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PubMed2001

Evidence for a new hepatitis C virus antigen encoded in an overlapping reading frame.

Many viruses have overlapping genes and/or regions in which a nucleic acid signal is embedded in a coding sequence. To search for dual-use regions in the hepatitis C virus (HCV), we developed a facile computer-based sequence analysis method to map dual-use regions in coding sequences. Eight diverse full-length HCV RNA and polyprotein sequences were aligned and analyzed. A cluster of unusually conserved synonymous codons was found in the core-encoding region, indicating a potential overlapping open reading frame (ORF). Four peptides (A1, A2, A3, and A4) representing this alternate reading frame protein (ARFP), two others from the HCV core protein, and one from bovine serum albumin (BSA) were conjugated to BSA and used in western blots to test sera for specific antibodies from 100 chronic HCV patients, 44 healthy controls, and 60 patients with non-HCV liver disease. At a 1:20,000 dilution, specific IgGs to three of the four ARFP peptides were detected in chronic HCV sera. Reactivity to either the A1 or A3 peptides (both ARFP derived) was significantly associated with chronic HCV infection, when compared to non-HCV liver disease serum samples (10/100 versus 1/60; p < 0.025). Antibodies to A4 were not detected in any serum sample. Our western blot assays confirmed the presence of specific antibodies to a new HCV antigen encoded, at least in part, in an alternate reading frame (ARF) overlapping the core-encoding region. Because this novel HCV protein stimulates specific immune responses, it has potential value in diagnostic tests and as a component of vaccines. This protein is predicted to be highly basic and may play a role in HCV replication, pathogenesis, and carcinogenesis.

Alternative Splicing↗
PubMed2000

Interspecific diversity of mitochondrial COI sequences in Japanese Panonychus species (Acari: Tetranychidae).

Sequences of a part of the mitochondrial cytochrome oxidase subunit I (COI) gene were analyzed in four Japanese Panonychus species to determine their phylogenetic relationships. Neighbor-Joining and maximum likelihood analysis resulted in a high bootstrap support of the relationships within the genus Panonychus. In contrast with a previous study based on ribosomal DNA data, the COI phylogeny suggested that P. mori was more distantly related to P. citri than to P. ulmi. This study shows for the first time that P. osmanthi is closely related to P. citri. Intraspecific variation analysis shows that the genetic distance between two local populations of P. mori is higher than between P. citri and P. osmanthi.

Animals↗
PubMed1979

Origins of metabolic diversity: evolutionary divergence by sequence repetition.

Recurring patterns of primary structure have been observed in enzymes that mediate sequential metabolic reactions in bacteria. The enzymes, muconolactone Delta-isomerase [(+)-4-hydroxy-4-carboxymethylisocrotonolactone Delta(2)-Delta(3)-isomerase, EC 5.3.3.4] and beta-ketoadipate enol-lactone hydrolase [4-carboxymethylbut-3-enolide(1,4)enol-lactone-hydrolase, EC 3.1.1.24], have been coselected in bacterial populations because the isomerase can confer no nutritional advantage in the absence of the hydrolase. Similar amino acid sequences recur within the structure of the isomerase, and the amino-terminal amino acid sequence of the isomerase from Pseudomonas putida appears to be evolutionarily homologous with the corresponding sequence of a beta-ketoadipate enol-lactone hydrolase from Acinetobacter calcoaceticus. One interpretation of the sequence repetitions is that they reflect tandem duplication mutations that took place early in the evolution of the proteins. According to this view, the mutations caused elongation of structural genes and the creation of duplicated genes as the metabolic pathways evolved. A review of the sequence data calls attention to a different hypothesis: repeated amino acid sequences were introduced in the course of the proteins' evolution by substitution of copies of DNA sequences into structural genes. Our observations are interpreted on the basis of a model proposing genetic exchange between misaligned DNA sequences. The model predicts that misalignments in one chromosomal region can influence the nature of mutations in another region. Thus, as often has been observed, the mutability of a base pair will be determined by its location in a DNA sequence. Furthermore, the intrachromosomal recombination of DNA sequences may account for complex genetic modifications that occur as new pathways evolve. The model provides an interpretation of an apparent paradox, the rapid creation of new metabolic traits by bacterial genomes that are remarkably resistant to genetic drift.

