. The transformants are now permissive for this gene G mutant, but not for the gene A or E mutants that have been tested. This paper describes the construction and the biochemical characterization of this plasmid, pphiXG, and describes some of the biological properties exhibited by the pphiXG-bearing strains.

Coliphages↗
PubMed1997

Loss of retinoblastoma gene function and heterozygosity at the RB locus in renal cortical neoplasms.

Alteration of the retinoblastoma (RB) gene, located on chromosome 13q14, has been implicated in the pathogenesis and biological behavior of several human cancers. We investigated the RB gene status by Western blotting and immunohistochemical analysis, as well as loss of heterozygosity (LOH) at the RB locus in 21 primary human renal neoplasms (including 3 oncocytomas). In only 1 of 21 tumors was there a discrepancy between Western blot and immunochemical staining. Overall, LOH was noted in 6 of 12 informative cases. However, only one of the tumors with LOH at the RB locus had loss of RB protein expression by both Western blot and immunohistochemical analysis. Loss of RB function was found in 4 of 18 carcinomas and in none of 3 oncocytomas as determined by absent RB nuclear staining in tumor cells. LOH at chromosome 13q14 was more noted in high-grade, DNA aneuploid, high-stage tumors and in patients with poor outcome. These results imply that (1) there is likely another tumor-suppressor gene on chromosome 13 involved in renal carcinogenesis, (2) LOH at chromosome 13q loci may be associated with aggressive behavior, and (3) the loss of RB function may have a role in a subset of renal carcinomas.

Adult↗
PubMed1991

Evidence that an endo-exonuclease controlled by the NUC2 gene functions in the induction of 'petite' mutations in Saccharomyces cerevisiae.

Defects in the RAD52 gene of the yeast Saccharomyces cerevisiae reduce the levels of the NUC2 endo-exonuclease by approximately 90% compared to the levels in wild-type strains. To examine the potential role of this nuclease in the induction of mitochondrial 'petite' mutations, congenic RAD52 and rad52-1 haploids were subjected to treatment with ethidium bromide, a well-known inducer of these mutations. The rad52 strain showed a much higher resistance to ethidium bromide-induced petite formation than the corresponding wild-type strain. Two approaches were taken to confirm that this finding reflected the nuclease deficiency, and not some other effect attributable to the rad52-1 mutation. First, a multicopy plasmid (YEp213-10) carrying NUC2 was transformed into a RAD52 strain. This resulted in an increased fraction of spontaneous petite mutations relative to that seen for the same strain without the plasmid and sensitized the strain carrying the plasmid to petite induction by ethidium bromide treatment. Second, a strain having a nuc2 allele that encodes a temperature-sensitive nuclease was treated with ethidium bromide at the restrictive and permissive temperatures. Petite induction was reduced under restrictive conditions. Enzyme assays revealed that the RAD52 (YEp213-10) strain had the highest level of antibody-precipitable NUC2 endo-exonuclease whereas the nuc2 and rad52 mutants had the lowest levels. Furthermore, addition of ethidium bromide to the reaction mixture stimulated the activity of the nuclease on double-stranded DNA. Petite induction by antifolate-mediated thymine nucleotide depletion was also inhibited by inactivation of RAD52 indicating that the effect of reduced NUC2 endo-exonuclease was not restricted to ethidium bromide treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Endonucleases↗
PubMed1984

Envelope proteins of human T-cell leukemia virus: expression in Escherichia coli and its application to studies of env gene functions.

The DNA fragments of the 5' and 3' halves of the putative env gene predicted from the DNA sequence of human T-cell leukemia virus (HTLV) provirus were inserted into expression vectors pORF2 and pORF1, respectively, and two hybrid proteins composed of env polypeptides and beta-galactosidase were efficiently produced in Escherichia coli. The hybrid proteins containing the NH2-terminal (EH9) and COOH-terminal (EA1) halves were both immunologically reactive with sera from adult T-cell leukemia patients, demonstrating the utility of the hybrid proteins for diagnosis of HTLV infection. Rabbit antisera against these hybrid proteins detected the two glycoproteins gp62 and gp46, which were previously identified as HTLV env gene products. With these rabbit antisera, two properties of the env gene products were studied. (i) The antisera inhibited syncytia formation of cat S+L- cells induced by HTLV, suggesting that one or both of the env gene products of HTLV, gp62 and gp46, are involved in induction of cell fusion. (ii) The env product gp62 or gp46 or both products are exposed on the surface of HTLV-infected cells and might modulate the proliferation of HTLV-infected T cells in the host because the antisera against the hybrid proteins were cytotoxic on HTLV-producing cell lines. The latter conclusion also is supported by the fact that adult T-cell leukemia patients and healthy HTLV carriers have antibodies to the env gene products.

Adult↗
PubMed2000

The Iroquois homeobox genes function as dorsal selectors in the Drosophila head.

The Iroquois complex (Iro-C) genes are expressed in the dorsal compartment of the Drosophila eye/antenna imaginal disc. Previous work has shown that the Iro-C homeoproteins are essential for establishing a dorsoventral pattern organizing center necessary for eye development. Here we show that, in addition, the Iro-C products are required for the specification of dorsal head structures. In mosaic animals, the removal of the Iro-C transforms the dorsal head capsule into ventral structures, namely, ptilinum, prefrons and suborbital bristles. Moreover, the Iro-C(-) cells can give rise to an ectopic antenna and maxillary palpus, the main derivatives of the antenna part of the imaginal disc. These transformations are cell-autonomous, which indicates that the descendants of a dorsal Iro-C(-) cell can give rise to essentially all the ventral derivatives of the eye/antenna disc. These results support a role of the Iro-C as a dorsal selector in the eye and head capsule. Moreover, they reinforce the idea that developmental cues inherited from the distinct embryonic segments from which the eye/antenna disc originates play a minimal role in the patterning of this disc.

