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PubMed1990

Transcriptional control of the alpha 1(I) collagen gene involves orientation- and position-specific intronic sequences.

The 3' half of the first intron of the human alpha 1(I) collagen gene interacts with the promoter to regulate transcription. We questioned whether this intronic sequence also exerted its effect when placed 5' to the promoter. In transient transfection assays using several cell lines, little or no stimulation of alpha 1(I)-driven chloroamphenicol acetyltransferase transcription was observed. We conclude that transcriptional control of the alpha 1(I) gene is dependent on a complex series of interactions that require both orientation and position specificity of the intronic segment.

Chloramphenicol O-Acetyltransferase↗
PubMed2003

The Anopheles gambiae glutathione transferase supergene family: annotation, phylogeny and expression profiles.

BACKGROUND: Twenty-eight genes putatively encoding cytosolic glutathione transferases have been identified in the Anopheles gambiae genome. We manually annotated these genes and then confirmed the annotation by sequencing of A. gambiae cDNAs. Phylogenetic analysis with the 37 putative GST genes from Drosophila and representative GSTs from other taxa was undertaken to develop a nomenclature for insect GSTs. The epsilon class of insect GSTs has previously been implicated in conferring insecticide resistance in several insect species. We compared the expression level of all members of this GST class in two strains of A. gambiae to determine whether epsilon GST expression is correlated with insecticide resistance status. RESULTS: Two A. gambiae GSTs are alternatively spliced resulting in a maximum number of 32 transcripts encoding cytosolic GSTs. We detected cDNAs for 31 of these in adult mosquitoes. There are at least six different classes of GSTs in insects but 20 of the A. gambiae GSTs belong to the two insect specific classes, delta and epsilon. Members of these two GST classes are clustered on chromosome arms 2L and 3R respectively. Two members of the GST supergene family are intronless. Amongst the remainder, there are 13 unique introns positions but within the epsilon and delta class, there is considerable conservation of intron positions. Five of the eight epsilon GSTs are overexpressed in a DDT resistant strain of A. gambiae. CONCLUSIONS: The GST supergene family in A. gambiae is extensive and regulation of transcription of these genes is complex. Expression profiling of the epsilon class supports earlier predictions that this class is important in conferring insecticide resistance.

Alternative Splicing↗
PubMed1996

Ferritin gene organization: differences between plants and animals suggest possible kingdom-specific selective constraints.

Ferritin, a protein widespread in nature, concentrates iron approximately 10(11)-10(12)-fold above the solubility within a spherical shell of 24 subunits; it derives in plants and animals from a common ancestor (based on sequence) but displays a cytoplasmic location in animals compared to the plastid in contemporary plants. Ferritin gene regulation in plants and animals is altered by development, hormones, and excess iron; iron signals target DNA in plants but mRNA in animals. Evolution has thus conserved the two end points of ferritin gene expression, the physiological signals and the protein structure, while allowing some divergence of the genetic mechanisms. Comparison of ferritin gene organization in plants and animals, made possible by the cloning of a dicot (soybean) ferritin gene presented here and the recent cloning of two monocot (maize) ferritin genes, shows evolutionary divergence in ferritin gene organization between plants and animals but conservation among plants or among animals; divergence in the genetic mechanism for iron regulation is reflected by the absence in all three plant genes of the IRE, a highly conserved, noncoding sequence in vertebrate animal ferritin mRNA. In plant ferritin genes, the number of introns (n = 7) is higher than in animals (n = 3). Second, no intron positions are conserved when ferritin genes of plants and animals are compared, although all ferritin gene introns are in the coding region; within kingdoms, the intron positions in ferritin genes are conserved. Finally, secondary protein structure has no apparent relationship to intron/exon boundaries in plant ferritin genes, whereas in animal ferritin genes the correspondence is high. The structural differences in introns/exons among phylogenetically related ferritin coding sequences and the high conservation of the gene structure within plant or animal kingdoms of the gene structure within plant or animal kingdoms suggest that kingdom-specific functional constraints may exist to maintain a particular intron/exon pattern within ferritin genes. In the case of plants, where ferritin gene intron placement is unrelated to triplet codons or protein structure, and where ferritin is targeted to the plastid, the selection pressure on gene organization may relate to RNA function and plastid/nuclear signaling.

