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PubMed1990

Computer prediction of the exon-intron structure of mammalian pre-mRNAs.

A novel approach to the problem of prediction of protein-coding regions is suggested. This approach combines the site prediction methods to predict splicing sites and the global coding region prediction methods to choose the best variant of spliced mRNA. One of the advantages of the suggested algorithm is that the resulting mRNA or protein sequence may then be immediately analyzed further. The true mRNA either coincides with the predicted one or ranks high in the list of variants. In the latter situation the predicted mRNA usually differs from the true one in only one or two of several exons. The combined approach allows the use of a priori information (e.g. the putative protein length or the number of exons). It is possible to use additional parameters not considered here, such as the preferred lengths of exons and introns, and particularly the preferred position of introns in the reading frame and the preferred codon position of exon termini.

Actins↗

PubMed1996

Association study of a null mutation in the dopamine D4 receptor gene in Italian patients with obsessive-compulsive disorder, bipolar mood disorder and schizophrenia.

Although serotonergic dysregulation is a leading pathogenetic hypothesis for obsessive-compulsive disorder (OCD), some evidence also suggests a possible dysregulation of the dopaminergic system in this disorder. Therefore, individual differences in deoxyribonucleic acid (DNA) coding for dopamine receptor proteins might contribute to the genetic background of this disorder. Previously we reported a null mutation in exon 1 of the dopamine D4 receptor gene. The variant type is characterized by a 13 bp deletion and is predicted to code for a truncated, non-functional receptor. We assessed the frequency of this polymorphism in 157 OCD patients, 196 schizophrenics, 111 bipolars and 162 healthy controls of Italian descent. Our findings do not implicate a role for this mutation in conferring a susceptibility to OCD and confirm previous negative results regarding its involvement in schizophrenia and bipolar disorder.

Bipolar Disorder↗

PubMed1998

Predicting survival, length of stay, and cost in the surgical intensive care unit: APACHE II versus ICISS.

BACKGROUND: Risk stratification of patients in the intensive care unit (ICU) is an important tool because it permits comparison of patient populations for research and quality control. Unfortunately, currently available scoring systems were developed primarily in medical ICUs and have only mediocre performance in surgical ICUs. Moreover, they are very expensive to purchase and use. We conceived a simple risk-stratification tool for the surgical ICU that uses readily available International Classification of Diseases, Ninth Revision, codes to predict outcome. Called ICISS (International Classification of Disease Illness Severity Score), our score is the product of the survival risk ratios (obtained from an independent data set) for all International Classification of Diseases, Ninth Revision, diagnosis codes. METHODS: A total of 5,322 noncardiac patients admitted to a surgical ICU during an 8-year period had their Acute Physiology and Chronic Health Evaluation (APACHE) II scores compared with their ICISS as predictors of outcome (survival/nonsurvival, length of stay, and charges). RESULTS: ICISS proved to be a much better predictor of survival than APACHE (receiver operating characteristic (ROC) APACHE = 0.806; Hosmer-Lemeshow (HL) APACHE = 22.56; ROC ICISS = 0.892; HL ICISS = 12.06) or the APACHE survival probability (ROC = 0.836; HL = 34.47). These differences were highly statistically significant (p < 0.001). ICISS was also better correlated with ICU length of stay (APACHE R2 = 0.06; ICISS R2 = 0.32) and ICU charges (APACHE R2 = 0.07; ICISS R2 = 0.39). When combined in a logistic model with ICISS, APACHE II added slightly to the predictive power of ICISS alone (combined ROC = 0.903) but degraded the calibration of the model (combined HL = 16.29; p = 0.038). CONCLUSION: Because ICISS is both more accurate and much less expensive to calculate than APACHE II score, ICISS should replace APACHE II score as the standard risk stratification tool in surgical ICUs.

APACHE↗

PubMed2000

Role of Sp1 response element in transcription of the human transglutaminase 1 gene.

