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PubMed1985

Definition of essential sequences and functional equivalence of elements downstream of the adenovirus E2A and the early simian virus 40 polyadenylation sites.

In addition to the highly conserved AATAAA sequence, there is a requirement for specific sequences downstream of polyadenylic acid [poly(A)] cleavage sites to generate correct mRNA 3' termini. Previous experiments demonstrated that 35 nucleotides downstream of the E2A poly(A) site were sufficient but 20 nucleotides were not. The construction and assay of bidirectional deletion mutants in the adenovirus E2A poly(A) site indicates that there may be redundant multiple sequence elements that affect poly(A) site usage. Sequences between the poly(A) site and 31 nucleotides downstream were not essential for efficient cleavage. Further deletion downstream (3' to +31) abolished efficient cleavage in certain constructions but not all. Between +20 and +38 the sequence T(A/G)TTTTT was duplicated. Function was retained when one copy of the sequence was present, suggesting that this sequence represents an essential element. There may also be additional sequences distal to +43 that can function. To establish common features of poly(A) sites, we also analyzed the early simian virus 40 (SV40) poly(A) site for essential sequences. An SV40 poly(A) site deletion that retained 18 nucleotides downstream of the cleavage site was fully functional while one that retained 5 nucleotides downstream was not, thus defining sequences required for cleavage. Comparison of the SV40 sequences with those from E2A did not reveal significant homologies. Nevertheless, normal cleavage and polyadenylation could be restored at the early SV40 poly(A) site by the addition of downstream sequences from the adenovirus E2A poly(A) site to the SV40 +5 mutant. The same sequences that were required in the E2A site for efficient cleavage also restored activity to the SV40 poly(A) site.

Adenovirus Early Proteins↗

PubMed2001

Models of sequence evolution for DNA sequences containing gaps.

Most evolutionary tree estimation methods for DNA sequences ignore or inefficiently use the phylogenetic information contained within shared patterns of gaps. This is largely due to the computational difficulties in implementing models for insertions and deletions. A simple way to incorporate this information is to treat a gap as a fifth character (with the four nucleotides being the other four) and to incorporate it within a Markov model of nucleotide substitution. This idea has been dismissed in the past, since it treats a multiple-site insertion or deletion as a sequence of independent events rather than a single event. While this is true, we have found that under many circumstances it is better to incorporate gap information inadequately than to ignore it, at least for topology estimation. We propose an extension to a class of nucleotide substitution models to incorporate the gap character and show that, for data sets (both real and simulated) with short and medium gaps, these models do lead to effective use of the information contained within insertions and deletions. We also implement an ad hoc method in which the likelihood at columns containing multiple-site gaps is downweighted in order to avoid giving them undue influence. The precision of the estimated tree, assessed using Markov chain Monte Carlo techniques to find the posterior distribution over tree space, improves under these five-state models compared with standard methods which effectively ignore gaps.

Algorithms↗

PubMed1993

Silk moth chorion pseudogenes: hallmarks of genomic evolution by sequence duplication and gene conversion.

The part of the genetic locus of the domesticated silk moth, Bombyx mori, in which high cysteine (Hc) chorion genes of late developmental specificity reside contains regions encompassing gene-like sequences which exhibit properties distinct from those of functional Hc genes. One of these regions has been characterized and shown to contain a chorion pseudogene, psi HcB.15, which shares pronounced similarities with a transcribed chorion pseudogene, psi HcB.12/13, which was characterized previously. Both pseudogenes are homologous to HcB chorion genes but bear multiple single nucleotide substitutions and short segmental mutations (insertions and deletions) which introduce translational frame shifts and termination codons in the coding regions. Structural characteristics unique to the two pseudogenes suggest that psi HcB.15 was generated first from a functional HcB gene and gave rise subsequently to psi HcB 12/13 as a result of a sequence duplication event. The two pseudogenes can be distinguished from each other by the presence of distinct regions of similarity to the consensus sequence of functional HcB genes which appear to have arisen from gene-conversion-mediated correctional events. These findings lend support to the hypothesis that chorion pseudogene sequences represent reservoirs of genetic information that participates in the evolution of the chorion locus rather than relics of inactivated genes passively awaiting extinction.

Animals↗

PubMed1996

Metabolic myopathies.