Amino Acid Sequence↗
PubMed1998

The human lamin B receptor/sterol reductase multigene family.

LBR (lamin B receptor) is an integral protein of the inner nuclear membrane encoded by a gene on human chromosome 1q42.1. LBR has a nucleoplasmic, amino-terminal domain of approximately 200 amino acids followed by a carboxyl-terminal domain similar in sequence to yeast and plant sterol reductases. We have determined the primary structures of two human proteins with strong sequence similarity to the carboxyl-terminal domain of LBR and sterol reductases. Their genes have recently been assigned the symbols TM7SF2 and DHCR7. TM7SF2 mRNA is most predominantly expressed in heart and DHCR7 mRNA mostly in liver and brain. Whereas LBR is localized to the inner nuclear membrane, these two related proteins are in the endoplasmic reticulum. The TM7SF2 gene contains 10 coding exons, and its intron positions are exactly conserved in the part of the LBR gene encoding its carboxyl-terminal domain. Intron positions in the DHCR7 gene are also similar. Both of these new LBR-like genes are on chromosome 11q13. These results describe a human gene family encoding proteins of the inner nuclear membrane and endoplasmic reticulum that function in nuclear organization and/or sterol metabolism.

Amino Acid Sequence↗
PubMed2004

Hypervariable and highly divergent intron-exon organizations in the chordate Oikopleura dioica.

Oikopleura dioica is a pelagic tunicate with a very small genome and a very short life cycle. In order to investigate the intron-exon organizations in Oikopleura, we have isolated and characterized ribosomal protein EF-1alpha, Hox, and alpha-tubulin genes. Their intron positions have been compared with those of the same genes from various invertebrates and vertebrates, including four species with entirely sequenced genomes. Oikopleura genes, like Caenorhabditis genes, have introns at a large number of nonconserved positions, which must originate from late insertions or intron sliding of ancient insertions. Both species exhibit hypervariable intron-exon organization within their alpha-tubulin gene family. This is due to localization of most nonconserved intron positions in single members of this gene family. The hypervariability and divergence of intron positions in Oikopleura and Caenorhabditis may be related to the predominance of short introns, the processing of which is not very dependent upon the exonic environment compared to large introns. Also, both species have an undermethylated genome, and the control of methylation-induced point mutations imposes a control on exon size, at least in vertebrate genes. That introns placed at such variable positions in Oikopleura or C. elegans may serve a specific purpose is not easy to infer from our current knowledge and hypotheses on intron functions. We propose that new introns are retained in species with very short life cycles, because illegitimate exchanges including gene conversion are repressed. We also speculate that introns placed at gene-specific positions may contribute to suppressing these exchanges and thereby favor their own persistence.

Amino Acid Sequence↗
PubMed2006

Very little intron loss/gain in Plasmodium: intron loss/gain mutation rates and intron number.

We compared intron positions in conserved regions of 3479 orthologous gene pairs from Plasmodium falciparum and Plasmodium yoelii, which likely diverged >or=100 million years ago (Mya). Only 27 out of 2212 positions were specific to one of the two species. Intron presence in related species shows that at least 19 and possibly 26 of the changes are due to intron loss, depending on phylogeny. The implied intron loss and gain rates are much lower than previously estimated for nematodes, arthropods, fungi, and plants, and are comparable only with the rates in vertebrates. That all observed changes were exact, occurring without loss or gain of flanking coding sequence, suggests intron loss via an mRNA intermediate, as does a nonsignificant trend toward loss of introns at adjacent positions. Many of the intron changes occurred in genes encoding proteins involved in nucleic acid-related processes, as previously found for intron gains in nematodes. Two changes occurred in the chloroquine resistance transporter, suggesting a role for positive selection in intron loss in Plasmodium. The dearth of intron loss and gain could be explained by the lack of known transposable elements in Plasmodium, since transposable elements and/or reverse transcriptase are thought to be necessary for both processes. The observed pattern suggests that the availability of stochastic intron loss and gain mutations can be a major determinant of changes in intron number.

