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PubMed1987

Cloning and characterization of human liver cDNA encoding a protein S precursor.

Human liver cDNA encoding a protein S precursor was isolated from two cDNA libraries by two different techniques. Based upon the frequency of positive clones, the abundance of mRNA for protein S is approximately 0.01%. Blot hybridization of electrophoretically fractionated poly(A)+ RNA revealed a major mRNA approximately 4 kilobases long and two minor forms of approximately 3.1 and approximately equal to 2.6 kilobases. One of the cDNA clones contains a segment encoding a 676 amino acid protein S precursor, as well as 108 and 1132 nucleotides of 5' and 3' noncoding sequence, respectively, plus a poly(A) region at the 3' end. The cDNAs are adenosine plus thymidine-rich (60%) except for the 5' noncoding region, where 78% of the nucleotides are guanosine or cytosine. The protein precursor consists of a 41 amino acid "leader" peptide followed by 635 amino acids corresponding to mature protein S. Comparison of the mature protein region with homologous vitamin K-dependent plasma proteins shows that it is composed of the following domains: an amino-terminal gamma-carboxyglutamic acid-rich region of 37 amino acids; a 36 amino acid linker region rich in hydroxy amino acids; four epidermal growth factor-like segments, each approximately 45 amino acids long; and a 387 amino acid carboxyl-terminal domain of unrecognized structure and unknown function.

Amino Acid Sequence↗
PubMed1984

Xenopus fibrinogen: characterization of the mRNAs for the three subunits.

We purified and characterized the mRNAs coding for each of the three subunits of Xenopus fibrinogen. Purification was accomplished by electrophoretic separation of liver polyadenylated RNA in a fully denaturing gel, followed by recovery of the RNA from the gel via transfer to an ion-exchange membrane. This procedure yielded fractions which were highly enriched for the mRNAs for each of the fibrinogen chains. The fibrinogen mRNAs were identified by two methods: (i) in vitro translation followed by subunit-specific cleavage with the proteases thrombin and batroxobin; and (ii) cross-hybridization with cDNA clones for individual subunits of rat fibrinogen. The results demonstrate that the A alpha and gamma chains of frog fibrinogen are each coded by a single mRNA species. The A alpha mRNA is ca. 3,100 nucleotides in length, which is nearly twice the minimum size required to code for the A alpha precursor polypeptide. The gamma chain mRNA comprises about 1,600 bases and includes only a small untranslated region. In contrast, the B beta subunit is synthesized from two mRNAs, one of which is 2,500 and the other 1,800 nucleotides long. The 2,500-base mRNA includes a large noncoding region, whereas the smaller one is near the minimum required size. The larger B beta mRNA is ca, fivefold more abundant that the smaller species.

Animals↗
PubMed2006

Discovery and profiling of bovine microRNAs from immune-related and embryonic tissues.

MicroRNAs are small approximately 22 nucleotide-long noncoding RNAs capable of controlling gene expression by inhibiting translation. Alignment of human microRNA stem-loop sequences (mir) against a recent draft sequence assembly of the bovine genome resulted in identification of 334 predicted bovine mir. We sequenced five tissue-specific cDNA libraries derived from the small RNA fractions of bovine embryo, thymus, small intestine, and lymph node to validate these predictions and identify new mir. This strategy combined with comparative sequence analysis identified 129 sequences that corresponded to mature microRNAs (miR). A total of 107 sequences aligned to known human mir, and 100 of these matched expressed miR. The other seven sequences represented novel miR expressed from the complementary strand of previously characterized human mir. The 22 sequences without matches displayed characteristic mir secondary structures when folded in silico, and 10 of these retained sequence conservation with other vertebrate species. Expression analysis based on sequence identity counts revealed that some miR were preferentially expressed in certain tissues, while bta-miR-26a and bta-miR-103 were prevalent in all tissues examined. These results support the premise that species differences in regulation of gene expression by miR occur primarily at the level of expression and processing.

Animals↗
PubMed2006

Patterns of sequence conservation in presynaptic neural genes.

