A G-to-T transversion at the +5 position of intron 1 in the glutaryl CoA dehydrogenase gene is associated with the Island Lake variant of glutaric acidemia type I.
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Amino Acid Sequence↗
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Genome-wide analysis of NBS-LRR-encoding genes in Arabidopsis.
The Arabidopsis genome contains approximately 200 genes that encode proteins with similarity to the nucleotide binding site and other domains characteristic of plant resistance proteins. Through a reiterative process of sequence analysis and reannotation, we identified 149 NBS-LRR-encoding genes in the Arabidopsis (ecotype Columbia) genomic sequence. Fifty-six of these genes were corrected from earlier annotations. At least 12 are predicted to be pseudogenes. As described previously, two distinct groups of sequences were identified: those that encoded an N-terminal domain with Toll/Interleukin-1 Receptor homology (TIR-NBS-LRR, or TNL), and those that encoded an N-terminal coiled-coil motif (CC-NBS-LRR, or CNL). The encoded proteins are distinct from the 58 predicted adapter proteins in the previously described TIR-X, TIR-NBS, and CC-NBS groups. Classification based on protein domains, intron positions, sequence conservation, and genome distribution defined four subgroups of CNL proteins, eight subgroups of TNL proteins, and a pair of divergent NL proteins that lack a defined N-terminal motif. CNL proteins generally were encoded in single exons, although two subclasses were identified that contained introns in unique positions. TNL proteins were encoded in modular exons, with conserved intron positions separating distinct protein domains. Conserved motifs were identified in the LRRs of both CNL and TNL proteins. In contrast to CNL proteins, TNL proteins contained large and variable C-terminal domains. The extant distribution and diversity of the NBS-LRR sequences has been generated by extensive duplication and ectopic rearrangements that involved segmental duplications as well as microscale events. The observed diversity of these NBS-LRR proteins indicates the variety of recognition molecules available in an individual genotype to detect diverse biotic challenges.
Amino Acid Sequence↗
XdomView: protein domain and exon position visualization.
SUMMARY: The relationship between intron distribution in the eukaryotic gene and protein structural elements is essential for understanding the origin and evolution of genes. XdomView is a web-based viewer mapping protein structural domains and intron positions in eukaryotic homologues to its tertiary structure. The association of sequence signals to 3D structure in XdomView provides a valuable visualization environment for eukaryotic gene organization, gene evolution, protein folding and protein structure classification. AVAILABILITY: Freely available from http://surya.bic.nus.edu.sg/xdom.
Database Management Systems↗
Comparative analyses of the structure of the 1,3-beta-glucan synthase gene in Paracoccidioides brasiliensis isolates.
The evolutionary origin and significance of spliceosomal introns have been the subject of many investigations. Two theories, "introns-early" theory and "introns-late" theory, have been proposed to explain the evolution of introns in eukaryotic genes. Intron position is generally conserved in paralogue and orthologue genes. Some introns occur at similar but not necessarily identical positions in homologous genes, which were separated by great evolutionary distances. This event can be explained by insertion, loss or movement of the intron over short distances. Intron loss and gain events are unique in evolution and can be useful as markers for phylogenetic analyses. The insertion of introns at an identical position suggests a common ancestor gene. Here we analyzed, using PCR and RT-PCR, the structure of the 1,3-beta-glucan synthase gene (FKS) in several clinical isolates of Paracoccidioides brasiliensis (Pb): isolates Pb 01, Pb 4940, Pb 8515, Pb 8311, Pb 8334, Pb 4268, Pb 1668, and Pb E. Our results showed that seven of the isolates examined showed identical structures concerning the position of introns in PbFKS1. PbFKS4940 showed the intron described at the 3' end and had lost that one at the 5' end. The presence of the PbFKS4940 transcript suggests that it could be a functional gene. These data suggest a divergent evolution for introns with regard to the 1,3-beta-glucan synthase gene in P. brasiliensis isolates.