This study addresses the contribution of an Sp1 response element in the proximal promoter of the transglutaminase 1 gene to transcription in normal epidermis and in a case of lamellar ichthyosis lacking transglutaminase 1 activity. The latter exhibited an Sp1 promoter mutation previously hypothesized to suppress transcription. In this study, several experiments indicated that the native Sp1 response element was functional, but it had only a small influence on transcription, and the previously observed mutation had no effect. These experiments involved mobility shift assays and transfections of promoter constructs in which the Sp1 site was mutated or lacking altogether. In addition the proximal 1.6 kb of the promoter from the affected individual was as active in transfections as the promoter from unaffected individuals. A search for sequence alterations in mRNA transcribed in keratinocytes from the patient revealed a novel single base mutation in codon 661 of the transglutaminase coding region predicted to result in premature termination of protein translation. The presence of this mutation in parental genomic DNA was confirmed by restriction digestion. Thus the lamellar ichthyosis phenotype in this case is likely attributable to a novel non-sense mutation in the coding region leading to reduced transglutaminase 1 mRNA levels rather than mutation of the Sp1 site.

Animals↗

PubMed1986

Probability of coding of a DNA sequence: an algorithm to predict translated reading frames from their thermodynamic characteristics.

An algorithm to determine the probability that a reading frame codifies for a protein is presented. It is based on the results of our previous studies on the thermodynamic characteristics of a translated reading frame. We also develop a prediction procedure to distinguish between coding and non-coding reading frames. The procedure is based on the characteristics of the putative product of the DNA sequence and not on periodicity characteristics of the sequence, so the prediction is not biased by the presence of overlapping translated reading frames or by the presence of translated reading frames on the complementary DNA strand.

Amino Acid Sequence↗

PubMed2000

Using database matches with for HMMGene for automated gene detection in Drosophila.

The application of the gene finder HMMGene to the Adh region of the Drosophila melanogaster is described, and the prediction results are analyzed. HMMGene is based on a probabilistic model called a hidden Markov model, and the probabilistic framework facilitates the inclusion of database matches of varying degrees of certainty. It is shown that database matches clearly improve the performance of the gene finder. For instance, the sensitivity for coding exons predicted with both ends correct grows from 62% to 70% on a high-quality test set, when matches to proteins, cDNAs, repeats, and transposons are included. The specificity drops more than the sensitivity increases when ESTs are used. This is due to the high noise level in EST matches, and it is discussed in more detail why this is and how it might be improved.

Alcohol Dehydrogenase↗

PubMed1996

Cloning and characterization of cDNAs for novel proteins with glutamic acid-proline dipeptide tandem repeats.

cDNAs with identical 3' sequences containing a hexanucleotide repeat -(GAGCCG)9- were isolated from rat pheochromocytoma and brain cDNA libraries. The cDNA with the longest open reading frame codes for a protein of 24.6 kDa containing a 16-fold -(Glu-Pro)- dipeptide repeat within a glutamate and proline rich region at its deduced C-terminus. cDNAs with the identical 3' sequence and a divergent 5' sequence were isolated from a rat skeletal muscle cDNA library. The latter are predicted to code for a protein of 15.5 kDa with a C-terminal repetitive domain identical to that in the pheochromocytoma and brain cDNAs. The cDNAs recognize a 1.8 kb mRNA species present in a variety of tissues, being particularly abundant in cardiac and skeletal muscle.

Amino Acid Sequence↗

PubMed1988

The mas oncogene encodes an angiotensin receptor.

The class of receptors coupled to GTP-binding proteins share a conserved structural motif which is described as a 'seven-transmembrane segment' following the prediction that these hydrophobic segments form membrane-spanning alpha-helices. Identified examples include the mammalian opsins, alpha 1-, alpha 2-, beta 1- and beta 2-adrenergic receptors, the muscarinic receptor family, the 5-HT1C-receptor, and the substance-K receptor. In addition, two mammalian genes have been identified that code for predicted gene products with sequence similarity to these receptors, but whose ligand specificity is unknown namely, G21 and the mas oncogene. The mas oncogene shows the greatest sequence similarity to the substance-K receptor, and on this basis it was predicted that it would encode a peptide receptor with mitogenic activity which would act through the inositol lipid signalling pathways. The mas oncogene product was transiently expressed in Xenopus oocytes, and stably expressed in a transfected mammalian cell line. The results demonstrate that the mas gene product is a functional angiotensin receptor.

Angiotensins↗

PubMed1995

Mutagenic analysis of human immunodeficiency virus type 1 Vpr: role of a predicted N-terminal alpha-helical structure in Vpr nuclear localization and virion incorporation.