Animals↗
PubMed1982

In vivo evidence for nusA and nusB gene function in general transcription of the Escherichia coli genome.

The requirements for nusA and nusB gene products for the effective transcription of E. coli genes, including the trp operon, were demonstrated by analysis of RNA transcripts produced in nusA, nusB and nusAnusB mutants. In the nusA1 mutant, the levels of overall synthesis of both bulk RNA and trp mRNA were reduced more at 37 C than at 30 C, consistent with the idea of temperature-sensitive nus protein function (Friedman et al., 1973). In the nusB27 and nusA1nusB27 mutants (Friedman et al., 1976), decrease in the overall rates of these RNA synthesis was notable even at 30 C. In nus mutants harboring trp delta LD1412, in which the trp operon attenuator site is deleted, the reduction in the trp mRNA level was less severe. Thus, the effect of nus mutations seems to result in part from more frequent transcription termination at the attenuator site. Also in nusA1nusB27 mutants, in which the distal portion of the trp operon is deleted, the trp mRNA level was not reduced much. Thus, transcription in the nus- mutants seems to be frequently and prematurely arrested at sites along the trp operon.

Escherichia coli↗
PubMed2000

Transforming growth factor beta inhibitory element in the rabbit matrix metalloproteinase-1 (collagenase-1) gene functions as a repressor of constitutive transcription.

Transforming growth factor beta (TGF-beta) is a potent modulator of the extracellular matrix, enhancing collagen synthesis and regulating expression of several genes that encode the matrix metalloproteinases (MMPs), enzymes that degrade the extracellular matrix. In this study, we explored the mechanisms whereby TGF-beta inhibits expression of the MMP-1 (collagenase 1) gene. We used transient transfection and gel mobility shift assays to characterize a TGF beta inhibitory element (TIE) at -249 bp in the rabbit MMP-1 promoter, which is also conserved at -246 bp in the human gene. This sequence shares homology to a previously identified TIE in the rat stromelysin-1 (MMP-3) promoter, where it is located at -709 bp. Mutational analyses and transient transfections indicate that MMP-1 TIE functions both as a constitutive repressor of MMP-1 gene expression and, in the presence of TGF-beta, as an antagonist of transcriptional induction by phorbol esters. c-Fos binds to the TIE in the rabbit MMP-1 promoter, along with other nuclear proteins, even in the absence of treatment with TGF-beta. However, the pattern of proteins binding to the TIE is altered in the presence of nuclear extracts from TGF-beta-treated cells, suggesting that TGF-beta leads to an alteration in protein/DNA interaction, with subsequent modulation of MMP-1 gene expression. We conclude that in the rabbit MMP-1 promoter, the TIE has dual functions as a repressor of basal transcription and as a mediator of the biologic effects of TGF-beta. Furthermore, these dual functions provide additional and subtle mechanisms for regulating MMP-1 gene expression under a variety of biological and pathological conditions.

Animals↗
PubMed2006

Identifying functional gene sets from hierarchically clustered expression data: map of abiotic stress regulated genes in Arabidopsis thaliana.

We present MultiGO, a web-enabled tool for the identification of biologically relevant gene sets from hierarchically clustered gene expression trees (http://ekhidna.biocenter.helsinki.fi/poxo/multigo). High-throughput gene expression measuring techniques, such as microarrays, are nowadays often used to monitor the expression of thousands of genes. Since these experiments can produce overwhelming amounts of data, computational methods that assist the data analysis and interpretation are essential. MultiGO is a tool that automatically extracts the biological information for multiple clusters and determines their biological relevance, and hence facilitates the interpretation of the data. Since the entire expression tree is analysed, MultiGO is guaranteed to report all clusters that share a common enriched biological function, as defined by Gene Ontology annotations. The tool also identifies a plausible cluster set, which represents the key biological functions affected by the experiment. The performance is demonstrated by analysing drought-, cold- and abscisic acid-related expression data sets from Arabidopsis thaliana. The analysis not only identified known biological functions, but also brought into focus the less established connections to defense-related gene clusters. Thus, in comparison to analyses of manually selected gene lists, the systematic analysis of every cluster can reveal unexpected biological phenomena and produce much more comprehensive biological insights to the experiment of interest.

Abscisic Acid↗
PubMed2001

Complementation of the Magnaporthe grisea deltacpkA mutation by the Blumeria graminis PKA-c gene: functional genetic analysis of an obligate plant pathogen.

Obligate plant-pathogenic fungi have proved extremely difficult to characterize with molecular genetics because they cannot be cultured away from host plants and only can be manipulated experimentally in limited circumstances. Previously, in order to characterize signal transduction processes during infection-related development of the powdery mildew fungus Blumeria graminis (syn. Erysiphe graminis) f. sp. hordei, we described a gene similar to the catalytic subunit of cyclic AMP-dependent protein kinase A (here renamed Bka1). Functional characterization of this gene has been achieved by expression in a deltacpkA mutant of the nonobligate pathogen Magnaporthe grisea. This nonpathogenic M. grisea deltacpkA mutant displays delayed and incomplete appressorium development, suggesting a role for PKA-c in the signal transduction processes that control the maturation of infection cells. Transformation of the deltacpkA mutant with the mildew Bka1 open reading frame, controlled by the M. grisea MPG1 promoter, restored pathogenicity and appressorium maturation kinetics. The results provide, to our knowledge, the first functional genetic analysis of pathogenicity in an obligate pathogen and highlight the remarkable conservation of signaling components regulating infection-related development in pathogenic fungi.

Archaeal Proteins↗