BACKGROUND: The neuronal synapse is a fundamental functional unit in the central nervous system of animals. Because synaptic function is evolutionarily conserved, we reasoned that functional sequences of genes and related genomic elements known to play important roles in neurotransmitter release would also be conserved. RESULTS: Evolutionary rate analysis revealed that presynaptic proteins evolve slowly, although some members of large gene families exhibit accelerated evolutionary rates relative to other family members. Comparative sequence analysis of 46 megabases spanning 150 presynaptic genes identified more than 26,000 elements that are highly conserved in eight vertebrate species, as well as a small subset of sequences (6%) that are shared among unrelated presynaptic genes. Analysis of large gene families revealed that upstream and intronic regions of closely related family members are extremely divergent. We also identified 504 exceptionally long conserved elements (> or =360 base pairs, > or =80% pair-wise identity between human and other mammals) in intergenic and intronic regions of presynaptic genes. Many of these elements form a highly stable stem-loop RNA structure and consequently are candidates for novel regulatory elements, whereas some conserved noncoding elements are shown to correlate with specific gene expression profiles. The SynapseDB online database integrates these findings and other functional genomic resources for synaptic genes. CONCLUSION: Highly conserved elements in nonprotein coding regions of 150 presynaptic genes represent sequences that may be involved in the transcriptional or post-transcriptional regulation of these genes. Furthermore, comparative sequence analysis will facilitate selection of genes and noncoding sequences for future functional studies and analysis of variation studies in neurodevelopmental and psychiatric disorders.

Animals↗
PubMed1980

The gene for polypeptide IX of adenovirus type 2 and its unspliced messenger RNA.

A 606 base pair segment of adenovirus type 2 DNA which includes the gene for polypeptide IX and its flanking regions has been sequenced. Comparison with the sequence of a cDNA copy of the 9S mRNA for polypeptide IX and direct analysis of its capped oligonucleotide show that the gene and its mRNA are colinear. The 9S mRNA has a length of 485 nucleotides, excluding the poly(A) tract and the m7G of the cap, and contains one single open translational reading frame which is sufficiently long to encode polypeptide IX. This reading frame contains three AUG codons, the first of which is used for initiation of protein synthesis. The mRNA has a 5' noncoding region of 24 nucleotides, excluding the m5G of the cap, and encodes a polypeptide which is 139 amino acids long and unusually rich in serine and alanine. The sequence TATATAA is found 25 nucleotides upstream from the cap site. The polyadenylation site has been identified but cannot be located unambiguously because of the presence of two A residues in the DNA sequence at this position. The 3' noncoding region is 41--43 nucleotides long and contains the hexanucleotide sequence AAUAAA. The mRNA for polypeptide IVa2 is encoded adjacent to that for polypeptide IX and is transcribed in the opposite direction. Sequence analysis revealed an overlap of 11--16 nucleotides, depending on the precise location of the polyadenylation sites, between 3' ends of these mRNAs.

Adenoviruses, Human↗
PubMed2006

Novel transcript nort is a downstream target gene of the Notch signaling pathway in zebrafish.

The Notch signaling pathway plays important roles in the regulation of diverse developmental processes. Although many Notch-signal target genes with different specificities have been identified, their regulation and functions are not fully understood. Here, we conducted a microarray screen to search for novel downstream target genes of the Notch pathway in zebrafish. From the screen, we isolated nort (Notch-regulated transcript) as a transcript whose expression was reduced by the inhibition of Notch signaling. The expression level of nort increased when Notch signaling was activated. nort was expressed in hypoblast cells and the developing nervous system. We found its expression pattern to be similar to that of her4, but it showed some differences, at least in the anterior and posterior neural plate at the 3-somite stage. The nort transcript did not contain any long open-reading frame (ORF) of more than 300 nt, and its ORF-encoded sequence showed no significant homology with the proteins in databases. However, nort has one SPS (suppressor of hairless paired binding site) in its 5'-flanking region. These data suggest that nort is a putative noncoding RNA regulated by Notch signaling.

5' Flanking Region↗
PubMed2000

Inhibition of translation of mRNAs containing gamma-monomethylphosphate cap structure in frog oocytes and in mammalian cells.

