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1.
J Evol Biol ; 30(12): 2204-2210, 2017 Dec.
Article in English | MEDLINE | ID: mdl-28977708

ABSTRACT

The spread of maternally inherited microorganisms, such as Wolbachia bacteria, can induce indirect selective sweeps on host mitochondria, to which they are linked within the cytoplasm. The resulting reduction in effective population size might lead to smaller mitochondrial diversity and reduced efficiency of natural selection. While documented in several host species, it is currently unclear if such a scenario is common enough to globally impact the diversity and evolution of mitochondria in Wolbachia-infected lineages. Here, we address this question using a mapping of Wolbachia acquisition/extinction events on a large mitochondrial DNA tree, including over 1000 species. Our analyses indicate that on a large phylogenetic scale, other sources of variation, such as mutation rates, tend to hide the effects of Wolbachia. However, paired comparisons between closely related infected and uninfected taxa reveal that Wolbachia is associated with a twofold reduction in silent mitochondrial polymorphism, and a 13% increase in nonsynonymous substitution rates. These findings validate the conjecture that the widespread distribution of Wolbachia infections throughout arthropods impacts the effective population size of mitochondria. These effects might in part explain the disconnection between genetic diversity and demographic population size in mitochondria, and also fuel red-queen-like cytonuclear co-evolution through the fixation of deleterious mitochondrial alleles.


Subject(s)
Arthropods/genetics , Biological Evolution , DNA, Mitochondrial/genetics , Wolbachia/physiology , Animals , Arthropods/microbiology , Female , Genetic Variation , Male , Phylogeny
2.
Nature ; 515(7526): 261-3, 2014 Nov 13.
Article in English | MEDLINE | ID: mdl-25141177

ABSTRACT

Genetic diversity is the amount of variation observed between DNA sequences from distinct individuals of a given species. This pivotal concept of population genetics has implications for species health, domestication, management and conservation. Levels of genetic diversity seem to vary greatly in natural populations and species, but the determinants of this variation, and particularly the relative influences of species biology and ecology versus population history, are still largely mysterious. Here we show that the diversity of a species is predictable, and is determined in the first place by its ecological strategy. We investigated the genome-wide diversity of 76 non-model animal species by sequencing the transcriptome of two to ten individuals in each species. The distribution of genetic diversity between species revealed no detectable influence of geographic range or invasive status but was accurately predicted by key species traits related to parental investment: long-lived or low-fecundity species with brooding ability were genetically less diverse than short-lived or highly fecund ones. Our analysis demonstrates the influence of long-term life-history strategies on species response to short-term environmental perturbations, a result with immediate implications for conservation policies.


Subject(s)
Evolution, Molecular , Genetic Variation/genetics , Genetics, Population , Genome/genetics , Genomics , Phylogeny , Animals , Ecology
3.
Genome Res ; 11(11): 1854-60, 2001 Nov.
Article in English | MEDLINE | ID: mdl-11691850

ABSTRACT

In an attempt to understand the origin of CpG islands (CGIs) in mammalian genomes, we have studied their location and structure according to the expression pattern of genes and to the G + C content of isochores in which they are embedded. We show that CGIs located over the transcription start site (named start CGIs) are very different structurally from the others (named no-start CGIs): (1) 61.6% of the no-start CGIs are due to repeated sequences (79 % are due to Alus), whereas only 5.6% of the start CGIs are due to such repeats; (2) start CGIs are longer and display a higher CpGo/e ratio and G + C level than no-start CGIs. The frequency of tissue-specific genes associated to a start CGI varies according to the genomic G + C content, from 25% in G + C-poor isochores to 64% in G + C-rich isochores. Conversely, the frequency of housekeeping genes associated to a start CGI (90%) is independent of the isochore context. Interestingly, the structure of start CGIs is very similar for tissue-specific and housekeeping genes. Moreover, 93% of genes expressed in early embryo are found to exhibit a CpG island over their transcription start point. These observations are consistent with the hypothesis that the occurrence of these CGIs is the consequence of gene expression at this stage, when the methylation pattern is installed.