Alternative Splicing↗
PubMed1988

5' splice site selection in yeast: genetic alterations in base-pairing with U1 reveal additional requirements.

Using a strategy of compensatory nucleotide changes between yeast U1 and a 5' splice site, we have analyzed the contribution of base-pairing to the efficiency and fidelity of pre-mRNA splicing in vivo. Watson-Crick base-pairing interactions with U1 can be demonstrated at intron positions 1 and 5 but not at position 4. Moreover, restoration of the ability to pair with U1 is not sufficient to restore activity in the second step of splicing to intron position 1 mutants. Finally, in contrast to recent observations in mammalian systems, we find that the precise position of 5' splice site cleavage is not determined solely by the base-pairing interaction with U1. Rather, the presence of a G residue at position 5 is required for the correct localization of the nucleolytic event. Taken together, these results indicate that the demands for 5' splice site selection and utilization are more complex than a simple maximization of Watson-Crick interactions with U1.

Base Composition↗
PubMed2003

Phylogenetically older introns strongly correlate with module boundaries in ancient proteins.

The hypothesis that some (but not all) introns were used to construct ancient genes by exon shuffling of modules at the earliest stages of evolution is supported by the finding of an excess of phase-zero intron positions in the boundary regions of such modules in 276 ancient proteins (defined as common to eukaryotes and prokaryotes). Here we show further that as phase-zero intron positions are shared by distant taxa, and thus are truly phylogenetically ancient, their excess in the boundaries becomes greater, rising to an 80% excess if shared by four out of the five taxa: vertebrates, invertebrates, fungi, plants, and protists.

Computational Biology↗
PubMed1994

The organization of the gene for Drosophila lamin C: limited homology with vertebrate lamin genes and lack of homology versus the Drosophila lamin Dmo gene.

Drosophila melanogaster has, in addition to the well characterized lamin Dmo, a second nuclear lamin called lamin C, which was recently defined by cDNA cloning. Here we characterize the gene encoding Drosophila lamin C. It is composed of 4 exons and 3 introns, which all interrupt the coding sequence. No intron position of the Drosophila lamin C gene has a counterpart in the Drosophila lamin Dmo gene, which has a structure unrelated to the highly conserved structures of vertebrate lamin genes. Surprisingly, however, two of the three intron positions of the Drosophila lamin C gene are also found in all currently known vertebrate lamin genes, which have an additional 8 to 9 introns. Thus, lamin genes from vertebrates and invertebrates can be more closely related in organization than earlier thought on the basis of only two invertebrate genes. The striking difference in structure of the two Drosophila lamin genes indicates that their ancestral genes separated earlier in metazoan evolution and that more than one lamin gene may also be expected in other invertebrates.

Amino Acid Sequence↗
PubMed1995

Structural organization of the human gene (LMNB1) encoding nuclear lamin B1.

We have determined the structural organization of the human gene (LMNB1) that encodes nuclear lamin B1, an intermediate filament protein of the nuclear envelope. The transcription unit spans more than 45 kb and the transcription start site is 348 nucleotides upstream from the translation initiation codon. Lamin B1 is encoded by 11 exons. Exon 1 codes for the amino-terminal head domain and the first portion of the central rod domain, exons 2 through 6 the central rod domain, and exons 7 through 11 the carboxyl-terminal tail domain of this intermediate filament protein. Intron positions are conserved in other lamin genes from frogs, mice, and humans but different in lamin genes from Drosophila melanogaster and Caenorhabditis elegans. In the region encoding the central rod domain, intron positions are also similar to those in the gene for an invertebrate nonneuronal cytoplasmic intermediate filament protein and the genes for most vertebrate cytoplasmic intermediate filament proteins except neurofilaments and nestin.

Animals↗
PubMed1999

Sequence analysis of cDNA and genomic DNA, and mRNA expression of the medaka fish homolog of mammalian guanylyl cyclase C.