The Vpr gene product of human immunodeficiency virus type 1 is a virion-associated protein that is important for efficient viral replication in nondividing cells such as macrophages. At the cellular level, Vpr is primarily localized in the nucleus when expressed in the absence of other viral proteins. Incorporation of Vpr into viral particles requires a determinant within the p6 domain of the Gag precursor polyprotein Pr55gag. In the present study, we have used site-directed mutagenesis to identify a domain(s) of Vpr involved in virion incorporation and nuclear localization. Truncations of the carboxyl (C)-terminal domain, rich in basic residues, resulted in a less stable Vpr protein and in the impairment of both virion incorporation and nuclear localization. However, introduction of individual substitution mutations in this region did not impair Vpr nuclear localization and virion incorporation, suggesting that this region is necessary for the stability and/or optimal protein conformation relevant to these Vpr functions. In contrast, the substitution mutations within the amino (N)-terminal region of Vpr that is predicted to adopt an alpha-helical structure (extending from amino acids 16 to 34) impaired both virion incorporation and nuclear localization, suggesting that this structure may play a pivotal role in modulating both of these biological properties. These results are in agreement with a recent study showing that the introduction of proline residues in this predicted alpha-helical region abolished Vpr virion incorporation, presumably by disrupting this secondary structure (S. Mahalingam, S. A. Khan, R. Murali, M. A. Jabbar, C. E. Monken, R. G. Collman, and A. Srinivasan, Proc. Natl. Acad. Sci. USA 92:3794-3798, 1995). Interestingly, our results show that two Vpr mutants harboring single amino acid substitutions (L to F at position 23 [L23F] and A30F) on the hydrophobic face of the predicted helix coded for relatively stable proteins that retained their ability to translocate to the nucleus but exhibited dramatic reduction in Vpr incorporation, suggesting that this hydrophobic face might mediate protein-protein interactions required for Vpr virion incorporation but not nuclear localization. Furthermore, a single mutation (E25K) located on the hydrophilic face of this predicted alpha-helical structure affected not only virion incorporation but also nuclear localization of Vpr. The differential impairment of Vpr nuclear localization and virion incorporation by mutations in the predicted N-terminal alpha-helical region suggests that this region of Vpr plays a role in both of these biological functions of Vpr.

Amino Acid Sequence↗

PubMed1995

Mutations of the androgen receptor coding sequence are infrequent in patients with isolated hypospadias.

Androgen receptor defects can cause severe hypospadias. To examine the possibility that androgen receptor defects are a common cause of such deficiencies, we have determined the coding sequence of the androgen receptor gene in nine patients with severe hypospadias. The analysis of the androgen receptor coding sequence predicts a normal amino acid sequence for the androgen receptor of eight of the nine patients, indicating that the observed defects in virilization are infrequently caused by mutations of the open-reading frame of the androgen receptor. These findings demonstrate the importance of family history and endocrine studies in identifying patients likely to harbor coding sequence mutations in the androgen receptor gene, and they serve to focus attention on other genes that may influence androgen action in this group of patients.

Base Sequence↗

PubMed1990

Molecular and biological characterization of a herpes simplex virus type 1 (HSV-1) neuroinvasiveness gene.

Pathogenetic studies of herpes simplex virus type 1 (HSV-1) strains ANG and its mouse brain-passaged descendant ANG path revealed no difference in neurovirulence but a significant difference in neuroinvasiveness. Thus, both viruses induced a fatal encephalitis in mice after direct injection into the brain, but only ANG path induced lethal neurologic disease after inoculation on rear footpads. The difference in neuroinvasiveness is not related to the capacity to replicate in mouse neural tissues or mouse cells in general, but is specifically related to virus entry into the peripheral nervous system in the footpad. Marker rescue experiments in which ANG path genes were used to confer neuroinvasiveness on ANG indicated that the gene that codes for glycoprotein D (gD) is responsible for the phenotypic difference. Analyses of the gD genes by dideoxy-sequencing techniques identified a base difference in the coding sequences and predicted that the ANG gD gene codes for alanine (GCC codon) at amino acid position 84 in the open reading frame and the ANG path gD gene codes for glycine (GGC codon) at this site. Using these data, an oligonucleotide probe predicted to be specific for the ANG path gD gene was prepared, and in Southern blot analyses, this probe revealed that neuroinvasiveness-rescued agents had incorporated the base change seen in the ANG path gD gene. We conclude that HSV-1 glycoprotein D functions to effect neuroinvasiveness and we discuss potential mechanisms that may be involved.