Subject(s)
CpG Islands/genetics , Embryo, Mammalian/metabolism , Gene Expression Regulation, Developmental/genetics , Transcription Initiation Site , Animals , Base Composition , Embryo, Mammalian/chemistry , Expressed Sequence Tags , GC Rich Sequence , Gene Expression Profiling/methods , Genes/genetics , Humans , Mice , Organ Specificity/genetics , Repetitive Sequences, Nucleic Acid
5.
Plant Physiol ; 126(4): 1706-15, 2001 Aug.
Article in English | MEDLINE | ID: mdl-11500568

ABSTRACT

Glutathione (GSH) and homo-GSH (hGSH) are the major low-molecular weight thiols synthesized in Medicago truncatula. Two M. truncatula cDNAs (gshs1 and gshs2) corresponding to a putative GSH synthetase (GSHS) and a putative hGSH synthetase (hGSHS) were characterized. Heterologous expression of gshs1 and gshs2 cDNAs in an Escherichia coli strain deficient in GSHS activity showed that GSHS1 and GSHS2 are a GSHS and an hGSHS, respectively. Leucine-534 and proline-535 present in hGSHS were substituted by alanines that are conserved in plant GSHS. These substitutions resulted in a strongly stimulated GSH accumulation in the transformed E. coli strain showing that these residues play a crucial role in the differential recognition of beta-alanine and glycine by hGSHS. Phylogenetic analysis of GSHS2 and GSHS1 with other eukaryotic GSHS sequences indicated that gshs2 and gshs1 are the result of a gene duplication that occurred after the divergence between Fabales, Solanales, and Brassicales. Analysis of the structure of gshs1 and gshs2 genes shows they are both present in a cluster and in the same orientation in the M. truncatula genome, suggesting that the duplication of gshs1 and gshs2 occurred via a tandem duplication.


Subject(s)
Gene Duplication , Glutathione Synthase/genetics , Medicago sativa/enzymology , Peptide Synthases/genetics , Amino Acid Sequence , Animals , Chromosome Mapping , DNA, Complementary/analysis , DNA, Plant/analysis , Escherichia coli/genetics , Genes, Plant , Glutathione Synthase/classification , Glutathione Synthase/metabolism , Humans , Medicago sativa/genetics , Molecular Sequence Data , Peptide Synthases/classification , Peptide Synthases/metabolism , Phylogeny , Sequence Homology, Amino Acid , Tandem Repeat Sequences
6.
J Mol Evol ; 52(3): 275-80, 2001 Mar.
Article in English | MEDLINE | ID: mdl-11428464

ABSTRACT

In many unicellular organisms, invertebrates, and plants, synonymous codon usage biases result from a coadaptation between codon usage and tRNAs abundance to optimize the efficiency of protein synthesis. However, it remains unclear whether natural selection acts at the level of the speed or the accuracy of mRNAs translation. Here we show that codon usage can improve the fidelity of protein synthesis in multicellular species. As predicted by the model of selection for translational accuracy, we find that the frequency of codons optimal for translation is significantly higher at codons encoding for conserved amino acids than at codons encoding for nonconserved amino acids in 548 genes compared between Caenorhabditis elegans and Homo sapiens. Although this model predicts that codon bias correlates positively with gene length, a negative correlation between codon bias and gene length has been observed in eukaryotes. This suggests that selection for fidelity of protein synthesis is not the main factor responsible for codon biases. The relationship between codon bias and gene length remains unexplained. Exploring the differences in gene expression process in eukaryotes and prokaryotes should provide new insights to understand this key question of codon usage.


Subject(s)
Caenorhabditis elegans/genetics , Codon/genetics , Protein Biosynthesis , Animals , Humans , Regression Analysis
7.
Mol Biol Evol ; 18(5): 757-62, 2001 May.
Article in English | MEDLINE | ID: mdl-11319260

ABSTRACT

The human genome is divided into isochores, large stretches (>>300 kb) of genomic DNA with more or less consistent GC content. Mutational/neutralist and selectionist models have been put forward to explain their existence. A major criticism of the mutational models is that they cannot account for the higher GC content at fourfold-redundant silent sites within exons (GC4) than in flanking introns (GCi). Indeed, it has been asserted that it is hard to envisage a mutational bias explanation, as it is difficult to see how repair enzymes might act differently in exons and their flanking introns. However, this rejection, we note, ignores the effects of transposable elements (TEs), which are a major component of introns and tend to cause them to have a GC content different from (usually lower than) that dictated by point mutational processes alone. As TEs tend not to insert at the extremities of introns, this model predicts that GC content at the extremities of introns should be more like that at GC4 than are the intronic interiors. This we show to be true. The model also correctly predicts that small introns should have a composition more like that at GC4 than large introns. We conclude that the logic of the previous rejection of neutralist models is unsafe.


