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PubMed2004

Improved techniques for the identification of pseudogenes.

MOTIVATION: Pseudogenes are the remnants of genomic sequences of genes which are no longer functional. They are frequent in most eukaryotic genomes, and an important resource for comparative genomics. However, pseudogenes are often mis-annotated as functional genes in sequence databases. Current methods for identifying pseudogenes include methods which rely on the presence of stop codons and frameshifts, as well as methods based on the ratio of non-silent to silent nucleotide substitution rates (dN/dS). A recent survey concluded that 50% of human pseudogenes have no detectable truncation in their pseudo-coding regions, indicating that the former methods lack sensitivity. The latter methods have been used to find sets of genes enriched for pseudogenes, but are not specific enough to accurately separate pseudogenes from expressed genes. RESULTS: We introduce a program called pseudogene inference from loss of constraint (PSILC) which incorporates novel methods for separating pseudogenes from functional genes. The methods calculate the log-odds score that evolution along the final branch of the gene tree to the query gene has been according to the following constraints: A neutral nucleotide model compared to a Pfam domain encoding model (PSILC(nuc/dom)); A protein coding model compared to a Pfam domain encoding model (PSILC(prot/dom)). Using the manual annotation of human chromosome 6, we show that both these methods result in a more accurate classification of pseudogenes than dN/dS when a Pfam domain alignment is available. AVAILABILITY: PSILC is available from http://www.sanger.ac.uk/Software/PSILC

Algorithms↗
PubMed1997

[Tumor suppressor gene p53--function and significance in gastroenterology].

The p53 gene is a tumor suppressor gene. The encoded p53 protein directly induces the expression of genes that are involved in cell cycle regulation. p53 was named "guardian of the genome" for its prevention of an otherwise fatal outcome under DNA damaging conditions. Under these conditions p53 inhibits cell cycle progression or induces apoptosis. The p53 protein has been structurally and functionally divided into four domains, two of which are of crucial importance: The sequence specific DNA-binding domain and the aminoterminal transactivation domain. They are both required to trigger the downstream processes following p53 expression. Mutations and inactivation of p53 by oncogenes are frequent events in the development of human neoplasia. That includes gastrointestinal tumors with their mutational spectra reflecting tissue-specific influences of endogenous and exogenous factors in carcinogenesis. Despite considerable progress in molecular biology, clinical applicability of p53 in both diagnostic and therapeutic strategies has not yet been validated.

Apoptosis↗
PubMed1983

The interaction between daughterless and sex-lethal in triploids: a lethal sex-transforming maternal effect linking sex determination and dosage compensation in Drosophila melanogaster.

Regulation of Drosophila sex determination and X-chromosome dosage compensation in response to the X-chromosome/autosome (X/A) balance of the zygote is shown to require proper functioning of both the da+ gene in the mother and the Sxl+ gene in the zygote. Previous studies led to the hypothesis that zygotic Sxl+ alleles are differentially active in females (XXAA) vs males (XYAA) in response to the X/A balance, and that maternal da+ gene product acts as a positive regulator in this connection. Sxl+ activity was proposed to impose the female developmental sequence on cells which would follow the male sequence in its absence. Important predictions of this proposal are verified. This study focuses primarily on the phenotype of triploid intersexes (XXAAA, X/A = 0.67). They are shown here to survive effects of da and Sxl mutations that would be lethal to diploids. The ambiguous X/A signal of intersexes normally causes them to develop as phenotypic mosaics of male and female tissue. Loss of maternal da+ or zygotic Sxl+ gene function shifts their somatic sexual phenotype to the male alternative. A gain-of-function mutation at Sxl has the opposite effect, imposing female development regardless of the maternal genotype with respect to da. It also reduces their rate of X-linked gene expression. The effects of a duplication of Sxl+ resemble those of the constitutive Sxl allele, but are less extreme. The role of these genes in the process of X-chromosome dosage compensation is inferred indirectly from the strict dependence of the mutations' lethal effects on the X/A balance in haploids, diploids, and triploids, and more directly from the effects of the mutations on the phenotypes of the X-linked neomorphic mutations, Bar and Hairy-wing. The relationship of da+ and Sxl+ gene functions to those of other sex-specific lethal loci in D. melanogaster, and to sex determination mechanisms in other species, is discussed.