Disorders of glycogen, lipid or mitochondrial metabolism may cause two main clinical syndromes, namely (1) progressive weakness (eg, acid maltase, debrancher enzyme, and brancher enzyme deficiencies among the glycogenoses; long- and very-long-chain acyl-CoA dehydrogenase (LCAD, VLCAD), and trifunctional enzyme deficiencies among the fatty acid oxidation (FAO) defects; and mitochondrial enzyme deficiencies) or (2) acute, recurrent, reversible muscle dysfunction with exercise intolerance and acute muscle breakdown or myoglobinuria (with or without cramps) (eg, phosphorylase (PPL), phosphorylase b kinase (PBK), phosphofructokinase (PFK), phosphoglycerate kinase (PGK), phosphoglycerate mutase (PGAM), and lactate dehydrogenase (LDH) among the glycogenoses and carnitine palmitoyltransferase II (CPT II) deficiency among the disorders of FAO or (3) both (eg, PPL, PBK, PFK among the glycogenoses; LCAD, VLCAD, short-chain L-3-hydroxyacyl-CoA dehydrogenase (SCHAD), and trifunctional enzyme deficiencies among the FAO defects; and multiple mitochondrial DNA (mtDNA) deletions). Myoadenylate deaminase deficiency, a purine nucleotide cycle defect, is somewhat controversial and is characterized by exercise-related cramps leading rarely to myoglobinuria.

Adolescent↗

PubMed2026

Bridging the gap between legacy polymerase chain reaction-based microsatellite data with high-throughput sequencing data for conservation genomics.

Microsatellites are powerful markers for tracking genetic variation in wildlife populations due to their high polymorphism and genome-wide abundance. While polymerase chain reaction (PCR)-based fragment size analysis has been the standard for genotyping microsatellites, high-throughput sequencing offers greater resolution and the opportunity to sync historical datasets with modern analyses. We evaluated how genotypes from whole-genome sequencing align with PCR data for 15 microsatellite loci in 11 North American brown bears (Ursus arctos). Brown bear populations in the 48 contiguous United States have declined from approximately 50,000 to fewer than 2,000 over the past decades. Their endangered status has prompted extensive research and genetic monitoring, yielding large, multiyear microsatellite datasets upon which future conservation efforts can build. We achieved an overall microsatellite genotype concordance rate of 94.5% comparing high-throughput sequencing results to PCR based-fragment size results. All discrepancies occurred at complex loci containing multiple insertions and/or deletions (indels). Physically linked indels or single nucleotide polymorphisms (SNPs) occurring within the loci were misinterpreted as independent insertions, underscoring the need for genotyping tools that incorporate phasing when genotyping. To evaluate coverage effects, we downsampled high-throughput sequence data from 30x to 2x. Concordance remained high at 20 to 30x but dropped sharply at 10x, with 5x and 2x having discordant genotypes or insufficient coverage for genotyping. Accurate genotyping required both sufficient depth and number of reads spanning the entire repeat regions. Our results show that short-read whole-genome sequencing can recover microsatellite genotypes with high accuracy when paired with careful variant interpretation. By aligning historical PCR datasets with modern sequencing data, we can preserve decades of genetic insight and strengthen long-term monitoring of at-risk populations.

Animals↗

PubMed1998

RNA editing: trypanosomes rewrite the genetic code.