We isolated the cDNA and genomic DNA encoding a membrane guanylyl cyclase of medaka fish (designated as OlGC6), and determined their complete nucleotide sequences. The open reading frame for OlGC6 cDNA predicted a protein of 1,075 amino acids. Phylogenetic analysis indicated that OlGC6 is a member of the enterotoxin/guanylin receptor family. We also determined the partial genomic structure of the gene of another membrane guanylyl cyclase of medaka fish, OlGC2, which is a member of the natriuretic peptide receptor family. The intron positions relative to the protein-coding sequence are highly conserved in the intracellular domains of OlGC6, OlGC2, mammalian GC-A, and GC-E. Despite their divergent primary structures, some intron positions also seem to be conserved in the extracellular domains of different membrane guanylyl cyclase genes. Northern blot analysis demonstrated that an OlGC6 transcript of 3.9 kb is only present in the intestine, while reverse transcription (RT)-PCR analysis demonstrated that the OlGC6 transcript is present in the kidney, spleen, liver, pancreas, gallbladder, ovary, testis, brain, and eye. RT-PCR also demonstrated that OlGC6 is only expressed zygotically and that transcripts are present from 1 day after fertilization, i.e. long before the intestinal tissues begin to develop.

Amino Acid Sequence↗
PubMed1998

Probing of the spliceosome with site-specifically derivatized 5' splice site RNA oligonucleotides.

We have developed a site-specific chemical modification technique to incorporate a photoreactive azidophenacyl (APA) group at designated internal positions along the RNA phosphodiester backbone. Using this technique, we have analyzed interactions of the 5' splice site (5'SS) RNA within the spliceosome. Several crosslinked products can be detected within complex B using the derivatized 5'SS RNAs, including U6 snRNA, hPrp8p, and 114-, 90-, 70-, 54-, and 27-kDa proteins. The 5'SS RNAs derivatized at intron positions +4 to +8 crosslink to U6 snRNA, confirming the previously reported pairing interaction between these sequences. hPrp8p and p70 are crosslinked to the 5'SS RNA when the APA is placed within the 5' exon. Finally, a set of unidentified proteins, including p114, p54, and p27, is detected with the 5'SS RNA derivatized at intron positions +4 to +8. Introduction of the bulky APA group near the 5'SS junction (positions -2 to +3) strongly interferes with complex B formation and thus no APA crosslinks are observed at these positions. Together with our earlier observation that hPrp8p crosslinks to the GU dinucleotide at the 5' end of the intron, these results suggest that the inhibitory effect of APA results from steric hindrance of the hPrp8p:5'SS interaction. Unexpectedly, thio-modifications within the region of the 5'SS RNA that is involved in base pairing to U6 snRNA strongly stimulate complex B formation.

Allosteric Site↗
PubMed2006

The mitochondrial genome of the moss Physcomitrella patens sheds new light on mitochondrial evolution in land plants.

The phylogenetic positions of bryophytes and charophytes, together with their genome features, are important for understanding early land plant evolution. Here we report the complete nucleotide sequence (105,340 bp) of the circular-mapping mitochondrial DNA of the moss Physcomitrella patens. Available evidence suggests that the multipartite structure of the mitochondrial genome in flowering plants does not occur in Physcomitrella. It contains genes for 3 rRNAs (rnl, rns, and rrn5), 24 tRNAs, and 42 conserved mitochondrial proteins (14 ribosomal proteins, 4 ccm proteins, 9 nicotinamide adenine dinucleotide dehydrogenase subunits, 5 ATPase subunits, 2 succinate dehydrogenase subunits, apocytochrome b, 3 cytochrome oxidase subunits, and 4 other proteins). We estimate that 5 tRNA genes are missing that might be encoded by the nuclear genome. The overall mitochondrial genome structure is similar in Physcomitrella, Chara vulgaris, Chaetosphaeridium globosum, and Marchantia polymorpha, with easily identifiable inversions and translocations. Significant synteny with angiosperm and chlorophyte mitochondrial genomes was not detected. Phylogenetic analysis of 18 conserved proteins suggests that the moss-liverwort clade is sister to angiosperms, which is consistent with a previous analysis of chloroplast genes but is not consistent with some analyses using mitochondrial sequences. In Physcomitrella, 27 introns are present within 16 genes. Nine of its intron positions are shared with angiosperms and 4 with Marchantia, which in turn shares only one intron position with angiosperms. The phylogenetic analysis as well as the syntenic structure suggest that the mitochondrial genomes of Physcomitrella and Marchantia retain prototype features among land plant mitochondrial genomes.