Amino Acid Sequence↗
Organization and structure of Volvox alpha-tubulin genes.
Southern analysis of Volvox genomic DNA revealed two genes homologous to Chlamydomonas reinhardtii alpha-tubulin cDNA. Restriction fragment length polymorphism analysis indicated that the two genes are not genetically linked. Clones representing one of the alpha-tubulin genes have been isolated from a genomic library of Volvox carteri f. nagariensis. A 3153 bp BamHI fragment containing the entire alpha-tubulin gene (1802 bp) plus 707 bp of the 5'- and 644 bp of the 3'-untranslated regions has been sequenced, revealing the following features: (1) the derived alpha-tubulin primary structure of 451 amino acids is highly conserved, differing in two residues from the alpha 1- and in two additional residues from the alpha 2-tubulin of C. reinhardtii; (2) in comparison to the C. reinhardtii genes, the Volvox alpha-tubulin gene contains a third intron; positions of the other two introns are precisely conserved; (3) codon usages are biased towards G or C, and against A, in the third position; 19 codons are absent from the alpha-tubulin coding sequence, and 5 of these are not used in any of 7 compiled Volvox genes; (4) transcription begins with an A, 30 bp downstream of the putative TATA box; upstream of the TATA box is a 14 bp sequence similar to consensus sequences found in all 4 C. reinhardtii tubulin genes and believed to regulate promoter function.
Amino Acid Sequence↗
Patterns of group I intron presence in nuclear SSU rDNA of the Lichen family Parmeliaceae.
Group I introns are commonly reported within nuclear SSU ribosomal DNA of eukaryotic micro-organisms, especially in lichen-forming fungi. We have studied the primary and secondary structure of 70 new nuclear SSU rDNA group I introns of Parmeliaceae (Ascomycota: Lecanorales) and compared them with those available in databases, covering more than 60 species. The analyzed samples of Parmeliaceae fell into two groups, one having an intron at the 1506 site and another lacking this one but having another at the 1516 or 1521 position. Introns at the 1521 position seem to be transposed from 1516 sites. Introns at the 1516 position were similar in structure to ones previously reported at this site and known from other lecanoralean fungi, while those at the 1506 position showed structural differences and no similar introns are known from related fungi. The study of the distribution of group I introns within a large monophyletic ensemble of fungi has revealed an unexpected correlation between intron types and ecological and geographical parameters. The introns at the 1516 position occurred in mainly arctic, boreal, and temperate lichens, while those at position 1506 were present in mainly tropical and subtropical to oceanic mild-temperate taxa. Further, the 1516 introns occurred in genera with few distributed species that could represent older taxa, while the 1506 ones were mainly in species-rich genera that could be of recent speciation, as many species have wide distribution areas. The transition between two different environments has been accompanied by a change in introns gained and lost.
Amino Acid Sequence↗
Genomic organization of nematode 4TM K+ channels.
As many as 50 genes in the C. elegans genome may encode K+ channels belonging to the novel structural class of two-pore (4TM) channels. Many 4TM channels can be grouped into channel subfamilies. We analyzed 4TM channels in C. elegans using methods made possible by having complete genomic sequence. Two genes were chosen for comprehensive analysis, n2P16 and n2P17. By comparing the pattern of conservation in genomic DNA sequences between C. elegans and a closely related species, C. briggsae, we were able to identify all coding regions and predict the gene structure for these two genes. Given the extent of the 4TM channel family, we were surprised to discover that n2P17 produced at least six alternative transcripts encoding a constant central region and variable amino- and carboxyl-termini. Blocks of highly conserved DNA sequences in noncoding regions were also apparent and most likely confer important regulatory functions. The interspecies comparison of the deduced channel proteins revealed that the extracellular loop between M1 and P1 is an apparent hot spot for evolutionary change in both channels. This contrasts with the membrane-spanning domains that are highly conserved. Analysis of intron positions for 36 channels revealed that introns are frequently present at an identical position within the pore region, but very few are located in membrane-spanning domains.