Subject(s)
Base Composition , Codon/genetics , Cytosine , DNA Transposable Elements/genetics , DNA/chemistry , Exons/genetics , Guanosine , Introns/genetics , Models, Genetic , DNA/genetics , Evolution, Molecular , Genome, Human , Humans , Likelihood Functions , Regression Analysis
8.
Proc Natl Acad Sci U S A ; 98(10): 5688-92, 2001 May 08.
Article in English | MEDLINE | ID: mdl-11320215

ABSTRACT

Understanding the factors responsible for variations in mutation patterns and selection efficacy along chromosomes is a prerequisite for deciphering genome sequences. Population genetics models predict a positive correlation between the efficacy of selection at a given locus and the local rate of recombination because of Hill-Robertson effects. Codon usage is considered one of the most striking examples that support this prediction at the molecular level. In a wide range of species including Caenorhabditis elegans and Drosophila melanogaster, codon usage is essentially shaped by selection acting for translational efficiency. Codon usage bias correlates positively with recombination rate in Drosophila, apparently supporting the hypothesis that selection on codon usage is improved by recombination. Here we present an exhaustive analysis of codon usage in C. elegans and D. melanogaster complete genomes. We show that in both genomes there is a positive correlation between recombination rate and the frequency of optimal codons. However, we demonstrate that in both species, this effect is due to a mutational bias toward G and C bases in regions of high recombination rate, possibly as a direct consequence of the recombination process. The correlation between codon usage bias and recombination rate in these species appears to be essentially determined by recombination-dependent mutational patterns, rather than selective effects. This result highlights that it is necessary to take into account the mutagenic effect of recombination to understand the evolutionary role and impact of recombination.


Subject(s)
Caenorhabditis elegans/genetics , Codon , Drosophila melanogaster/genetics , Recombination, Genetic , Selection, Genetic , Animals
10.
Genetics ; 156(4): 1661-9, 2000 Dec.
Article in English | MEDLINE | ID: mdl-11102365

ABSTRACT

We analyzed the distribution of transposable elements (TEs: transposons, LTR retrotransposons, and non-LTR retrotransposons) in the chromosomes of the nematode Caenorhabditis elegans. The density of transposons (DNA-based elements) along the chromosomes was found to be positively correlated with recombination rate, but this relationship was not observed for LTR or non-LTR retrotransposons (RNA-based elements). Gene (coding region) density is higher in regions of low recombination rate. However, the lower TE density in these regions is not due to the counterselection of TE insertions within exons since the same positive correlation between TE density and recombination rate was found in noncoding regions (both in introns and intergenic DNA). These data are not compatible with a global model of selection acting against TE insertions, for which an accumulation of elements in regions of reduced recombination is expected. We also found no evidence for a stronger selection against TE insertions on the X chromosome compared to the autosomes. The difference in distribution of the DNA and RNA-based elements along the chromosomes in relation to recombination rate can be explained by differences in the transposition processes.


Subject(s)
Caenorhabditis elegans/genetics , DNA Transposable Elements , DNA, Helminth/genetics , Recombination, Genetic , Retroelements , Animals , Chromosome Mapping , Disorders of Sex Development , Female , Genes, Helminth , Genome , Introns/genetics , Male , Mutagenesis, Insertional , Selection, Genetic , Terminal Repeat Sequences , X Chromosome/genetics
11.
Mol Biol Evol ; 17(11): 1620-5, 2000 Nov.
Article in English | MEDLINE | ID: mdl-11070050

ABSTRACT

CpG and TpA dinucleotides are underrepresented in the human genome. The CpG deficiency is due to the high mutation rate from C to T in methylated CpG's. The TpA suppression was thought to reflect a counterselection against TpA's destabilizing effect in RNA. Unexpectedly, the TpA and CpG deficiencies vary according to the G+C contents of sequences. It has been proposed that the variation in CpG suppression was correlated with a particular chromatin organization in G+C-rich isochores. Here, we present an improved model of dinucleotide evolution accounting for the overlap between successive dinucleotides. We show that an increased mutation rate from CpG to TpG or CpA induces both an apparent TpA deficiency and a correlation between CpG and TpA deficiencies and G+C content. Moreover, this model shows that the ratio of observed over expected CpG frequency underestimates the real CpG deficiency in G+C-rich sequences. The predictions of our model fit well with observed frequencies in human genomic data. This study suggests that previously published selectionist interpretations of patterns of dinucleotide frequencies should be taken with caution. Moreover, we propose new criteria to identify unmethylated CpG islands taking into account this bias in the measure of CpG depletion.