Base Sequence↗
PubMed2000

The genomic structure of the scallop, Patinopecten yessoensis, troponin C gene: a hypothesis for the evolution of troponin C.

Two cDNAs encoding troponin C (TnC) isoforms are isolated from the scallop, Patinopecten yessoensis, striated adductor muscle. The sequential differences between these isoforms, named TnC(long) and TnC(short), are restricted in several residues of the C-terminal region. TnC(long) is commonly expressed in both the striated and the smooth adductor muscle; however, TnC(short) is only in the striated adductor muscle. The TnC gene is a single copy gene in the scallop, thus they are expressed through the alternative splicing from the same gene. The scallop TnC gene is constructed from five exons and four introns, and positions of introns are identical with chordate TnC genes, although the scallop TnC possesses no corresponding intron to the fourth intron of chordates. The loss of this intron is also observed in Drosophila TnC; these may be remnants of their ancestor, namely the early metazoan TnC gene might be a five exons-four introns structure. In addition, the absence of the corresponding intron is also observed among protostomian calmodulins (CaMs), a molecule closely related to TnC. This suggests that the common ancestor gene of the TnC superfamily might also be a five exons-four introns structure. Assuming this to be true, the discordance of the fourth intron positions observed among members of the family is well explained by the evolutionary independent gain of the intron on each member's lineage.

Amino Acid Sequence↗
PubMed2005

In silico characterization of the family of PARP-like poly(ADP-ribosyl)transferases (pARTs).

BACKGROUND: ADP-ribosylation is an enzyme-catalyzed posttranslational protein modification in which mono(ADP-ribosyl)transferases (mARTs) and poly(ADP-ribosyl)transferases (pARTs) transfer the ADP-ribose moiety from NAD onto specific amino acid side chains and/or ADP-ribose units on target proteins. RESULTS: Using a combination of database search tools we identified the genes encoding recognizable pART domains in the public genome databases. In humans, the pART family encompasses 17 members. For 16 of these genes, an orthologue exists also in the mouse, rat, and pufferfish. Based on the degree of amino acid sequence similarity in the catalytic domain, conserved intron positions, and fused protein domains, pARTs can be divided into five major subgroups. All six members of groups 1 and 2 contain the H-Y-E trias of amino acid residues found also in the active sites of Diphtheria toxin and Pseudomonas exotoxin A, while the eleven members of groups 3 - 5 carry variations of this motif. The pART catalytic domain is found associated in Lego-like fashion with a variety of domains, including nucleic acid-binding, protein-protein interaction, and ubiquitylation domains. Some of these domain associations appear to be very ancient since they are observed also in insects, fungi, amoebae, and plants. The recently completed genome of the pufferfish T. nigroviridis contains recognizable orthologues for all pARTs except for pART7. The nearly completed albeit still fragmentary chicken genome contains recognizable orthologues for twelve pARTs. Simpler eucaryotes generally contain fewer pARTs: two in the fly D. melanogaster, three each in the mosquito A. gambiae, the nematode C. elegans, and the ascomycete microfungus G. zeae, six in the amoeba E. histolytica, nine in the slime mold D. discoideum, and ten in the cress plant A. thaliana. GenBank contains two pART homologues from the large double stranded DNA viruses Chilo iridescent virus and Bacteriophage Aeh1 and only a single entry (from V. cholerae) showing recognizable homology to the pART-like catalytic domains of Diphtheria toxin and Pseudomonas exotoxin A. CONCLUSION: The pART family, which encompasses 17 members in the human and 16 members in the mouse, can be divided into five subgroups on the basis of sequence similarity, phylogeny, conserved intron positions, and patterns of genetically fused protein domains.

Adenosine Diphosphate↗
PubMed1993

Temperature sensitivity of aberrant RNA splicing with a mutation in the G+5 position of intron 37 of the gene for type III procollagen from a patient with Ehlers-Danlos syndrome type IV.