Amino Acid Sequence↗
PubMed1980

Origins of metabolic diversity: substitution of homologous sequences into genes for enzymes with different catalytic activities.

Similar amino acid sequences were found in portions of bacterial enzymes that mediate different biochemical transformations. Reaction catalyzed by the enzymes include oxygenation, decarboxylation, isomerization, and hydrolysis. The proteins share a common evolutionary history because they participate in an overall catabolic process known as the beta-ketoadipate pathway. One interpretation of the sequence similarities might be that duplication of a single gene gave rise to ancestral genes for the enzymes with different catalytic activities. According to this view, homologous sequences from the ancestral gene were conserved as the proteins diverged to assume different functions. This hypothesis is vitiated by comparison of the NH2-terminal amino acid sequences of sets of enzymes that mediate identical or analogous metabolic reactions within an organism. Gene duplications giving rise to the enzymes within each set must have followed duplication of a putative ancestral gene for all the sets. Yet the amino acid sequences of the proteins within each set have diverged widely, and against this background of divergence the conservation of sequences from an ancestor common to all the enzymes is unlikely. Rather, it appears that most regions of sequence similarity shared by enzymes from different sets were acquired subsequent to their divergence from any common ancestor. In some cases it appears that relatively short regions of sequence homology were achieved by mutations causing the transfer of sequence information from one set of structural genes to structural genes in another set. Alignment of homologous amino acid sequences within any single set requires the introduction of few gaps. Because gaps are required to align sequences that have been altered by the insertion of genetic material, the evidence indicates that copies of oligonucleotides were exchanged by genetic substitution among different structural genes as they coevolved.

Acinetobacter↗
PubMed1996

Interspecies diversity of the occludin sequence: cDNA cloning of human, mouse, dog, and rat-kangaroo homologues.

Occludin has been identified from chick liver as a novel integral membrane protein localizing at tight junctions (Furuse, M., T. Hirase, M. Itoh, A. Nagafuchi, S. Yonemura, Sa. Tsukita, and Sh. Tsukita. 1993. J. Cell Biol. 123:1777-1788). To analyze and modulate the functions of tight junctions, it would be advantageous to know the mammalian homologues of occludin and their genes. Here we describe the nucleotide sequences of full length cDNAs encoding occludin of rat-kangaroo (potoroo), human, mouse, and dog. Rat-kangaroo occludin cDNA was prepared from RNA isolated from PtK2 cell culture, using a mAb against chicken occludin, whereas the others were amplified by polymerase chain reaction based on the sequence found around the human neuronal apoptosis inhibitory protein gene. The amino acid sequences of the three mammalian (human, murine, and canine) occludins were very closely related to each other (approximately 90% identity), whereas they diverged considerably from those of chicken and rat-kangaroo (approximately 50% identity). Implications of these data and novel experimental options in cell biological research are discussed.

Amino Acid Sequence↗
PubMed1985

The divergent region of the Leishmania tarentolae kinetoplast maxicircle DNA contains a diverse set of repetitive sequences.

A 2.76 kb segment of the 12 kb divergent region of the Leishmania tarentolae kinetoplast maxicircle DNA consists almost entirely of repeated sequences. The repeats can be grouped into six families, some of which are present throughout the remainder of the divergent region. The repeats are oriented in a head-to-tail fashion with the three simplest repeats clustered into large arrays. A 47 bp palindrome and two copies of a "supercluster" of three different types of repeats are also present in the sequenced region. A sequence change in the divergent region is described for a clonal strain of L. tarentolae which was passaged continuously for several years. The repetitive sequences found in the divergent region appear to be appropriate substrates for the presumed deletion/insertion/recombination events occurring in this rapidly evolving portion of the maxicircle.

Animals↗
PubMed1991

Complex pattern of alternative splicing generates unusual diversity in the leader sequence of the chicken link protein mRNA.