Animals↗
PubMed2002

Effects of caloric restriction on mitochondrial function and gene transcripts in rat muscle.

Rodent skeletal muscle mitochondrial DNA has been shown to be a potential site of oxidative damage during aging. Caloric restriction (CR) is reported to reduce oxidative stress and prolong life expectancy in rodents. Gene expression profiling and measurement of mitochondrial ATP production capacity were performed in skeletal muscle of male rats after feeding them either a control diet or calorie-restricted diet (60% of control diet) for 36 wk to determine the potential mechanism of the beneficial effects of CR. CR enhanced the transcripts of genes involved in reactive oxygen free radical scavenging function, tissue development, and energy metabolism while decreasing expression of those genes involved in signal transduction, stress response, and structural and contractile proteins. Real-time PCR measurements confirmed the changes in transcript levels of cytochrome-c oxidase III, superoxide dismutase (SOD)1, and SOD2 that were noted by the microarray approach. Mitochondrial ATP production and citrate synthase were unaltered by the dietary changes. We conclude that CR alters transcript levels of several genes in skeletal muscle and that mitochondrial function in skeletal muscle remains unaltered by the dietary intervention. Alterations in transcripts of many genes involved in reactive oxygen scavenging function may contribute to the increase in longevity reported with CR.

Adenosine Triphosphate↗
PubMed2001

Taking a functional genomics approach in molecular medicine.

The elucidation of genetic components of human diseases at the molecular level provides crucial information for developing future causal therapeutic intervention. High-throughput genome sequencing and systematic experimental approaches are fuelling strategic programs designed to investigate gene function at the biochemical, cellular and organism levels. Bioinformatics is one important tool in functional genomics, although showing clear limitations in predicting ab initio gene structures, gene function and protein folds from raw sequence data. Systematic large-scale data-set generation, using the same type of experiments that are used to decipher the function of single genes, are being applied on entire genomes. Comparative genomics, establishment of gene catalogues, and investigation of cellular and tissue molecular profiles are providing essential tools for understanding gene function in complex biological networks.

Animals↗
PubMed2000

Complex structure of a maize Myb gene promoter: functional analysis in transgenic plants.

The maize P gene encodes a Myb-like transcription factor that regulates synthesis of red flavonoid pigments in floral organs. To study the transcriptional regulation of the P gene, candidate regulatory sequences of the P1-rr gene promoter were identified by Ac insertional mutagenesis and subjected to functional testing in transgenic maize plants. The results indicate that a 561 bp fragment (Pb) encompassing the transcription start site (-235 to +326) supports weak expression of a GUS reporter gene in floral organs, including husk, silk, kernel pericarp, cob and male inflorescence. Two other fragments, located approximately 1 and 5 kb 5' of the transcription start site, increased the levels of GUS activity in floral tissues and thus appear to contain enhancer elements. All of the tested constructs gave similar patterns of GUS expression, suggesting that the 561 bp Pb fragment that is common among the transgene constructs contains regulatory elements that promote activation in floral organs. The basal promoter and proximal enhancer fragments contain putative binding sites for bZip regulatory factors, and a complex arrangement of palindromes including a large inverted repeat of two tRNA-like genes. Possibly, interconversions between linear and cruciform conformations of the palindromes may affect protein/DNA interactions and thereby modulate P1-rr expression.

Base Sequence↗
PubMed2006

High-resolution fine mapping of ps-2, a mutated gene conferring functional male sterility in tomato due to non-dehiscent anthers.

Functional male sterility is an important trait for the production of hybrid seeds. Among the genes coding for functional male sterility in tomato is the positional sterility gene ps-2. ps-2 is monogenic recessive, confers non-dehiscent anthers and is the most suitable for practical uses. In order to have tools for molecular-assisted selection (MAS) we fine mapped the ps-2 locus. This was done in an F(2) segregating population derived from the interspecific cross between a functionally male sterile line (ps-2/ps-2; Solanum lycopersicum) and a functionally male fertile line (S. pimpinellifolium). Here we report the procedure that has led to the high-resolution fine mapping of the ps-2 locus in a 1.65 cM interval delimited by markers T0958 and T0635 on the short arm of Chromosome 4. The presence of many COS markers in the local high-resolution map allowed us to study the synteny between tomato and Arabidopsis at the ps-2 locus region. No obvious candidate gene for ps-2 was identified among the known functional male sterility genes in Arabidopsis.