Amino Acid Sequence↗

PubMed1996

Perspectives: sequence data base searching in the era of large-scale genomic sequencing.

Large-scale sequencing of human and model organism genomes will have a profound impact on our ability to use sequence data base searching to predict the biochemical functions of sequences of interest. Despite the great value of more sequences in the data bases, a huge increase in data base size will also have adverse effects on data base searches. Upcoming problems will include (1) greatly increased search times, (2) an increase in background noise of high-scoring but biologically irrelevant matches, (3) inaccurate coding region prediction, leading to problems in protein data base searching, and (4) limited first-pass sequence annotation, making it difficult to determine the biological relevance of data base hits. Improved data base annotation tools and construction of smaller data bases of representative and highly-annotated sequences for first-pass analyses will be essential to deal with the impending flood of new genomic sequence.

Animals↗

PubMed1995

The napEDABC gene cluster encoding the periplasmic nitrate reductase system of Thiosphaera pantotropha.

The napEDABC locus coding for the periplasmic nitrate reductase of Thiosphaera pantotropha has been cloned and sequenced. The large and small subunits of the enzyme are coded by napA and napB. The sequence of NapA indicates that this protein binds the GMP-conjugated form of the molybdopterin cofactor. Cysteine-181 is proposed to ligate the molybdenum atom. It is inferred that the active site of the periplasmic nitrate reductase is structurally related to those of the molybdenum-dependent formate dehydrogenases and bacterial assimilatory nitrate reductases, but is distinct from that of the membrane-bound respiratory nitrate reductases. A four-cysteine motif at the N-terminus of NapA binds a [4Fe-4S] cluster. The DNA- and protein-derived primary sequence of NapB confirm that this protein is a dihaem c-type cytochrome and, together with spectroscopic data, indicate that both NapB haems have bis-histidine ligation. napC is predicted to code for a membrane-anchored tetrahaem c-type cytochrome that shows sequence similarity to the NirT cytochrome c family. NapC may be the direct electron donor to the NapAB complex. napD is predicted to encode a soluble cytoplasmic protein and napE a monotopic integral membrane protein, napDABC genes can be discerned at the aeg-46.5 locus of Escherichia coli K-12, suggesting that this operon encodes a periplasmic nitrate reductase system, while napD and napC are identified adjacent to the napAB genes of Alcaligenes eutrophus H16.

Amino Acid Sequence↗

PubMed1999

Isolation and characterization of mouse homologue for the human epilepsy gene, EPM2A.

Mutations in the novel gene, EPM2A, have been shown recently to cause the progressive myoclonus epilepsy of Lafora type. EPM2A is predicted to encode a putative protein-tyrosine phosphatase but its specific role in normal brain function and in the Lafora disease is not known. As a first step towards understanding the cellular function of EPM2A in an animal model, we have isolated cDNA clones for mouse EPM2A and analyzed its expression. Sequence analyses of the mouse cDNA clones revealed a complete ORF that supports the 5' coding sequence predicted for human EPM2A from the genomic sequence. When compared to EPM2A, the mouse homologue, named Epm2a, shows 86% identity at the nucleotide level and 88% identity and 93% similarity at the amino acid level. Similar to the human counterpart, Epm2a showed ubiquitous expression in Northern with a major transcript size of 3.5 kb. We have mapped the Epm2a to the proximal region of mouse chromosome 10 which is the syntenic region for human chromosome band, 6q24. Our results suggest that EPM2A is highly conserved in mammals and might have a conserved function.

3' Untranslated Regions↗

PubMed1995

At least four MHC class I genes are transcribed in the horse: phylogenetic analysis suggests an unusual evolutionary history for the MHC in this species.

Nineteen horse MHC class I specificities have been serologically identified previously at a single locus (ELA-A), and two other specificities appear to be coded at other loci. Biochemical studies indicate that there are at least two expressed loci. In order to establish the number of transcribed horse MHC class I genes, we made a cDNA library from a heterozygous animal (ELA-A3/A7), and screened for positive clones using a bovine class I probe. More than 200 class I clones were isolated in this way, and so far seven unique full length sequences have been identified. All of the sequences are predicted to code for surface expressed, functional molecules. The number of different sequences identified demonstrate that at least four genes are transcribed, although variations in transmembrane length (which is generally conserved in class I loci) suggest that five genes could be represented. Evolutionary analysis of these sequences (and two additional sequences known to represent different horse class I loci) reveals no firm relationships, such that the division between the different loci cannot be discerned. These results suggest an unusual evolutionary history for the horse MHC, the precise nature of which may be revealed only following further cross-species comparisons.