We report here the isolation of the 5' end and the promoter region of the gene for chicken cartilage link protein, and demonstrate extensive heterogeneity of the leader sequence arising from differential utilization of multiple splice sites within the 5'-most exon. The 500-base pairs (bp) exon 1 consists of solely untranslated sequence and is followed by an intron greater than 33 kilobase pairs (kb). Together, the five exons predict a gene size longer than 100 kb. Multiple transcription initiation sites were mapped 34, 46, 56, 66 and 76 bp downstream of a TATA-like motif. Sequence analysis revealed that in addition to the non-spliced variant, multiple mRNA species were generated by alternative splicing resulting in the exclusion of 92, 166, 170, 174 and 263 nucleotides (nt), respectively, from exon 1. Polymerase chain reaction confirmed the existence of various splice forms, and showed cell type- and developmental stage-specific expression for one group of them. Secondary structure predictions indicated that the leaders of the splice forms could form stable hairpin structures with different free energies of formation (up to delta G = -110 kcal/mol), suggesting translational control. The splice variant detected in the largest amount had the least stable predicted hairpin (delta G = -31.7 kcal/mol).

Animals↗
PubMed2004

Pronounced genetic population structure in a potentially vagile fish species (Pristipomoides multidens, Teleostei; Perciformes; Lutjanidae) from the East Indies triangle.

The East Indies triangle, bordered by the Phillipines, Malay Peninsula and New Guinea, has a high level of tropical marine species biodiversity. Pristipomoides multidens is a large, long-lived, fecund snapper species that is distributed throughout the East Indies and Indo-Pacific. Samples were analysed from central and eastern Indonesia and northern Australia to test for genetic discontinuities in population structure. Fish (n = 377) were collected from the Indonesian islands of Bali, Sumbawa, Flores, West Timor, Tanimbar and Tual along with 131 fish from two northern Australian locations (Arafura and Timor Seas) from a previous study. Genetic variation in the control region of the mitochondrial genome was assayed using restriction fragment length polymorphism and direct sequencing. Haplotype diversity was high (0.67-0.82), as was intraspecific sequence divergence (range 0-5.8%). F(ST) between pairs of populations ranged from 0 to 0.2753. Genetic subdivision was apparent on a small spatial scale; F(ST) was 0.16 over 191 km (Bali/Sumbawa) and 0.17 over 491 km (Bali/Flores). Constraints to dispersal that contribute to, and maintain, the observed degree of genetic subdivision are experienced presumably by all life history stages of this tropical marine finfish. The constraints may include (1) little or no movement of eggs or larvae, (2) little or no home range or migratory movement of adults and (3) loss of larval cohorts due to transport of larvae away from suitable habitat by prevailing currents.

Analysis of Variance↗
PubMed2006

Composition-modified matrices improve identification of homologs of saccharomyces cerevisiae low-complexity glycoproteins.

Yeast glycoproteins are representative of low-complexity sequences, those sequences rich in a few types of amino acids. Low-complexity protein sequences comprise more than 10% of the proteome but are poorly aligned by existing methods. Under default conditions, BLAST and FASTA use the scoring matrix BLOSUM62, which is optimized for sequences with diverse amino acid compositions. Because low-complexity sequences are rich in a few amino acids, these tools tend to align the most common residues in nonhomologous positions, thereby generating anomalously high scores, deviations from the expected extreme value distribution, and small e values. This anomalous scoring prevents BLOSUM62-based BLAST and FASTA from identifying correct homologs for proteins with low-complexity sequences, including Saccharomyces cerevisiae wall proteins. We have devised and empirically tested scoring matrices that compensate for the overrepresentation of some amino acids in any query sequence in different ways. These matrices were tested for sensitivity in finding true homologs, discrimination against nonhomologous and random sequences, conformance to the extreme value distribution, and accuracy of e values. Of the tested matrices, the two best matrices (called E and gtQ) gave reliable alignments in BLAST and FASTA searches, identified a consistent set of paralogs of the yeast cell wall test set proteins, and improved the consistency of secondary structure predictions for cell wall proteins.

Algorithms↗
PubMed1993

Variation in HTLV-I sequences from rabbit cell lines with diverse in vivo effects.