The gamma-monomethylphosphate cap structure is found in several eukaryotic small RNAs including nuclear U6, U6atac, 7SK, plant nucleolar U3, and rodent cytoplasmic B2 RNAs. In the case of human U6 snRNA, the 5' end sequence corresponding to nucleotides 1-25 serves as the capping signal and directs the formation of methylphosphate cap structure. In this study, we show that the U6 RNA capping signal, when introduced at the 5' end of RNAs, can efficiently direct the methylphosphate cap formation in RNAs of up to 2.7 kb long, as well as in different mRNAs. These data show that the methylphosphate capping signal functions in mRNAs having different primary sequences and different lengths. Presence of the methylphosphate cap structure on the 5' end of a luciferase mRNA with EMCV 5' noncoding region, which is translated in an IRES-dependent pathway, resulted in a 6- to 100-fold inhibition of translation compared to the same mRNA with a 5' triphosphate when microinjected into frog oocytes or expressed in mouse cells in tissue culture. Thus, conversion of the pppG structure to a methyl-pppG structure on the 5' end of an mRNA, which is translated in an IRES-dependent pathway, results in severe inhibition of translation. These data show that the 5' end motif of mRNAs plays an important role even in the IRES-mediated mRNA translation.

3T3 Cells↗
PubMed1982

Recent duplication and germ-line diversification of rat immunoglobulin kappa chain gene joining segments.

Sequence determination of the joining segment gene (J) cluster in the kappa chain (J kappa) in the embryonic context demonstrates that rat genome contains seven J kappa gene segments that expanded from an ancestral cluster of five J kappa genes. The rat J segments are separated by about 300 base pairs (bp) and are flanked 5' by the presumed variable region (V)/J recombination signal sequence and 3' by the RNA splicing signal. Two of the J gene segments designated J2A and J2B and their 5'-flanking spacer DNA bear striking homology to J2 and its 5'-flanking spacer. Thus, the unit of duplication was the entire J kappa coding region and 5' noncoding spacer (345 bp). The duplication probably occurred as two separate unequal crossing-over (UXO) events. The first UXO event can be confined to recombination within an identical stretch (14 bp long) located at the 3' ends of the coding regions of J1 and J2. The second event could involve a longer segment (372 bp) of tight homology generated by the first UXO event, thus increasing the probability of repeated expansion of the same DNA segment. The sequence homology among the rat duplicated segments (98-99%) is larger than the homology between the corresponding rat and mouse segments (89%), showing that the rat J kappa gene expansion must have occurred after rat and mouse divergence 10 X 10(6) yr ago. We estimate that the first and second UXO events occurred 2 X 10(6) and 1 X 10(6) yr ago, respectively. J3 of rat and mouse share the same mutation (G leads to C) in the RNA splicing signal that presumably inactivates J3. This mutation preceded divergence of the two species. A mutation in the first nucleotide of codon 96 has occurred in both duplicated segments, the only position along 345 bp where J2, J2A, and J2B differ from each other. This results in three different amino acids at position 96 not present in any other J kappa. These mutations are physiologically significant because they diversify the third complementarity-determining region (CDR3) and, thus, may reflect selective pressure to increase antibody diversity. The germ-line diversification of CDR3 was exercised within the last 1-2 X 10(6) yr.

Amino Acid Sequence↗
PubMed2003

MicroRNAs and other tiny endogenous RNAs in C. elegans.

BACKGROUND: MicroRNAs (miRNAs) are small noncoding RNAs that are processed from hairpin precursor transcripts by Dicer. miRNAs probably inhibit translation of mRNAs via imprecise antisense base-pairing. Small interfering RNAs (siRNAs) are similar in size to miRNAs, but they recognize targets by precise complementarity and elicit RNA-mediated interference (RNAi). We employed cDNA sequencing and comparative genomics to identify additional C. elegans small RNAs with properties similar to miRNAs and siRNAs. RESULTS: We found three broad classes of small RNAs in C. elegans: (1) 21 new miRNA genes (we estimate that C. elegans contains approximately 100 distinct miRNA genes, about 30% of which are conserved in vertebrates; (2), 33 distinct members of a class of tiny noncoding RNA (tncRNA) genes with transcripts that are similar in length to miRNAs (approximately 20-21 nt) and that are in some cases developmentally regulated but are apparently not processed from a miRNA-like hairpin precursor and are not phylogenetically conserved; (3) more than 700 distinct small antisense RNAs, about 20 nt long, that are precisely complementary to protein coding regions of more than 500 different genes and therefore seem to be endogenous siRNAs. CONCLUSIONS: The presence of diverse endogenous siRNAs in normal worms suggests ongoing, genome-wide gene silencing by RNAi. miRNAs and tncRNAs are not predicted to form complete Watson-Crick hybrids with any C. elegans RNA target, and so they are likely to regulate the activity of other genes by non-RNAi mechanisms. These results suggest that diverse modes of small RNA-mediated gene regulation are deployed in normal worms.