The understanding of how genetic information is stored and expressed has advanced considerably since the "central dogma" asserted that genetic information flows from the nucleotide sequence of DNA to that of messenger RNA (mRNA) which in turn specifies the amino acid sequence of a protein. It was found that genetic information can be stored as RNA (e.g. in RNA viruses) and can flow from RNA to DNA by reverse transcriptase enzyme activity. In addition, some genes contain introns, nucleotide sequences that are removed from their RNA (by RNA splicing) and thus are not represented in the resultant protein. Furthermore, alternative splicing was found to produce variant proteins from a single gene. More recently, the study of trypanosome parasites revealed an unexpected and indeed counter-intuitive genetic complexity. Genetic information for a single protein can be dispersed among several (DNA) genes in these organisms. One of these genes specifies an encrypted precursor mRNA that is converted to a functional mRNA by a process called RNA editing that inserts and deletes uridylate nucleotides. The sequence of the edited mRNA is specified by multiple small RNAs, named guide RNAs, (gRNAs) each of which is encoded in a separate gene. Thus, edited mRNA sequences are assembled from multiple genes by the transfer of information from one type of RNA to another. The existence of editing was surprising but has stimulated the discovery of other types of RNA editing. The Stuart laboratory has been exploring RNA editing in trypanosomes from the time of its discovery. They found dramatic differences between the mitochondrial gene sequences and those of the corresponding mRNAs, which indicated editing by the insertion and deletion of uridylates. Some editing was modest; simply eliminating shifts in sequence register of minimally extending the protein coding sequence. However, editing of many mRNAs was startingly extensive. The RNA sequence was essentially entirely remodeled with its sequence more the result of editing than the gene sequence. The identities of genes for such extensively edited RNA were not recognizable from the DNA sequence but they were readily identifiable from the edited mRNA sequence. Thus, despite the complex and extensive editing the resultant mRNA sequence is precise. Characterization of partially edited RNAs indicated that editing proceeds in the direction opposite to that used to specify the protein which reflects the use of the gRNAs. The numerous gRNAs that are used for editing are encoded in the DNA molecules whose role was previously a mystery. Using information gained in our earlier studies, the Stuart group developed an in vitro system that reproduces the fundamental process of editing in order to resolve the mechanism by which it occurs. They determined that editing entails a series of enzymatic steps rather than the mechanism used in RNA splicing. They also showed that chimeric gRNA-mRNA molecules are aberrant by-products of editing rather than intermediates in the process as had been proposed. Additional studies are exploring precisely how the number of added and deleted uridylates is specified by the gRNA. The Stuart laboratory showed that editing is performed by an aggregation of enzymes that catalyze the separate steps of editing. It also developed a method to purify this multimolecule complex that contains several, perhaps tens of, proteins. This will allow the study of its composition and the functions of its component parts. Indeed, the gene for one component has been identified and its detailed characterization begun. These studies are developing tools to explore related processes. An early finding in the lab was that the various mRNAs are differentially edited during the life cycle of the parasite. The pattern of this editing indicates that editing serves to regulate the alternation between two modes of energy generation. This regulation is coordinated with other events that are occurring during the life c

Animals↗

PubMed1995

A transcriptional enhancer of the glutamine synthetase gene that is selective for retinal Müller glial cells.

This article demonstrates that the chicken glutamine synthetase (GS) promoter contains cis-acting elements that direct transcription to retinal Müller glial cells. The transient assay system developed to identify these elements involved electroporation of intact retinal tissue with GS-beta-galactosidase fusion genes followed by preparation of primary cultures and histochemical assay of cells expressing beta-galactosidase. Plasmids containing beta-galactosidase under transcriptional control by two different viral promoters are expressed primarily in neuronal cells after transfection of intact embryonic d 12 retina. In sharp contrast, expression is primarily in Müller glia after transfection with a GS-beta-galactosidase fusion gene. Although GS is glucocorticoid inducible, steroid hormone is not required to achieve Müller cell-selective expression of the GS-beta-galactosidase fusion gene. Deletion studies indicate that multiple cis-acting elements located between nucleotides-436 and -61 relative to the GS transcription start site contribute to produce Müller cell selectivity. Moreover, these upstream elements enhance expression of a heterologous promoter in Müller cells not neurons. These results indicate that an enhancer located between 61 and 436 nucleotides upstream of the transcription start site contributes to Müller cell-selective expression of the GS gene in the retina.

Animals↗

PubMed2003

A region of the Epstein-Barr virus (EBV) mRNA export factor EB2 containing an arginine-rich motif mediates direct binding to RNA.