Alleles↗
PubMed2004

RNA interference and its current application in mammals.

OBJECTIVE: The aim of this review was to assess RNA interference (RNAi) and its possibility as a potential and powerful tool to develop highly specific double-stranded RNA (dsRNA) or small interfering RNA (siRNA) based gene-silencing therapeutics. DATA SOURCES: The data used in this review were obtained from the current RNAi-related research reports. STUDY SELECTION: dsRNA-mediated RNAi has recently emerged as a powerful reverse genetic tool to silence gene expression in multiple organisms. The discovery that synthetic duplexes of 21 nucleotides siRNAs trigger gene-specific silencing in mammalian cells has further expanded the utility of RNAi in to the mammalian system. DATA EXTRACTION: The currently published papers reporting the discovery and mechanism of RNAi phenomena and application of RNAi on gene function in mammalian cells were included. DATA SYNTHESIS: Since the recent development of RNAi technology in the mammalian system, investigators have used RNAi to elucidate gene function, and to develop gene-based therapeutics by delivery exogenous siRNA or siRNA expressing vector. The general and sequence-specific inhibitory effects of RNAi that will be selective, long-term, and systemic to modulate gene targets mentioned in similar reports have caused much concern about its effectiveness in mammals and its eventual use as a therapeutic mordality. CONCLUSIONS: It is certain that the ability of RNAi in mammals to silence specific genes, either when transfected directly as siRNAs or when generated from DNA vectors, will undoubtedly accelerate the study of gene function and might also be used as a potentially useful method to develop highly gene-specific therapeutic methods. It is also expected that RNAi might one day be used to treat human diseases.

Animals↗
PubMedDate not supplied

A functional gamma gene formed from known gamma-gene segments is not necessary for antigen-specific responses of murine cytotoxic T lymphocytes.

Structural similarities between surface immunoglobulins (s Ig) on B cells and antigen-specific receptors on T cells suggest that a T cell, like a B cell, should express only two immunoglobulin-like genes, one for each subunit of the disulphide-linked, heterodimeric, antigen-specific (alpha beta) T-cell receptor. However, cytotoxic T lymphocytes (Tc cells) and immature thymocytes also contain RNA transcripts of a third immunoglobulin-like gene, called gamma (refs 1-4). A polypeptide corresponding to the gamma gene has not yet been identified and the function of this gene remains an enigma. Judging from its nucleotide sequence, the rearranged gamma gene is expected to encode an integral membrane polypeptide chain, and gamma complementary DNAs from two cloned Tc cell lines have previously been found to have different sequences around the V-J (variable region-joining region) junction, suggesting that, in these cells, the gamma-gene product is a clonally diverse surface structure that may form part of an as yet unidentified, antigen-specific receptor. To analyse further the extent of diversity of the gamma-gene product, we have determined the partial sequences of 11 gamma cDNA clones from three other cloned Tc cell lines, and report here that the sequences are indeed clonally diverse, but in all instances they are out-of-phase in the region of the V-J junction. This finding and the pattern of gamma-gene rearrangements in these cell lines indicate that a polypeptide product of the previously reported gamma gene, V2J2-C2, is not expressed in them and is, therefore, not necessary for the antigen-specific cytotoxic and proliferative responses of these mature T cells.

Animals↗
PubMed1995

Evolution of immunoglobulin VH pseudogenes in chickens.

In chickens, there is a single functional gene (VH1) coding for the heavy chain variable region of immunoglobulins, and immunoglobulin diversity is generated by gene conversion of the VH1 gene by many variable region pseudogenes (psi VH's) that exist on the 5' side of the VH1 gene. To understand the evolution of this unique genetic system, we conducted statistical analyses of VH1 and psi VH genes together with functional VH genes from other higher vertebrate species. The results indicate, first, that chicken VH genes are all closely related to one another and were derived relatively recently from an ancestral gene belonging to one of the three major groups of VH genes in higher vertebrates. Second, the rate of nonsynonymous substitution is slightly higher than that of synonymous substitution in the complementarity-determining regions (CDRs), which suggests that diversity-enhancing selection has operated in the CDRs even for pseudogenes. However, both the rates of synonymous and nonsynonymous substitution are higher in the CDRs than in the framework regions (FRs), apparently because of an interaction between positive selection and meiotic gene conversion in the CDRs. Third, a dot matrix analysis of the psi VH genes and genomic diversity (D) genes has indicated that the 3' end of psi VH genes is attached by D-gene-like sequences, and this region of psi VH genes has high similarity with D gene sequences. This suggests that V and D genes were fused at some point of evolutionary time and this fused element multiplied by gene duplication. Finally, two alternative hypotheses of explaining the evolution of the chicken VH gene system are presented.