Animals↗
PubMed1984

The sequences of the N protein gene and intergenic region of the S RNA of pichinde arenavirus.

Two overlapping DNA clones representing more than half of the Pichinde arenavirus S RNA segment were cloned into pBR322 and their nucleotide sequences were determined. The analyses predict that the viral nucleocapsid protein (N) is encoded in a reading frame in the viral complementary RNA sequence starting at viral S RNA nucleotide residue 84 from the 3' end and terminating with an opal codon at residues 1767-1769. The position of the termination codon has been confirmed by primer directed dideoxynucleotide sequencing. The N protein has a calculated size of 62,911 Da and a net positive charge of +9. Viral complementary 15 S mRNA that directs the synthesis of N protein and hybridizes to the predicted N gene DNA has been identified in infected cell extracts. A second nonoverlapping reading frame in the viral complementary sequence originates at nucleotide position 1827 and remains open for at least 71 amino acids (i.e., the extent of the second clone). A long stretch of hydrophobic amino acids is near the amino terminus of this predicted gene product. Between the two reading frames is a 60-nucleotide-long noncoding intergenic region. This nucleotide sequence can be arranged in hairpin configuration involving 14 G-C and 4 A-U base pairs. The possible function of this intergenic region in the regulation of transcription and/or translation is discussed.

Amino Acid Sequence↗
PubMed1989

Sequence analyses and structural predictions of double-stranded RNA segment S1 and VP7 from United States prototype bluetongue virus serotypes 13 and 10.

The nucleotide sequence of segment S1 and the deduced amino acid sequence of VP7 from bluetongue virus (BTV) serotype 13 was determined. Sequences were obtained by use of standard dideoxy DNA sequencing and by direct sequencing of genomic double-stranded RNA (dsRNA). The dsRNA was sequenced with a new dideoxy protocol that produces 300 to 350 bases per set of reactions. Segment S1 is 1156 bp long and contains one long open reading frame capable of coding for 349 amino acids. The protein, VP7, is rather hydrophobic, and has a calculated molecular weight of 38,619 and a net charge of +1.5 at pH 7.0. Segment S1 of BTV-13 has 79.6% of its nucleotides conserved when compared with segment S1 of BTV-10. While most of these differences occur at the third codon position of the open reading frame, the differences between the 89-base-long, 3' noncoding regions occur predominantly in pockets at positions 1092-1098, 1112-1114, and 1125-1129. Potential stem-loop structures encompassing the stop codon of the open reading frame are proposed for both serotypes. Comparisons of VP7 from BTV-13 and BTV-10 indicate that 93.7% of the amino acid residues are conserved, including a single lysine at position 255. Secondary structure predictions infer an eight-stranded beta-barrel structure between residues 150 and 250. This putative beta-barrel may serve as a target for the development of drugs to combat bluetongue disease. Comparable structures detected in the core proteins of single-stranded RNA viruses from both plants and animals suggest that these viruses and BTV had a common origin.

Amino Acid Sequence↗
PubMed2003

[Rapid construction of infectious clones of infectious bursal disease virus].