Alternative Splicing↗
The excess of 5' introns in eukaryotic genomes.
In this work, 21 completely sequenced eukaryotic genomes were analyzed using an intragene comparison approach. We found that all of these genomes show a significant 5'-biased distribution of introns of protein-coding genes. Our findings are different from previous studies based on the intergene method, where introns are biased towards the 5' end of genes only in intron-poor genomes, but are evenly distributed in intron-rich genomes. In addition, by analyzing the patterns of intron distribution of a set of well-compiled housekeeping genes from human and their respective orthologs identified by a bidirectional best BLAST hit method from the other genomes, we found that the trend of 5'-biased intron positions of the set of housekeeping genes for each genome is much more skewed than that of all genes of the same genome, and rarely if any of the housekeeping genes examined have an extremely 3'-biased position distribution in which all introns of a gene are located only at the 3' portion of the gene. The most parsimonious explanation for our findings may be the model in which intron loss is caused by homologous recombination between the genomic copy of a gene and a reverse transcriptase product of a spliced mRNA.
Animals↗
Cloning, genomic organization, and chromosomal localization of human cathepsin L.
Cathepsin L is a lysosomal cysteine protease whose expression and secretion is induced by malignant transformation, growth factors, and tumor promoters. Many human tumors express high levels of cathepsin L, which is a broad spectrum protease with potent elastase and collagenase activities. Two published human cathepsin L cDNA sequences differ only in their 5'-untranslated regions. In this study, we demonstrate the concurrent expression of two distinct human cathepsin L mRNAs (hCATL-A and hCATL-B) in adenocarcinoma, hepatoma, and renal cancer cell lines. Cloning of the human cathepsin L gene by polymerase chain reaction amplification of genomic DNA and subsequent sequencing reveals that hCATL-A and hCATL-B mRNAs are encoded by a single gene. The 3' end of the first intron contains the 5' portion of hCATL-B and is contiguous to the second exon of the gene. These data suggest either the possibility of alternative splicing or the presence of a second promoter within the first intron of the hCATL gene. We mapped the hCATL gene to chromosome 9q21-22. Sequencing of both the mouse and human cathepsin L genes demonstrates almost complete conservation of exon and intron position, but significant divergence in intron structure, possibly reflecting differences in regulation of expression of the mouse and human cathepsin L genes.
Amino Acid Sequence↗
Structure of the genes of two homologous intracellularly heterotopic isoenzymes. Cytosolic and mitochondrial aspartate aminotransferase of chicken.
The genes of mitochondrial and cytosolic aspartate aminotransferase of chicken were cloned and sequenced. In both genes nine exons encode the mature enzyme. The additional exon for the N-terminal presequence that directs mitochondrial aspartate aminotransferase into the mitochondria is separated by the largest intron from the rest of the gene. A comparison of the two genes of chicken with the aspartate aminotransferase genes of mouse [Tsuzuki, T., Obaru, K., Setoyama, C. & Shimada, K. (1987) J. Mol. Biol. 198, 21-31; Obaru, K., Tsuzuki, T., Setoyama, C. & Shimada, K. (1988) J. Mol. Biol. 200, 13-22] reveals closely similar structures: in the gene of both the mitochondrial and the cytosolic isoenzyme all but one intron positions are conserved in the two species and five introns out of nine are placed at the same positions in all four genes indicating that the introns were in place before the genes of the two isoenzymes diverged. The variant consensus sequence (T/C)11 T(C/T)AG at the 3' splice site of the introns of the genes for nuclear-encoded mitochondrial proteins, which had been deduced from a total of 34 introns [Juretić, N., Jaussi, R., Mattes, U. & Christen, P. (1987) Nucleic Acids Res. 15, 10,083-10,086], was confirmed by including an additional 22 introns into the comparison. The position -4 at the 3' splice site is occupied by base T in 43% of the total 56 introns and appears to be subject to a special evolutionary constraint in this particular group of genes. The following course of evolution of the aspartate aminotransferase genes is proposed. Originating from a common ancestor, the genes of the two isoenzymes intermediarily evolved in separate lineages, i.e. the ancestor eukaryotic and ancestor endosymbiontic cells. When endosymbiosis was established, part of the endosymbiontic genome, including the aspartate aminotransferase gene, was transferred to the nucleus. This process probably led to the conservation of certain splicing factors specific for nuclear-encoded mitochondrial proteins. The presequence for the mitochondrial isoenzyme was acquired by DNA rearrangement. In the eukaryotic lineage, the mitochondrial isoenzyme evolved more slowly than its cytosolic counterpart.