Animals↗
PubMedDate not supplied

[Genes, polymorphism and function of the HLA gene region].

Great biological significance of the HLA complex and its impact on practical medicine impels researchers to study it, the result of which is an annual expansion of our knowledge on the system. The polymorphism of the HLA complex has increased--altogether 664 alleles are officially recognised. The genetic defect leading to the bare lymphocyte syndrome was elucidated, too--the mutations in genes coding transcription factors RFX5 and CIITA are responsible for. Also the role of HLA-DM antigens in the exogenous pathway of antigen presentation was elucidated. They are principle molecules which dislodge CLIP from the groove of HLA class II molecules leaving it free to accommodate more suitable immunogenic peptide. It was also discovered that HLA class I antigens are target structures for NK-cells. NK-cell receptors recognising them transduce negative signals switching their cytotoxic activity off. (Fig. 8, Tab. 1, Ref. 34.)

Alleles↗
PubMed2004

Gene expression profile of human chondrocyte HCS-2/8 cell line by EST sequencing analysis.

Large-scale single-pass sequencing of randomly selected cDNA clones from cell type specific libraries has proven to be a powerful approach for the discovery of novel gene functions, identification of novel gene family members, and definition of gene expression profiles. HCS-2/8 chondrocyte has been used as a cell culture model to study chondrocyte differentiation. Here we performed 3350 single-pass sequencing reactions obtained from the 5' ends of cDNAs from HCS-2/8 cells. To define the expression profiles of HCS-2/8 chondrocytes, we analyzed the identity of these representative cDNA sequences using database searches (BLAST). The sequences represent 1927 unique genes with known function (i.e., unigene clusters), 38 transcripts that are similar to genes with known function, 739 expressed genes with unknown function (i.e., expressed sequence tags), and 18 cDNAs which have not previously been sequenced. Interestingly, many transcripts were expressed from chromosome 12 compared with total genes, while the fewer numbers of cDNAs were derived from genes on chromosomes 14, 18 and Y. The chondrocytic phenotype of HCS-2/8 cells is reflected by abundant expression of genes related to cell structure and motility and the 20 most frequently expressed unigenes reflect a chondrocyte-related gene expression signature. Thus, our data establish a representative set of more than 2000 genes expressed in a chondrocytic cell line. This finding provides a framework for understanding cell growth and differentiation of chondrocytes and their metabolic function in the formation and remodeling of cartilage.

Cell Line, Tumor↗
PubMed2005

Cardiac transgenesis with the tetracycline transactivator changes myocardial function and gene expression.

The cardiac-specific tetracycline-regulated gene expression system (tet-system) is a powerful tool using double-transgenic mice. The cardiac alpha-myosin heavy chain promoter (alphaMHC) drives lifetime expression of a tetracycline-inhibited transcription activator (tTA). Crossing alphaMHC-tTA mice with mice containing a tTA-responsive promoter linked to a target gene yields double-transgenic mice having tetracycline-repressed expression of the target gene in the heart. Using the tet-system, some studies use nontransgenic mice for the control group, whereas others use single-transgenic alphaMHC-tTA mice. However, previous studies found that high-level expression of a modified activator protein caused cardiomyopathy. Therefore, we tested whether cardiac expression of tTA was associated with altered function of alphaMHC-tTA mice compared with wild-type (WT) littermates. We monitored in vivo and in vitro function and gene expression profiles for myocardium from WT and alphaMHC-tTA mice. Compared with WT littermates, alphaMHC-tTA mice had a greater heart-to-body weight ratio (approximately 10%), ventricular dilation, and decreased ejection fraction, suggesting mild cardiomyopathy. In vitro, submaximal contractions were greater compared with WT and were associated with greater myofilament Ca2+ sensitivity. Gene expression profiling revealed that the expression of 153 genes was significantly changed by >20% when comparing alphaMHC-tTA with WT myocardium. These findings demonstrate that introduction of the alphaMHC-tTA construct causes significant effects on myocardial gene expression and major functional abnormalities in vivo and in vitro. For studies using the tet-system, these results suggest caution in the use of controls, since alphaMHC-tTA myocardium differs appreciably from WT. Furthermore, the results raise the possibility that the phenotype conferred by a target gene may be influenced by the modified genetic background of alphaMHC-tTA myocardium.