A rapid procedure was established for rescuing infectious bursal disease virus (IBDV), an important pathogen in poultry. A full-length cDNA clone of the segment B of a CEF-adapted IBDV strain HZ2 was constructed by long RT-PCR, and the 2827 bp nucleotide sequence, including the 5 - and 3 -noncoding regions (NCR), was established. Then the cDNA clone of segment B was engineered to make it contain three silent nucleotide changes, creating a new EcoRV site that was different from the parent virus sequences, by site-directed silent mutagenesis. Cotransfection of eukaryotic expression recombinants containing modified segment A and segment B with Lipofectamine into Vero cells resulted in the expression of IBDV RNA and proteins, as confirmed by Northern RNA dot hybridization and indirect immunofluorescence assay analysis. The change of cell morphology after cotransfection and passages of cell cultures was similar to that of cells infected by authentic IBDV, causing cellular pathogenic effects (CPE). The virus-like particles at 55-60 nm were observed under electron microscopy, affirming the rescue of IBDV. The genetic markers were retained in the recovered progeny virus.

Animals↗
PubMed2005

Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose.

BACKGROUND: The management of warfarin therapy is complicated by a wide variation among patients in drug response. Variants in the gene encoding vitamin K epoxide reductase complex 1 (VKORC1) may affect the response to warfarin. METHODS: We conducted a retrospective study of European-American patients receiving long-term warfarin maintenance therapy. Multiple linear-regression analysis was used to determine the effect of VKORC1 haplotypes on the warfarin dose. We determined VKORC1 haplotype frequencies in African-American, European-American, and Asian-American populations and VKORC1 messenger RNA (mRNA) expression in human liver samples. RESULTS: We identified 10 common noncoding VKORC1 single-nucleotide polymorphisms and inferred five major haplotypes. We identified a low-dose haplotype group (A) and a high-dose haplotype group (B). The mean (+/-SE) maintenance dose of warfarin differed significantly among the three haplotype group combinations, at 2.7+/-0.2 mg per day for A/A, 4.9+/-0.2 mg per day for A/B, and 6.2+/-0.3 mg per day for B/B (P<0.001). VKORC1 haplotype groups A and B explained approximately 25 percent of the variance in dose. Asian Americans had a higher proportion of group A haplotypes and African Americans a higher proportion of group B haplotypes. VKORC1 mRNA levels varied according to the haplotype combination. CONCLUSIONS: VKORC1 haplotypes can be used to stratify patients into low-, intermediate-, and high-dose warfarin groups and may explain differences in dose requirements among patients of different ancestries. The molecular mechanism of this warfarin dose response appears to be regulated at the transcriptional level.

Anticoagulants↗
PubMed1991

Nucleotide sequence of tomato ringspot virus RNA-2.

The sequence of tomato ringspot virus (TomRSV) RNA-2 has been determined. It is 7273 nucleotides in length excluding the 3' poly(A) tail and contains a single long open reading frame (ORF) of 5646 nucleotides in the positive sense beginning at position 78 and terminating at position 5723. A second in-frame AUG at position 441 is in a more favourable context for initiation of translation and may act as a site for initiation of translation. The TomRSV RNA-2 3' noncoding region is 1550 nucleotides in length. The coat protein is located in the C-terminal region of the large polypeptide and shows significant but limited amino acid sequence similarity to the putative coat proteins of the nepoviruses tomato black ring (TBRV), Hungarian grapevine chrome mosaic (GCMV) and grapevine fanleaf (GFLV). Comparisons of the coding and non-coding regions of TomRSV RNA-2 and the RNA components of TBRV, GCMV, GFLV and the comovirus cowpea mosaic virus revealed significant similarity for over 300 amino acids between the coding region immediately to the N-terminal side of the putative coat proteins of TomRSV and GFLV; very little similarity could be detected among the non-coding regions of TomRSV and any of these viruses.

Amino Acid Sequence↗
PubMed2004

The human DiGeorge syndrome critical region gene 8 and Its D. melanogaster homolog are required for miRNA biogenesis.