A single-base mutation in intron 37 of the gene for type III procollagen (COL3A1) was found in a proband with the type IV variant of Ehlers-Danlos syndrome. Probe-protection experiments with S1 nuclease and RNA from fibroblasts incubated at 37 degrees C demonstrated that about 35% of the total mRNA or about 70% of the mRNA from mutated allele was spliced by exon skipping. The effects of the mutation were temperature-sensitive in that the amount of RNA from the mutated allele that was spliced by exon skipping was 87.1 +/- 7.7% at 31 degrees C, 70.1 +/- 6.5% at 37 degrees C, and 85.4 +/- 11.1% at 42 degrees C. The effects of temperature on aberrant RNA splicing were, therefore, the reverse of those reported for four previous mutants in collagen genes. The increase in abnormal RNA splicing when the temperature was raised from 31 degrees to 37 degrees C seen with previously reported mutants suggested that RNA-RNA hybridization of U1snRNA to the 5'-splice site in the substrate may be limiting in the processing of transcripts from the mutated alleles, since RNA-RNA hybridizations become less favorable at higher temperatures. The decrease in abnormal RNA splicing seen here when the temperature was raised from 31 degrees to 37 degrees C suggested that protein-RNA or protein-protein binding steps become rate limiting with the G+5 mutation in intron 37 of the COL3A1 gene.

Adolescent↗
PubMed1997

Cloning, expression, and characterization of two manganese superoxide dismutases from Caenorhabditis elegans.

Two genes encoding manganese superoxide dismutase (sod-2 and sod-3) have been identified in the nematode Caenorhabditis elegans. Each gene is composed of five exons, and intron positions are identical; however, intron sizes and sequences are not the same. The predicted protein sequences are 86.3% homologous (91.8% conservative), and the cDNAs are only 75.2% homologous. Both deduced protein sequences contain the expected N-terminal mitochondrial transit peptides. Reverse transcriptase polymerase chain reaction analysis shows that both genes are expressed under normal growth conditions and that their RNA transcripts are trans-spliced to the SL-1 leader sequence. The latter result together with Northern blot analysis indicate that both genes have mono-cistronic transcripts. The sod-3 gene was mapped to chromosome X, and the location of sod-2 was confirmed to be chromosome I. Polymerase chain reaction was used to amplify the cDNA regions encoding the predicted mature manganese superoxide dismutase proteins and each was cloned and expressed to high levels in Escherichia coli cells deficient in cytosolic superoxide dismutases. Both proteins were shown to be active in E. coli, providing similar protection against methyl viologen-induced oxidative stress. The expressed enzymes, which were not inhibited by hydrogen peroxide or cyanide, are dimeric, show quite different electrophoretic mobilities and isoelectric points, but exhibit comparable specific activities.

Amino Acid Sequence↗
PubMed2003

Phospholipase C-gamma contains introns shared by src homology 2 domains in many unrelated proteins.

Many proteins with novel functions were created by exon shuffling around the time of the metazoan radiation. Phospholipase C-gamma (PLC-gamma) is typical of proteins that appeared at this time, containing several different modules that probably originated elsewhere. To gain insight into both PLC-gamma evolution and structure-function relationships within the Drosophila PLC-gamma encoded by small wing (sl), we cloned and sequenced the PLC-gamma homologs from Drosophila pseudoobscura and D. virilis and compared their gene structure and predicted amino acid sequences with PLC-gamma homologs in other animals. PLC-gamma has been well conserved throughout, although structural differences suggest that the role of tyrosine phosphorylation in enzyme activation differs between vertebrates and invertebrates. Comparison of intron positions demonstrates that extensive intron loss has occurred during invertebrate evolution and also reveals the presence of conserved introns in both the N- and C-terminal PLC-gamma SH2 domains that are present in SH2 domains in many other genes. These and other conserved SH2 introns suggest that the SH2 domains in PLC-gamma are derived from an ancestral domain that was shuffled not only into PLC-gamma, but also into many other unrelated genes during animal evolution.

Amino Acid Sequence↗