Amino Acid Sequence↗

PubMed1998

Temporal encoding as a determinant of overshadowing.

Three conditioned lick suppression experiments explored the effects on overshadowing of the temporal relationships of two conditioned stimuli (CSs) with an unconditioned stimulus (US). Assuming overshadowing is maximal when the potential information conveyed by two competing CSs is equivalent, the temporal coding hypothesis predicts that greater overshadowing will be observed when the CSs share the same temporal relationship with the US. Rats were exposed to an overshadowing CS that had either a forward, simultaneous, or backward relationship to the US. The relationship of the overshadowed CSs to the US was either forward (Experiment 1), simultaneous (Experiment 2), or backward (Experiment 3). The greatest amount of overshadowing was observed when both CSs had the same temporal relationship to the US. The data are discussed within the framework of the temporal coding hypothesis and of alternative models of Pavlovian conditioning based on the informational hypothesis.

Animals↗

PubMed1992

Characterization of the extracellular region of the human thyrotrophin receptor expressed as a recombinant protein.

DNA encoding the N-terminal 415 residues of the human thyrotrophin receptor (predicted to code for the large extracellular region) was introduced into Chinese hamster ovary (CHO) cells using the glutamine synthetase/cytomegalovirus amplifiable expression system, and into E. coli using the pGEX-3X expression vector. Substantial quantities of insoluble fusion protein product resulted from bacterial expression; by Western blot analysis, this was shown to be reactive with anti-receptor antibodies raised against a peptide corresponding to residues 313-330. Immunoreactivity was not retained by the solubilized protein. In eukaryotic expression, several successful CHO transfectants were observed and one (ExG2) was characterized thoroughly. Using agarose-bound Concanavalin A, a glycoprotein with an M(r) of approximately 60,000 was detected in a detergent extract of metabolically labelled ExG2 cells, agreeing with the predicted molecular size of 45,000, plus carbohydrate. The same protein could also be detected by immunoprecipitation using the experimental anti-peptide antisera and also sera from patients with Graves' disease. The protein was immunoreactive in Western blot analyses of ExG2 cells using the experimental antisera but not the pathological sera, supporting the view that linear sequences are not sufficient for autoantibody binding. These are the first studies in which visualization of eukaryotically expressed recombinant receptor by such immunological techniques has been possible, presumably because of the higher expression of the glutamine synthetase system. Surprisingly, the recombinant protein was retained within the cells rather than being secreted. The recombinant protein was very effective at absorbing the adenylate cyclase-stimulating activity of the sera from patients with Graves' disease, but not that of thyrotrophin. This suggests that the large N-terminal extracellular region contains epitopes for stimulatory autoantibodies, but that high affinity thyrotrophin binding requires additional components.

Adenylyl Cyclases↗

PubMedDate not supplied

An unusual coding sequence from a Drosophila clock gene is conserved in vertebrates.

The per locus has a fundamental involvement in the expression of biological rhythms in Drosophila. Mutations at this locus can shorten, lengthen or eliminate a variety of rhythmic activities that range from circadian behaviours, exemplified by eclosion and locomotor activities, to short-period behaviour such as the 55-s rhythm of courtship song. DNA from the per locus has been cloned, and we have used P-element-mediated DNA transformation to establish that a 7.1-kilobase(kb) HindIII fragment contains a functional copy of the gene. This transforming DNA contains a single transcription unit which gives rise to a 4.5-kb poly(A)+ RNA. Here we report the results of a search for sequences homologous to the per locus DNA in the genomic DNA of several species of vertebrates. An unusual, tandemly repeated sequence forming a portion of the 4.5-kb per transcript is homologous to DNA in chicken, mouse and man. Cloned DNAs from the mouse and Drosophila are related by long, uninterrupted tandem repetitions of the sequence ACNGGN. At the per locus, these tandem repeats are predicted to code for poly(Thr-Gly) tracts up to 48 amino acids long. These repeated sequences are also transcribed in the mouse. Several long tracts of poly(Thr-Gly) appear to be encoded by DNA cloned from the mouse.

Amino Acid Sequence↗