MicroRNAs (miRNAs) represent a family of small noncoding RNAs that are found in plants and animals (for recent reviews, see ). miRNAs are expressed in a developmentally and tissue-specific manner and regulate the translational efficiency and stability of partial or fully sequence-complementary mRNAs. miRNAs are excised in a stepwise process from double-stranded RNA precursors that are embedded in long RNA polymerase II primary transcripts (pri-miRNA). Drosha RNase III catalyzes the first excision event, the release in the nucleus of a hairpin RNA (pre-miRNA), which is followed by export of the pre-miRNA to the cytoplasm and further processing by Dicer to mature miRNAs. Here, we characterize the human DGCR8, the DiGeorge syndrome critical region gene 8, and its Drosophila melanogaster homolog. We provide biochemical and cell-based readouts to demonstrate the requirement of DGCR8 for the maturation of miRNA primary transcripts. RNAi knockdown experiments of fly and human DGCR8 resulted in accumulation of pri-miRNAs and reduction of pre-miRNAs and mature miRNAs. Our results suggest that DGCR8 and Drosha interact in human cells and reside in a functional pri-miRNA processing complex.

Animals↗
PubMed2006

Short blocks from the noncoding parts of the human genome have instances within nearly all known genes and relate to biological processes.

Using an unsupervised pattern-discovery method, we processed the human intergenic and intronic regions and catalogued all variable-length patterns with identically conserved copies and multiplicities above what is expected by chance. Among the millions of discovered patterns, we found a subset of 127,998 patterns, termed pyknons, which have additional nonoverlapping instances in the untranslated and protein-coding regions of 30,675 transcripts from 20,059 human genes. The pyknons arrange combinatorially in the untranslated and coding regions of numerous human genes where they form mosaics. Consecutive instances of pyknons in these regions show a strong bias in their relative placement, favoring distances of approximately 22 nucleotides. We also found pyknons to be enriched in a statistically significant manner in genes involved in specific processes, e.g., cell communication, transcription, regulation of transcription, signaling, transport, etc. For approximately 1/3 of the pyknons, the intergenic/intronic instances of their reverse complement lie within 380,084 nonoverlapping regions, typically 60-80 nucleotides long, which are predicted to form double-stranded, energetically stable, hairpin-shaped RNA secondary structures; additionally, the pyknons subsume approximately 40% of the known microRNA sequences, thus suggesting a possible link with posttranscriptional gene silencing and RNA interference. Cross-genome comparisons reveal that many of the pyknons have instances in the 3' UTRs of genes from other vertebrates and invertebrates where they are overrepresented in similar biological processes, as in the human genome. These unexpected findings suggest potential unique functional connections between the coding and noncoding parts of the human genome.

3' Untranslated Regions↗
PubMed1991

Genome cloning and analysis of the large RNA segment (segment A) of a naturally avirulent serotype 2 infectious bursal disease virus.

The genome of infectious bursal disease virus (IBDV) of serotype 2 (strain OH) has been cloned, and 3171 nucleotides of genome segment A cDNA sequence have been determined for the first time. Sequence homology of OH-IBDV with the most distant serotype 1 IBDV at the nucleotide level is 83.1%, and the amino acid sequence homology of the polyprotein is 89.6%. Alignment of the polyprotein amino acid sequences showed the hypervariable region in VP2 to be 151-152 amino acid residues long in IBDV. A second variable region, 37 amino acid residues long, was identified in the N-terminal third of the IBDV VP2 molecule. IBDV strains, like the IPNV strains, also contain inverted repeats that may form stem-and-loop structures in the 5' noncoding sequences. These inverted repeats are variable between the two IBDV serotypes, particularly at the AT basepairs.

Animals↗
PubMed1986

Secondary structure model for mouse beta Maj globin mRNA derived from enzymatic digestion data, comparative sequence and computer analysis.

A model for the secondary structure of mouse beta Maj globin messenger RNA is presented based on enzymatic digestion data, comparative sequence and computer analysis. Using 5'-32P-end-labeled beta globin mRNA as a substrate, single-stranded regions were determined with S1 and T1 nucleases and double-stranded regions with V1 ribonuclease from cobra venom. The structure data obtained for ca. 75% of the molecule was introduced into a computer algorithm which predicts secondary structures of minimum free energy consistent with the enzymatic data. Two prominent base paired regions independently derived by phylogenetic analysis were also present in the computer generated structure lending support for the model. An interesting feature of the model is the presence of long-range base pairing interactions which permit the beta globin mRNA to fold back on itself, thereby bringing the 5'- and 3'-noncoding regions within close proximity. This feature is consistent with data from other laboratories suggesting an interaction of the 5'- and 3'-domains in the mammalian globin mRNAs.

Animals↗