Amino Acid Sequence↗
Nucleotide sequence and organization of the human S-protein gene: repeating peptide motifs in the "pexin" family and a model for their evolution.
The S-protein/vitronectin gene was isolated from a human genomic DNA library, and its sequence of about 5.3 kilobases including the adjacent 5' and 3' flanking regions was established. Alignment of the genomic DNA nucleotide sequence and the cDNA sequence indicated that the gene consisted of eight exons and seven introns. The intron positions in the S-protein gene and their phase type were compared to those in the hemopexin gene which shares amino acid sequence homologies with transin and the S-protein. Three introns have been found at equivalent positions; two other introns are very close to these positions and are interpreted as cases of intron sliding. Introns 3-7 occur at a conserved glycine residue within repeating peptide segments, whereas introns 1 and 2 are at the boundaries of the Somatomedin B domain of S-protein. The analysis of the exon structure in relation to repeating peptide motifs within the S-protein strongly suggests that it contains only seven repeats, one less than the hemopexin molecule. A very similar repeat pattern like that in hemopexin is shown to be present also in two other related proteins, transin and interstitial collagenase. An evolutionary model for the generation of the repeat pattern in the S-protein and the other members of this novel "pexin" gene family is proposed, and the sequence modifications for some of the repeats during divergent evolution are discussed in relation to known unique functional properties of hemopexin and S-protein.
Amino Acid Sequence↗
Conservation of the positions of metazoan introns from sponges to humans.
Sponges (phylum Porifera) are the phylogenetic oldest Metazoa still extant. They can be considered as reference animals (Urmetazoa) for the understanding of the evolutionary processes resulting in the creation of Metazoa in general and also for the metazoan gene organization in particular. In the marine sponge Suberites domuncula, genes encoding p38 and JNK kinases contain nine and twelve introns, respectively. Eight introns in both genes share the same positions and the identical phases. One p38 intron slipped for six bases and the JNK gene has three more introns. However, the sequences of the introns are not conserved and the introns in JNK gene are generally much longer. Introns interrupt most of the conserved kinase subdomains I-XI and are found in all three phases (0, 1 and 2). We analyzed in details p38 and JNK genes from human, Caenorhabditis elegans and Drosophila melanogaster and found in most genes introns at the positions identical to those in sponge genes. The exceptions are two p38 genes from D. melanogaster that have lost all introns in the coding sequence. The positions of 11 introns in each of four human p38 genes are fully conserved and ten introns occupy identical positions as the introns in sponge p38 or JNK genes. The same is true for nine, out of ten introns in the human JNK-1 gene. The introns in human p38 and JNK genes are on average more than ten times longer than corresponding introns in sponges. It was proposed that yeast HOG1-like kinases (from i.e. Saccharomyces cerevisiae and Emericella nidulans) and metazoan p38 and JNK kinases are orthologues. p38 and JNK genes were created after the split from fungi by the duplication and diversification of the HOG1-like progenitor gene. Our results further support the common origin of p38 and JNK genes and speak in favor of a very early time of duplication. The ancestral gene contained at least ten introns, which are still present at the very conserved positions in p38 and JNK genes of extant animals. Four of these introns are present at the same positions in the HOG-like gene in the fungus E. nidulans. The others probably entered the ancestral gene after the split of fungi, but before the duplication of the gene and before the creation of the common, urmetazoan progenitor of all multicellular animals. A second gene coding for an immune molecule is described, the allograft inflammatory factor, which likewise showed a highly conserved exon/intron structure in S. domuncula and in human. These data show that the intron/exon borders are highly conserved in genes from sponges to human.