Subject(s)
Base Composition/genetics , Genome, Human , Animals , CpG Islands/genetics , Dinucleotide Repeats/genetics , Evolution, Molecular , Genetic Variation , Humans , Mathematics , Models, Genetic
12.
Gene ; 253(2): 189-96, 2000 Aug 08.
Article in English | MEDLINE | ID: mdl-10940556

ABSTRACT

BTG3 belongs to a family of structurally related genes whose biochemical functions remain elusive. In order to investigate the mechanism underlying BTG3-mediated functions, we tried to identify BTG3 potential partners. The use of the yeast 'two-hybrid system', with BTG3 as bait, enabled us to isolate BANP (BTG3 Associated Nuclear Protein). Other commonly used protein-binding assays did not confirm this yeast interaction. However, BANP had never been described before, and this prompted us to further characterise this gene. In this paper, we present data on its molecular organization in mouse, then we speculate on the nature of this nuclear protein, and finally we localise BANP on the human chromosome 16q24 subregion; we discuss the fact that frequent loss of heterozygosity within this region has been observed in different tumours.


Subject(s)
Cell Cycle Proteins , DNA-Binding Proteins , Nuclear Proteins/genetics , 3T3 Cells , Amino Acid Sequence , Animals , Base Sequence , Blotting, Northern , Cell Nucleus/metabolism , Chromosome Mapping , Chromosomes, Human, Pair 16/genetics , Cloning, Molecular , DNA/chemistry , DNA/genetics , DNA, Complementary/chemistry , DNA, Complementary/genetics , Epitopes , Gene Expression , HeLa Cells , Humans , In Situ Hybridization, Fluorescence , Luciferases/genetics , Luciferases/metabolism , Mice , Microscopy, Fluorescence , Molecular Sequence Data , Nuclear Proteins/isolation & purification , Nuclear Proteins/metabolism , Oligopeptides , Peptides/genetics , Promoter Regions, Genetic/genetics , Protein Binding , RNA/genetics , RNA/metabolism , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/metabolism , Saccharomyces cerevisiae/genetics , Sequence Alignment , Sequence Analysis, DNA , Sequence Homology, Amino Acid , Tissue Distribution , Two-Hybrid System Techniques
14.
AIDS Res Hum Retroviruses ; 16(8): 731-40, 2000 May 20.
Article in English | MEDLINE | ID: mdl-10826480

ABSTRACT

Some genomic elements of the multicopy HERV-W endogenous retroviral family have been previously identified in databases. One of them, located on chromosome 7, contains a single complete open reading frame (ORF) putatively encoding an envelope protein. We have experimentally investigated the genomic complexity and coding capacity of the HERV-W family. The human haploid genome contains at least 70, 100, and 30 HERV-W-related gag, pro, and env regions, respectively, widely and heterogeneously dispersed among chromosomes. Using in vitro transcription-translation procedures, three putative HERV-W gag, pro, and env ORFs were detected on chromosomes 3, 6, and 7, respectively, and their sequences analyzed. A 363 amino acid gag ORF containing matrix and carboxy-terminal truncated capsid domains encoded a putative 45-kDa protein. No gag-pro ORF was found, but a pro sequence containing a DTG active site was detected. Finally, the previously described 538 amino acid HERV-W env ORF, located on chromosome 7, was shown to be unique and encoded a putative 80-kDa glycosylated protein. Proteins of molecular mass identical to the one obtained by an in vitro transcription-translation procedure were detected in human placenta, using anti HERV-W Gag- and Env-specific antibodies. The absence of an HERV-W replication-competent provirus versus the existence of HERV-W-related Gag and Env proteins in healthy human placenta is discussed with respect to particle formation, physiology, and pathology.


Subject(s)
Chromosome Mapping , Endogenous Retroviruses/genetics , Endogenous Retroviruses/metabolism , Amino Acid Sequence , Animals , Blotting, Southern , Chromosomes, Human, Pair 3/genetics , Chromosomes, Human, Pair 6/genetics , Chromosomes, Human, Pair 7/genetics , Endopeptidases/genetics , Gene Products, env/chemistry , Gene Products, env/genetics , Genes, Viral , Genes, env/genetics , Genes, gag/genetics , Humans , Molecular Sequence Data , Placenta/metabolism , Polymerase Chain Reaction
15.
Genome Res ; 10(5): 672-8, 2000 May.
Article in English | MEDLINE | ID: mdl-10810090

ABSTRACT

The human genome is estimated to contain 23,000 to 33,000 retropseudogenes. To study the properties of genes giving rise to these retroelements, we compared the structure and expression of genes with or without known retropseudogenes. Four main features have emerged from the analysis of 181 genes associated to retropseudogenes: Reverse-transcribed genes are (1) widely expressed, (2) highly conserved, (3) short, and (4) GC-poor. The first two properties probably reflect the fact that genes giving rise to retropseudogenes have to be expressed in the germ-line. The two latter points suggest that reverse-transcription and transposition is more efficient for short GC-poor mRNAs. In addition, this analysis allowed us to reject previous hypotheses that widely expressed genes are GC rich. Rather, globally, genes with a wide tissue distribution are GC poor.