The Epstein-Barr virus (EBV) protein EB2 (also called Mta, SM, or BMLF1) has properties in common with mRNA export factors and is essential for the production of EBV infectious virions. However, to date no RNA-binding motif essential for EB2-mediated mRNA export has been located in the protein. We show here by Northwestern blot analysis that the EB2 protein purified from mammalian cells binds directly to RNA. Furthermore, using overlapping glutathione S-transferase (GST)-EB2 peptides, we have, by RNA electrophoretic mobility shift assays (REMSAs) and Northwestern blotting, located an RNA-binding motif in a 33-amino acid segment of EB2 that has structural features of the arginine-rich RNA-binding motifs (ARMs) also found in many RNA-binding proteins. A synthetic peptide (called Da), which contains this EB2 ARM, bound RNA in REMSA. A GST-Da fusion protein also bound RNA in REMSA without apparent RNA sequence specificity, because approximately 10 GST-Da molecules bound at multiple sites on a 180-nucleotide RNA fragment. Importantly, a short deletion in the ARM region impaired both EB2 binding to RNA in vivo and in vitro and EB2-mediated mRNA export without affecting the shuttling of EB2 between the nucleus and the cytoplasm. Moreover, ectopic expression of ARM-deleted EB2 did not rescue the production of infectious virions by 293 cells carrying an EBVDeltaEB2 genome, which suggests that the binding of EB2 to RNA plays an essential role in the EBV productive cycle.

Amino Acid Motifs↗

PubMed1997

Formation of multimers of cucumber mosaic virus satellite RNA.

Double-stranded RNA multimers of cucumber mosaic virus (CMV) satellite RNA were detected in CMV-infected plants. RT-PCR showed that plus-sense and minus-sense monomers and plus-sense multimers of satellite RNA were present. Multimeric minus-sense RNA was not present except in the form of multimeric dsRNA. Sequence analysis of 52 cloned junction regions in head-to-tail repeats of unit-length satellite RNA indicated that about 35% of the junction sequences were precise fusions of monomer units, 56% lacked sequence of the 5' component, and 10% lacked sequence of both 3' and 5' components. No junction contained additional nucleotides. Deletions at the junction regions may have accumulated during CMV multiplication in inoculated plants. These data suggest that replicase is not released from the template during synthesis of multimeric molecules of satellite RNA.

Base Sequence↗

PubMed1987

Identification of a promoter element located upstream from the hepatitis B virus X gene.

We have analyzed a series of plasmids in which the sequences located upstream from the hepatitis B virus (HBV) X gene were linked to the chloramphenicol acetyl transferase (CAT) gene. Expression of the marker CAT gene in transfected cells clearly demonstrated that sequences preceding the X gene contain an active promoter. RNA mapping by primer extension indicated that the RNA encoded by the X gene promoter initiates at multiple sites spanning nucleotides 1250 to 1350 on the HBV genome. Deletion within the adjacent HBV enhancer element region significantly reduced the activity of the X gene promoter, suggesting that the X gene promoter requires the enhancer element for maximal activity.

Acetyltransferases↗

PubMed2004

A new technology for mutation detection.

A sensitive, accurate, and simple method, called shifted termination assay (STA), was developed for detection of genetic mutations. The STA technology can be used to detect genetic mutations in polymerase chain reaction (PCR)-amplified samples of tissue, and plasma and serum that include circulating DNA containing point mutations, insertions, deletions, translocations, or single nucleotide polymorphisms (SNPs). STA is a multiple-base and multiple-cycle primer extension based detection method that can identify mutant DNA in samples containing as little as 1% mutant DNA in a mixture with 99% wild-type DNA. On the basis of the STA method, a mutation detection kit, called Mutector, was developed. Mutector is a 96-well microplate format test kit with colorimetric or luminescent detection options. An initial study shows that Mutector is more accurate and sensitive than sequencing and PCR restriction enzyme analysis methods in detecting DNA mutations from clinical samples.

Base Sequence↗

PubMed1995

A three-nucleotide deletion in the UL97 open reading frame is responsible for the ganciclovir resistance of a human cytomegalovirus clinical isolate.

Multiple human cytomegalovirus (HCMV) strains frequently coexist in patients with AIDS, and chronic ganciclovir treatment may favor the emergence of ganciclovir-resistant viral mutants. We report the molecular and biochemical characterization of a HCMV ganciclovir-resistant strain (VR3480) previously recovered from a patient with AIDS who was undergoing multiple courses of ganciclovir treatment (G. Gerna, F. Baldanti, M. Zavattoni, A. Sarasini, E. Percivalle, and M. G. Revello, Antiviral Res. 19:333-345, 1992). Ganciclovir resistance of strain VR3480 was related to impaired ability to monophosphorylate the drug, as indicated by the finding that ganciclovir phosphorylation values for VR3480 were 30% of those shown by the HCMV reference strain AD169 in an in vitro activity assay. Sequencing of the UL97 gene of VR3480, which encodes the viral kinase responsible for ganciclovir phosphorylation, showed an in-frame deletion of three nucleotides resulting in the loss of a leucine at position 595 in the polypeptide. Mutant VR3480 UL97 DNA was able to transfer resistance to the AD169 strain in marker rescue experiments. Analysis of virus isolates and blood polymorphonuclear leukocyte samples spanning the 2-year follow-up period of the patient showed that ganciclovir-resistant strain VR3480 arose ex novo during prolonged antiviral treatment and accounted for the majority of virus load circulating in blood during the period of clinical resistance to ganciclovir treatment.