Amino Acid Sequence↗
A variable intron distribution in globin genes of Chironomus: evidence for recent intron gain.
The intron positions found in globin genes of plants, protozoa and invertebrates have been interpreted as evidence for a three-intron-four-exon structure of the ancestral globin gene. In particular, the so-called 'central' introns, which are not found in vertebrate globin genes but are present in a variety of invertebrate and plant species, have been used as an argument for an ancestral gene structure featuring three introns. We have analyzed the presence or absence of central introns in the Gb genes 2beta, 9 and 7A of various European and Australasian species of the insect Chironomus. We find unrelated central introns at different positions in some of the species investigated, while other species completely lack introns in these genes. This variable distribution of introns is parsimoniously explained by independent intron additions. Such a gain of introns may occur convergently at identical positions in unrelated taxa. Insertion by gene conversion may be a viable mechanism to explain intron gain.
Animals↗
Structure-function analysis of the trypanosomatid spliced leader RNA.
In trypanosomes, all mRNAs possess a spliced leader (SL) at their 5' end. SL is added to pre-mRNA via trans -splicing from a small RNA, the SL RNA. To examine structure-function aspects of the trypanosomatid SL RNA, an in vivo system was developed in the monogenetic trypanosomatid Leptomonas collosoma to analyze the function of chimeric and site-directed SL RNA mutants in trans -splicing. Stable cell lines expressing chimeric and mutated SL RNA from the authentic SL RNA regulatory unit were obtained. The chimeric RNA was expressed and assembled into an SL RNP particle, but could not serve as a substrate in splicing. Mutations in loop II and III of L.collosoma SL RNA formed the Y structure intermediate. In addition, a double SL RNA mutant in loop II, and positions 7 and 8 of the intron, also formed the Y structure intermediate, suggesting that these intron positions, although proposed to participate in the interaction of SL RNA with U5, may not be crucial for the first step of the trans -splicing reaction. A mutation in the exon located in loop I was not utilized in splicing, suggesting the importance of exon sequences for trans -splicing in trypanosomes. However, a double SL RNA mutant in loop II and exon position 31 was utilized in both steps of splicing; the mutant thus provides a model molecule for further analysis of positions essential for the function of the SL RNA.
Animals↗
Molecular evolution and structure--function relationships of the superoxide dismutase gene families in angiosperms and their relationship to other eukaryotic and prokaryotic superoxide dismutases.
This study assesses whether the phylogenetic relationships between SODs from different organisms could assist in elucidating the functional relationships among these enzymes from evolutionarily distinct species. Phylogenetic trees and intron positions were compared to determine the relationships among these enzymes. Alignment of Cu/ZnSOD amino acid sequences indicates high homology among plant sequences, with some features that distinguish chloroplastic from cytosolic Cu/ZnSODs. Among eukaryotes, the plant SODs group together. Alignment of the Mn and FeSOD amino acid sequences indicates a higher degree of homology within the group of MnSODs (>70%) than within FeSODs (approximately 60%). Tree topologies are similar and reflect the taxonomic classification of the corresponding species. Intron number and position in the Cu/Zn Sod genes are highly conserved in plants. Genes encoding cytosolic SODs have seven introns and genes encoding chloroplastic SODs have eight introns, except the chloroplastic maize Sod1, which has seven. In Mn Sod genes the number and position of introns are highly conserved among plant species, but not among nonplant species. The link between the phylogenetic relationships and SOD functions remains unclear. Our findings suggest that the 5' region of these genes played a pivotal role in the evolution of function of these enzymes. Nevertheless, the system of SODs is highly structured and it is critical to understand the physiological differences between the SODs in response to different stresses in order to compare their functions and evolutionary history.