Subject(s)
Pseudogenes/genetics , Retroelements/genetics , Base Sequence/genetics , Computational Biology , Conserved Sequence/genetics , Databases, Factual , Evolution, Molecular , GC Rich Sequence , Gene Expression Regulation/genetics , Humans , Organ Specificity/genetics
16.
Genome Res ; 10(3): 379-85, 2000 Mar.
Article in English | MEDLINE | ID: mdl-10720578

ABSTRACT

We present here HOBACGEN, a database system devoted to comparative genomics in bacteria. HOBACGEN contains all available protein genes from bacteria, archaea, and yeast, taken from SWISS-PROT/TrEMBL and classified into families. It also includes multiple alignments and phylogenetic trees built from these families. The database is organized under a client/server architecture with a client written in Java, which may run on any platform. This client integrates a graphical interface allowing users to select families according to various criteria and notably to select homologs common to a given set of taxa. This interface also allows users to visualize multiple alignments and trees associated to families. In tree displays, protein gene names are colored according to the taxonomy of the corresponding organisms. Users may access all information associated to sequences and multiple alignments by clicking on genes. This graphic tool thus gives a rapid and simple access to all data required to interpret homology relationships between genes and distinguish orthologs from paralogs. Instructions for installation of the client or the server are available at http://pbil.univ-lyon1. fr/databases/hobacgen.html.


Subject(s)
Databases, Factual , Genetics, Microbial , Genome, Bacterial , Sequence Homology, Amino Acid , Software , Amino Acid Sequence , Base Sequence , Internet , Molecular Sequence Data , Sequence Alignment
17.
Mol Biol Evol ; 17(1): 68-74, 2000 Jan.
Article in English | MEDLINE | ID: mdl-10666707

ABSTRACT

To determine whether gene expression patterns affect mutation rates and/or selection intensity in mammalian genes, we studied the relationships between substitution rates and tissue distribution of gene expression. For this purpose, we analyzed 2,400 human/rodent and 834 mouse/rat orthologous genes, and we measured (using expressed sequence tag data) their expression patterns in 19 tissues from three development states. We show that substitution rates at nonsynonymous sites are strongly negatively correlated with tissue distribution breadth: almost threefold lower in ubiquitous than in tissue-specific genes. Nonsynonymous substitution rates also vary considerably according to the tissues: the average rate is twofold lower in brain-, muscle-, retina- and neuron-specific genes than in lymphocyte-, lung-, and liver-specific genes. Interestingly, 5' and 3' untranslated regions (UTRs) show exactly the same trend. These results demonstrate that the expression pattern is an essential factor in determining the selective pressure on functional sites in both coding and noncoding regions. Conversely, silent substitution rates do not vary with expression pattern, even in ubiquitously expressed genes. This latter result thus suggests that synonymous codon usage is not constrained by selection in mammals. Furthermore, this result also indicates that there is no reduction of mutation rates in genes expressed in the germ line, contrary to what had been hypothesized based on the fact that transcribed DNA is more efficiently repaired than nontranscribed DNA.


Subject(s)
Evolution, Molecular , Mammals/genetics , Mutation , Animals , Humans
18.
Gene ; 238(1): 163-70, 1999 Sep 30.
Article in English | MEDLINE | ID: mdl-10570994

ABSTRACT

Recently, we have defined and analyzed over 1800 orthologous human and rodent genes. Here we extend this work to compare human and Caenorhabditis elegans coding sequences. 1880 human proteins were compared with about 20000 predicted nematode proteins presumably comprising nearly the complete proteome of C. elegans. We found that 44% of human/rodent orthologs have convincing nematode counterparts. On average, the amino acid similarity and identity between aligned human and C. elegans orthologous gene products are 69.3% and 49.1% respectively, and the nucleotide identity is 49.8%. Detailed investigation of our results suggests that some nematode gene predictions are incorrect, leading to erroneous pairing with human genes (e.g. calcineurin and polymerase II elongation factor III). Furthermore, other proteins (i.e. homologs of human ribosomal proteins S20 and L41, thymosin) are missing entirely from the nematode proteome, suggesting that it may not be complete. These results underscore the fact that metazoan gene prediction is a very challenging task and that most computer-predicted nematode genes require supporting evidence of their existence from comparative genomics and/or laboratory investigation.