Comparison of nucleotide sequences determined for HTLV-I integrated provirus from two rabbit cell lines, RH/K30 and RH/K34, revealed greater than 99% identity to one another. Substitutions encoding amino acid interchanges were observed in the gag, pol, and rex regions whereas the env and tax proteins were identical in the two lines. Comparison with the human prototypic HTLV-I sequence revealed considerably more variation, especially in the viral envelope region where the rabbit sequences are identical. The HTLV-I lines differed in their potential to cause disease in rabbits: injection of the RH/K34 cell line caused human adult T-cell leukemia/lymphoma-like (ATLL) disease which was fatal within 10 days, whereas all rabbits injected with the same or higher doses of RH/K30 survived with a low-grade leukemia that showed evidence of acute rejection. Correlation of lethality with viral sequence was tested by injection of rabbits with two other rabbit cell lines with HTLV-I provirus identical to RH/K34 in LTR, gag, and env regions. The fact that only one of these lines produced fatal disease suggests that pathogenic determinants lie outside of these regions or, alternatively, that the structure of the integrated virus is not the sole factor in the cell lines' ability to cause ATLL-like disease.

Animals↗
PubMed2000

The lipocalin protein family: structural and sequence overview.

Lipocalins are remarkably diverse at the sequence level yet have highly conserved structures. Most lipocalins share three characteristic conserved sequence motifs - the kernel lipocalins - while others are more divergent family members - the outlier lipocalins - typically sharing only one or two. This classification is a useful tool for analysing the family, and within these large sets are smaller groups sharing much higher levels of sequence similarity. The lipocalins are also part of a larger protein superfamily: the calycins, which includes the fatty acid binding proteins, avidins, a group of metalloproteinase inhibitors, and triabin. The superfamily is characterised by a similar structure (a repeated +1 topology beta-barrel) and by the conservation of a remarkable structural signature.

Amino Acid Sequence↗
PubMed1998

Molecular population genetics of the red kangaroo (Macropus rufus): mtDNA variation.

The genetic population structure of a large, wide-ranging marsupial, the red kangaroo (Macropus rufus) was assessed using sequence and haplotype frequency data of mitochondrial DNA (mtDNA) from locations across the species range in Australia. Results from sequence data revealed extensive haplotype diversity within the red kangaroo (32/34 sequences were unique). Sequence diversity was distributed within rather than between geographical regions across the species range. Genetic connectivity across the range of the species has therefore been maintained over the long term. On a smaller within-region scale, significant genetic structuring was evident from heterogeneity of haplotype frequencies amongst sampling sites. The geographical scale of panmictic populations differed across the continent with more restricted genetic populations occurring in areas with greater topographic and habitat complexity. We propose that these differences in area of genetic populations are the result of population responses to limiting ecological factors during drought.

Animals↗
PubMed1999

Repetitive conundrums of centromere structure and function.

In the last few years, a paradox has emerged regarding the relationship of centromere structure and its function. Most centromeric DNAs analyzed to date are composed of a remarkably complex array of repeat structures. In contrast, recent analyses of neocentromeric DNA reveal that repetitive DNA is not a prerequisite for centromere activity. The ubiquity of repetitive sequences among diverse species at sites of primary constriction argues that there is a strong evolutionary link between centromere structure and function. Dynamic mutational processes resulting in amplification, deletion and transposition of repetitive sequences appear to occur frequently in such regions, resulting in considerable interspecific diversity in structure and sequence. One possible solution to this conundrum may be that the rapid accumulation of repetitive sequences within centromeric and pericentromeric DNA is a consequence of functionally active centromeres. Emerging repetitive structures at centromeric sites may be an important byproduct of a functional centromere which ensures that site as an evolutionarily favored position in subsequent meiotic and mitotic lineages. The recent identification of large gene duplications in the vicinity of centromeres may be another example of the enhanced mutational lability of such regions of the genome.

Centromere↗
PubMed2005

Expectations from structural genomics revisited: an analysis of structural genomics targets.