Actin Cytoskeleton↗
PubMed1992

Gene and pseudogene of the mouse cation-dependent mannose 6-phosphate receptor. Genomic organization, expression, and chromosomal localization.

The cation-dependent mannose 6-phosphate receptor (CD-MPR) is one of the two transmembrane proteins involved in transport of lysosomal enzymes. We have cloned the mouse CD-MPR gene and also a very unusual processed-type CD-MPR pseudogene. They are both present at one copy per haploid genome and map to chromosomes 6 and 3, respectively. Comparison of the complete 10-kilobase (kb) sequence of the functional gene with the cDNA indicates that it contains seven exons. Exon 1 encodes the 5'-untranslated region of the mRNA, the others (exons 2-7) encode the luminal, transmembrane, and cytoplasmic domains of the CD-MPR. Exon 7 also contains a 1.2-kb-long 3'-untranslated region of the mRNA. A unique transcription-initiation site was determined by primer extension of mouse liver mRNA. The promoter elements in the 5' upstream region of this site resemble those contained in genes constitutively transcribed. However, Northern blot analysis demonstrates that the CD-MPR is variably expressed in adult mouse tissues and during mouse development. The pseudogene, which is flanked by direct repeats, is almost colinear with the cDNA indicating that it presumably arose by reverse transcription of an mRNA. However, the pseudogene differs from the cDNA. It contains at its 5' end, an additional 340-nucleotide (nt) sequence homologous to the promoter region of the functional gene. This sequence exhibits some promoter activity in vitro. Furthermore, a 24-nt insertion interrupts the region homologous to the 5'-noncoding region of the cDNA. In the functional gene, this 24-nt sequence occurs between exon 1 and 2, where it is flanked by typical consensus sequences of exon/intron boundaries. Therefore, it may represent an additional exon of the functional gene. These two features of the pseudogene suggest that expression of the CD-MPR gene may be regulated by use of different promoters and/or alternative splicing.

Amino Acid Sequence↗
PubMed2005

Gene discovery by ribozyme and siRNA libraries.

Catalytic RNAs, also known as ribozymes, can be engineered to optimize their activities in the intracellular environment. The introduction of a library of active ribozymes into cells, and the subsequent screening for phenotypic changes, allows the rapid identification of gene function. For the determination of gene function, ribozyme technology complements another RNA-based tool that is based on libraries of small interfering RNAs.

Animals↗
PubMed2002

The product of Saccharomyces cerevisiae WHIP/MGS1, a gene related to replication factor C genes, interacts functionally with DNA polymerase delta.

The Saccharomyces cerevisiae gene WHIP/ MGS1 encodes a protein related to the subunits of Replication Factor C (RFC). We found that the RFC-like motifs in Whip/Mgs1 are essential for its function. Furthermore, by screening for synthetic dosage lethality, we have shown that overexpression of MGS1 causes lethality in combination with mutations in genes that encode replication proteins such as DNA polymerase delta, RFC, PCNA and RPA. Moreover, loss of MGS1 function interferes with the ability of multicopy PCNA to suppress the replication defect of the rfc5-1 mutant. At permissive temperatures, deletion of MGS1 suppresses the hydroxyurea (HU) sensitivity of pol31 and pol32 mutants, which bear mutations in the smaller subunits of DNA polymerase delta, and at semipermissive and non-permissive temperatures mgs1delta partially alleviates the growth defects of the pol31 mutant. We also report that the growth defect and HU sensitivity of the pol31 mutant are suppressed by mms2delta and rad18delta mutations. We suggest that Mgs1 interacts with the DNA replication machinery to modulate the function of DNA polymerase delta during replication or replication-associated repair, and influences the choice of the pathway employed for replication fork reactivation. Possible roles of Mgs1, DNA polymerase delta, Rad18 and Mms2 in replication and replication fork restart are discussed.

Adenosine Triphosphatases↗