Subject(s)
Caenorhabditis elegans/genetics , Proteome/genetics , Animals , Evolution, Molecular , Humans , RNA, Messenger/genetics , Sequence Homology, Nucleic Acid
19.
Proc Natl Acad Sci U S A ; 96(8): 4482-7, 1999 Apr 13.
Article in English | MEDLINE | ID: mdl-10200288

ABSTRACT

We measured the expression pattern and analyzed codon usage in 8,133, 1,550, and 2,917 genes, respectively, from Caenorhabditis elegans, Drosophila melanogaster, and Arabidopsis thaliana. In those three species, we observed a clear correlation between codon usage and gene expression levels and showed that this correlation is not due to a mutational bias. This provides direct evidence for selection on silent sites in those three distantly related multicellular eukaryotes. Surprisingly, there is a strong negative correlation between codon usage and protein length. This effect is not due to a smaller size of highly expressed proteins. Thus, for a same-expression pattern, the selective pressure on codon usage appears to be lower in genes encoding long rather than short proteins. This puzzling observation is not predicted by any of the current models of selection on codon usage and thus raises the question of how translation efficiency affects fitness in multicellular organisms.


Subject(s)
Arabidopsis/genetics , Biological Evolution , Caenorhabditis elegans/genetics , Codon/genetics , Drosophila melanogaster/genetics , Gene Expression Regulation , Animals , Caenorhabditis elegans/embryology , Caenorhabditis elegans/growth & development , Expressed Sequence Tags , Gene Expression Regulation, Developmental , Gene Expression Regulation, Plant , Mutation , RNA, Messenger/analysis , Selection, Genetic
20.
Curr Biol ; 9(6): 329-32, 1999 Mar 25.
Article in English | MEDLINE | ID: mdl-10209098

ABSTRACT

The tumour suppressor gene PTEN (also called MMAC1 or TEP1) is somatically mutated in a variety of cancer types [1] [2] [3] [4]. In addition, germline mutation of PTEN is responsible for two dominantly inherited, related cancer syndromes called Cowden disease and Bannayan-Ruvalcaba-Riley syndrome [4]. PTEN encodes a dual-specificity phosphatase that inhibits cell spreading and migration partly by inhibiting integrin-mediated signalling [5] [6] [7]. Furthermore, PTEN regulates the levels of phosphatidylinositol 3,4,5-trisphosphate (PIP3) by specifically dephosphorylating position 3 on the inositol ring [8]. We report here that the dauer formation gene daf-18 is the Caenorhabditis elegans homologue of PTEN. DAF-18 is a component of the insulin-like signalling pathway controlling entry into diapause and adult longevity that is regulated by the DAF-2 receptor tyrosine kinase and the AGE-1 PI 3-kinase [9]. Others have shown that mutation of daf-18 suppresses the life extension and constitutive dauer formation associated with daf-2 or age-1 mutants. Similarly, we show that inactivation of daf-18 by RNA-mediated interference mimics this suppression, and that a wild-type daf-18 transgene rescues the dauer defect. These results indicate that PTEN/daf-18 antagonizes the DAF-2-AGE-1 pathway, perhaps by catalyzing dephosphorylation of the PIP3 generated by AGE-1. These data further support the notion that mutations of PTEN contribute to the development of human neoplasia through an aberrant activation of the PI 3-kinase signalling cascade.


Subject(s)
Caenorhabditis elegans Proteins , Caenorhabditis elegans/growth & development , Genes, Helminth , Genes, Tumor Suppressor , Helminth Proteins/physiology , Phosphatidylinositol 3-Kinases , Phosphoric Monoester Hydrolases/genetics , Tumor Suppressor Proteins , Animals , Caenorhabditis elegans/genetics , Catalysis , DNA, Complementary/genetics , Helminth Proteins/genetics , Humans , Larva/growth & development , Longevity/genetics , Membrane Lipids/metabolism , Multigene Family , PTEN Phosphohydrolase , Phosphatidylinositol Phosphates/metabolism , Phosphorylation , Receptor, Insulin/genetics , Receptor, Insulin/physiology
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