BACKGROUND: Current structural genomics projects are being driven by two main goals; to produce a representative set of protein folds that could be used as templates for comparative modeling purposes, and to provide insight into the function of the currently unannotated protein sequences. Such projects may reveal that a newly determined protein structure shares structural similarity with a previously observed structure or that it is a novel fold. The manner in which structure can be used to suggest the function of a protein will depend on the number and diversity of homologous sequences and the extent to which these sequences are functionally characterized. METHOD AND RESULTS: Using sequence searching methods, we analyzed structural genomics target sequences to ascertain if they were members of functionally characterized protein families, protein families of unknown function, or orphan sequences. This analysis provided an indication of what could be expected to emerge from structural genomics projects. Matches were found to approximately 25% of the current functionally unannotated protein families in the PFAM database (protein families database of alignments and hidden Markov models). The 16% of strict orphan sequences will be the most problematic if their structures reveal novel folds. However, out of the remaining target sequences that match families whose members are largely of unknown function, 28% are particularly interesting in that they are part of protein families with considerable sequence diversity. CONCLUSION: The determination of a new structure of a member of these families is likely to offer considerable insight into possible functional roles of these proteins even if it is a new fold. Mapping the sequence conservation onto the structure may reveal functionally important residues for further study by experimental methods.

Databases, Protein↗
PubMed1991

Detection of homeobox genes in development and evolution.

The homeobox genes encode a family of DNA-binding regulatory proteins whose function and genomic organization make them an important model system for the study of development and differentiation. Oligonucleotide primers corresponding to highly conserved regions of Antennapediaclass homeodomains were designed to detect and identify homeobox sequences in populations of DNA or RNA by means of the polymerase chain reaction (PCR). Here we present a survey of sequences detected by PCR using an initial set of primers (HoxA and HoxB) based on an early nucleotide consensus for vertebrate Antennapedia-class homeodomains. Several novel sequences are reported from both mouse genomic DNA and RNA from the developing mouse telencephalon. Forebrain-derived clones are similar to the chicken CHox7, Drosophila H2.0, and mouse Hlx genes. PCR also proved to be a rapid method for identifying homeobox sequences from diverse metazoan species. Cloning of three Antennapedia-related sequences from cnidarians provides evidence of ancient roles for homeobox genes early in metazoan evolution.

Amino Acid Sequence↗
PubMed1999

CAGGG repeats and the pericentromeric duplication of the hominoid genome.

Gene duplication is one of the primary forces of evolutionary change. We present data from three different pericentromeric regions of human chromosomes, which indicate that such regions of the genome have been sites of recent genomic duplication. This form of duplication has involved the evolutionary movement of segments of genomic material, including both intronic and exonic sequence, from diverse regions of the genome toward the pericentromeric regions. Sequence analyses of the target sites of duplication have identified a novel class of interspersed GC-rich repeats located precisely at the boundaries of duplication. Estimates of the evolutionary age of these duplications indicate that they have occurred between 10 and 25 mya. In contrast, comparative analyses confirm that the GC-rich pericentromeric repeats have existed within the pericentromeric regions of primate chromosomes before the divergence of the cercopithecoid and hominoid lineages ( approximately 30 mya). These data provide molecular evidence for considerable interchromosomal duplication of genic segments during the evolution of the hominoid genome and strongly implicate GC-rich repeat elements as playing a direct role in the pericentromeric localization of these events

Animals↗
PubMed2004

Comparative analysis of noncoding sequences of orthologous bovine and human gene pairs.

Genomic sequence comparison across species has enabled the elucidation of important coding and regulatory sequences encoded within DNA. Of particular interest are the noncoding regulatory sequences, which influence gene transcriptional and posttranscriptional processes. A phylogenetic footprinting strategy was employed to identify noncoding conservation patterns of 39 human and bovine orthologous genes. Seventy-three conserved noncoding sequences were identified that shared greater than 70% identity over at least 100 bp. Thirteen of these conserved sequences were also identified in the mouse genome. Evolutionary conservation of noncoding sequences across diverse species may have functional significance, and these conserved sequences may be good candidates for regulatory elements.

3' Untranslated Regions↗