Acquired Immunodeficiency Syndrome↗

PubMed2005

Dominantly inherited beta thalassaemia intermedia caused by a new single nucleotide deletion in exon 2 of the beta globin gene: Hb morgantown (beta91 CTG>CG).

Family members in multiple generations of an Irish-American family were investigated for moderate to severe microcytic anaemia, inherited in an autosomal dominant fashion. A novel frameshift mutation of the beta globin gene was discovered. This study highlights the importance of considering dominantly inherited beta thalassemia in the investigation of anaemia, even in patients with ethnic backgrounds not usually associated with beta thalassaemia.

Adult↗

PubMed1996

Structural requirements for initiation of translation by internal ribosome entry within genome-length hepatitis C virus RNA.

Cap-independent translation of hepatitis C virus (HCV) RNA is mediated by an internal ribosomal entry segment (IRES) located within the 5' nontranslated RNA (5'NTR), but previous studies provide conflicting views of the viral sequences which are required for translation initiation. These discrepancies could have resulted from the inclusion of less than full-length 5'NTR in constructs studied for translation or destabilization of RNA secondary structure due to fusion of the 5'NTR to heterologous reporter sequences. In an effort to resolve this confusion, we constructed a series of mutations within the 5'NTR of a nearly full-length 9.5-kb HCV cDNA clone and examined the impact of these mutations on HCV translation in vitro in rabbit reticulocyte lysates and in transfected Huh-T7 cells. The inclusion of the entire open reading frame in HCV transcripts did not lead to an increase in IRES-directed translation of the capsid and E1 proteins, suggesting that the nonstructural proteins of HCV do not include a translational transactivator. However, in reticulocyte lysates programmed with full-length transcripts, there were multiple aberrent translation initiation sites resembling those identified in some picornaviruses. The deletion of nucleotides (nt) 28-69 of the 5'NTR (stem-loop IIa) sharply reduced capsid translation both in vitro and in vivo. A small deletion mutation involving nt 328-334, immediately upstream of the initiator AUG at nt 342, also resulted in a nearly complete inhibition of translation, as did the deletion of multiple intervening structural elements. An in-frame 12-nt insertion placed within the capsid-coding region 9 nt downstream of the initiator AUG strongly inhibited translation both in vitro and in vivo, while multiple silent mutations within the first 42 nt of the open reading frame also reduced translation in reticulocyte lysates. Thus, domains II and III of the 5'NTR are both essential to activity of the IRES, while conservation of sequence downstream of the initiator AUG is required for optimal IRES-directed translation.

Amino Acid Sequence↗

PubMed1997

Mitochondrial DNA mutations in multiple symmetric lipomatosis.

Multiple symmetric lipomatosis (MSL) is a rare disorder of middle life characterized by large subcutaneous fat masses around the neck, shoulders and other parts of the trunk. Peripheral neuropathy is a common finding in these predominantly male patients. Employing electrophysiological measures, we found additional signs of central nervous system involvement in a majority of patients. Etiologically, there is an association with mitochondrial dysfunction. In muscle biopsy, we found ragged red fibers in 8 of 12 patients. Molecular genetic analysis revealed multiple deletions of mitochondrial DNA in one patient and the MERRF mutation at nucleotide 8344 in another. In this review, we summarize our clinical, electrophysiological morphological, biochemical and molecular genetic findings in 17 MSL patients, and give a survey of the literature.

Adult↗

PubMed2002

Identification of truncated form of mouse HAX-1s gene (HAX-1xs) and characterization of its expression in small intestine and thymus of mice after burn injury.