Amino Acid Sequence↗
Introns in the 3'-untranslated region can inhibit chimeric CAT and beta-galactosidase gene expression.
The expression of a cyc::cat [cytochrome c/chloramphenicol acetyltransferase (CAT)] chimeric gene was stimulated 100-fold by the inclusion of a cyc intron in the 5'-untranslated region. In contrast, a single intron in the 3'-untranslated region was at best only slightly stimulatory, and surprisingly, inhibited expression of cat when an intron was also included in the 5'-untranslated region. This inhibition was independent of the identity of the downstream intron, occurring when either the simian virus 40 (SV40) small t intron or a cyc intron was located downstream from the cat coding region. Analysis of CAT mRNA levels, using a riboprobe spanning the 5' end of the CAT message, revealed that the stimulatory effect of a 5'-noncoding region intron were manifest at both the protein and RNA levels, whereas the inhibitory effects of 3'-noncoding region introns were detectable only at the protein level. The effects of intron position on chimeric gene expression were observed in both primate and rodent cell lines and also when the beta-galactosidase coding region was substituted for that of cat. Therefore, the common placement of an intron in the 3'-noncoding region is not the most beneficial to the expression of cyc chimeric genes. The position of introns within a transcriptional unit is a major factor to be considered when optimizing the efficiency of animal cell expression vectors.
Animals↗
Fibrinogen alpha genes: conservation of bipartite transcripts and carboxy-terminal-extended alpha subunits in vertebrates.
All three well-studied subunits of the clotting protein fibrinogen (alpha, beta, gamma) share N-terminal structural homologies, but until recently only the beta and gamma chains were recognized as having similar globular C-termini. With the discovery of an extra exon in the human fibrinogen alpha gene (exon VI), a minor form of the alpha subunit (alpha E) with an extended beta- and gamma-like C-terminus has been identified (Fu et al., Biochemistry 31, 11968, 1992). In the present study, the polymerase chain reaction has been used to identify sequences that encode counterparts to alpha E in chicken, rabbit, rat, and baboon. The basic six-exon structure of the fibrinogen alpha genes is shown to be conserved among mammals and birds, as are the intron positions. Bipartite transcripts--still bearing an intron prior to the last exon--are found among the products of the various vertebrate fibrinogen alpha genes. The last exon represents the largest conserved segment of the gene and, in each species examined, encodes exactly 236 amino acids. The C-termini of these alpha E chains align without a single gap and are between 76 and 99% identical. Since the exon VI-encoded domain of alpha E is as well conserved as the corresponding regions of the beta and gamma chains, it follows that it is equally important and that alpha E-fibrinogen plays a vital, if as-yet unrecognized physiological role.
Amino Acid Sequence↗
Tempo and mode of spliceosomal intron evolution in actin of foraminifera.
Spliceosomal introns are present in almost all eukaryotic genes, yet little is known about their origin and turnover in the majority of eukaryotic phyla. There is no agreement whether most introns are ancestral and have been lost in some lineage or have been gained recently. We addressed this question by analyzing the spatial and temporal distribution of introns in actins of foraminifera, a group of testate protists whose exceptionally rich fossil record permits the calibration of molecular phylogenies to date intron origins. We identified 24 introns dispersed along the sequence of two foraminiferan actin paralogues and actin deviating proteins, an unconventional type of fast-evolving actin found in some foraminifera. Comparison of intron positions indicates that 20 of 24 introns are specific to foraminifera. Four introns shared between foraminifera and other eukaryotes were interpreted as parallel gains because they have been found only in single species belonging to phylogenetically distinctive lineages. Moreover, additional recent intron gain due to the transfer between the actin paralogues was observed in two cultured species. Based on a relaxed molecular clock timescale, we conclude that intron gains in actin took place throughout the evolution of foraminifera, with the oldest introns inserted between 550 and 500 million years ago and the youngest ones acquired less than 100 million years ago.
Actins↗