Burn injury often leads to distant organ injury such as acute respiratory distress syndrome. We hypothesize that the pathophysiologic changes in distant organs result from orchestrated regulation of multiple genes in response to bum injury. Differential display was performed to identify genes regulated in distant organs in response to burn injury. Initial characterization of differentially amplified products demonstrated that HAX-1s mRNA was regulated in several distant organs after 18% total body surface area (TBSA) full-thickness flame burn injury in mice. Further characterization of HAX-1s mRNA revealed a novel transcript variant, which is rapidly and transiently induced in multiple tissues of mice within 6 h after burn injury. This novel HAX-1s transcript variant, called HAX-1xs, has an internal deletion of 252 nucleotides and single point mutation, resulting in reading frame intact. Western blot and immunohistochemical analyses of multiple tissues of mice using rabbit antibody raised against a 15-mer synthetic peptide clearly revealed the presence of HAX-1xs protein in the duodenum, and suggested that expression of HAX-1xs and/or HAX-1s was tissue- and cell type-specific. The expression of HAX-1xs and/or HAX-1s was distinctively regulated in Paneth cells of the duodenum and macrophages of the thymus after burn injury. These findings suggest that HAX-1xs has a different biological activity from HAX-1s and participates in a cascade of immediate-early cellular events in response to burn injury.

Adaptor Proteins, Signal Transducing↗

PubMed1983

Activation of the genes for variant surface glycoproteins 117 and 118 in Trypanosoma brucei.

We have studied the activation of genes for VSGs (variant surface glycoproteins) in Trypanosoma brucei (strain 427) in six independently isolated trypanosome clones; four expressing the gene for VSG 118 and two the gene for VSG 117. In all cases, gene activation is brought about by a duplicative transposition of the gene to an expression site located close to the end of a chromosome. The DNA segments flanking the expression-linked extra gene copy are nearly devoid of restriction enzyme recognition sites and their lengths vary by more than 10,000 base-pairs among different variants. From the correspondence of five upstream restriction sites, we conclude that the same expression site is used in each case. The transposition event does not lead to detectable alterations in the sequence coding for the mature protein. All restriction enzyme recognition sites detected in the basic copy gene are present also in each of the expression-linked copies. This argues against the introduction of mutations by an error-prone polymerase during the synthesis of the expression-linked copy. In five of the six variants, the 3' end of the VSG messenger RNA differs from that of the corresponding basic copy gene by multiple point mutations, insertions and deletions, starting at positions varying from 16 nucleotides upstream to 113 downstream of the last codon of the mature protein. We attribute this end alteration to the recombination process that introduces the gene into the expression site. We confirm that the expression-linked gene copy is more sensitive to DNase I than the corresponding basic copy gene. This appears to be due to its activated state and not to its location near the end of a chromosome, because another basic copy VSG gene permanently located near a chromosome end is not hypersensitive to DNase I. The mature transcripts of the 117 and 118 genes all possess the same 35 nucleotides at their 5' ends and these are not encoded contiguously in the basic gene copies with the remainder of the mRNAs. This extends our previous conclusion, that mature VSG mRNAs are formed by a splicing process in which the 35-nucleotide sequence encoded in the expression site is fused onto the body of the mRNA contributed by the transposed gene.

Animals↗

PubMed1994

Phenotypic and genotypic characterization of acyclovir-resistant varicella-zoster viruses isolated from persons with AIDS.

Phenotypic and genotypic analyses were done on 17 varicella-zoster virus (VZV) isolates recovered from 10 persons with AIDS (mean CD4 cell count, 16.4/mm3) who had chronic VZV lesions. Eleven acyclovir-resistant isolates were recovered from 10 patients after a mean of 20.1 weeks of therapy. Six susceptible isolates were recovered before acyclovir treatment (n = 1), early during therapy (n = 4; mean time, 4.2 weeks), or after discontinuation of acyclovir (n = 1). Acyclovir-resistant VZV isolates were deficient in thymidine kinase (TK) or induced a TK with altered substrate specificity; all isolates were susceptible to foscarnet. Ten of 11 acyclovir-resistant mutants contained tk gene mutations, including single nucleotide substitutions in highly conserved binding sites (n = 2) as well as nucleotide deletions (n = 4) and insertions (n = 4). These findings suggest that multiple, nonuniform mutations within the tk gene are associated with acyclovir-resistant VZV phenotypes.

AIDS-Related Opportunistic Infections↗