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PubMed2019

Distinct types of short open reading frames are translated in plant cells.

Genomes contain millions of short (<100 codons) open reading frames (sORFs), which are usually dismissed during gene annotation. Nevertheless, peptides encoded by such sORFs can play important biological roles, and their impact on cellular processes has long been underestimated. Here, we analyzed approximately 70,000 transcribed sORFs in the model plant Physcomitrella patens (moss). Several distinct classes of sORFs that differ in terms of their position on transcripts and the level of evolutionary conservation are present in the moss genome. Over 5000 sORFs were conserved in at least one of 10 plant species examined. Mass spectrometry analysis of proteomic and peptidomic data sets suggested that tens of sORFs located on distinct parts of mRNAs and long noncoding RNAs (lncRNAs) are translated, including conserved sORFs. Translational analysis of the sORFs and main ORFs at a single locus suggested the existence of genes that code for multiple proteins and peptides with tissue-specific expression. Functional analysis of four lncRNA-encoded peptides showed that sORFs-encoded peptides are involved in regulation of growth and differentiation in moss. Knocking out lncRNA-encoded peptides resulted in a decrease of moss growth. In contrast, the overexpression of these peptides resulted in a diverse range of phenotypic effects. Our results thus open new avenues for discovering novel, biologically active peptides in the plant kingdom.

Bryopsida↗

PubMed1990

Organization of the human protein S genes.

Human genomic clones that span the entire protein S expressed gene (PS alpha) and the 3' two-thirds of the protein S pseudogene (PS beta) have been isolated and characterized. The PS alpha gene is greater than 80 kilobases in length and contains 14 introns and 15 exons, as well as 6 repetitive "Alu" sequences. Exons I and XV contain 112 and 1139 bp 5' and 3' noncoding segments in addition to the amino and carboxyl termini, respectively. Exons I-VIII encode protein segments that are homologous to the vitamin K dependent clotting proteins and are bounded by introns whose position and type are identical with other members of this protein family. Exons IX-XV encode protein segments homologous to sex hormone binding globulin (SHBG) and are bounded by introns of identical type and position as in the SHBG gene. Genomic clones for the PS beta gene cover a distance of greater than 55 kilobases and contain segments corresponding to amino acids 46-635 of the mature protein and the 1.1-kb 3' noncoding region of the cDNA. The presence of multiple base changes in the coding portions of this gene, resulting in termination codons and frame shifts, suggests that it is a pseudogene. Comparison of DNA sequences for the two genes reveals 97% identity for coding and 3' noncoding, and 95.4% for intronic regions, suggesting divergence of the two genes is a relatively recent event.

Amino Acid Sequence↗

PubMed2000

Single nucleotide polymorphism analyses of the human proliferating cell nuclear antigen (pCNA) and flap endonuclease (FEN1) genes.

The products of proliferating cell nuclear antigen (PCNA) and flap endonuclease (FEN1) genes are multifunctional proteins that are involved in DNA replication and damage repair. Yeast models suggest association of mutant forms of PCNA and FEN1 with genomic instability. In our study, we have determined the single nucleotide polymorphisms in human PCNA and FEN1 genes. We sequenced the coding region and adjacent noncoding region of both the PCNA and FEN1 genes in 120 alleles (60 individuals). In the PCNA gene, we detected 9 sequence variants with Hardy-Weinberg allele frequency ranging from 0.008 to 0.088. No polymorphism was detected in the FEN1 gene. The sequence variants in the PCNA gene included 7 intronic single nucleotide polymorphisms (SNP) and 2 synonymous exonic SNPs. All the intronic SNPs were located in introns 1 and 4, which contain several regulatory elements involved in the control of PCNA gene expression. Six of the 7 intronic SNPs showed complete linkage disequilibrium. We confirmed this allelic linkage disequilibrium by allele-specific PCR sequencing. We genotyped 117 additional individuals belonging to 3 population subgroups using the PCR-RFLP method. Finally, to see if the detected polymorphisms are associated with any cancer type, we genotyped cases with melanomas (37 cases), breast cancers (118 cases) and lung cancers (100 cases). We did not find statistical difference in frequency of polymorphism in any cancer type compared with healthy controls, although in breast cancer the frequency was low. Our results suggest that the coding regions of the PCNA and FEN1 genes are highly conserved when compared with other DNA repair genes. The potential of some of the detected intronic polymorphisms to effect regulation of the PCNA gene expression remains to be determined.

Alleles↗

PubMed1998

Chromosome localization and genomic structure of the KiSS-1 metastasis suppressor gene (KISS1).

The identification and sequence of KiSS-1 (HGMW-approved symbol, KISS1), a human malignant melanoma metastasis-suppressor gene, was recently published. In this report, we present a corrected genomic sequence, genomic structure, and refined chromosomal location for KiSS-1. The genomic organization of the sequence reveals a gene consisting of four exons. The first two exons are not translated; the third exon contains 38 5' noncoding bases followed by the translational start site and another 100 translated bases. The terminal exon contains a further 332 translated bases, the translational stop codon, and the polyadenylation signal. The gene maps to chromosome 1q32 as determined by radiation hybrid mapping and FISH analysis. The relatively simple organization of this gene will facilitate analyses for mutations and abnormal expression in human tumors.

Amino Acid Sequence↗

PubMed2002

Functional evolution of noncoding DNA.

Noncoding DNA in eukaryotes encodes functionally important signals for the regulation of chromosome assembly, DNA replication, and gene expression. The increasing availability of whole-genome sequences of related taxa has led to interest in the evolution of these signals, and the phylogenetic footprints they produce. Cis-regulatory sequences controlling gene expression are often conserved among related species, but are rarely conserved between distantly related taxa. Several experimentally characterized regulatory elements have failed to show sequence similarity even between closely related species.

Animals↗

PubMed1993

A cytoplasmic 57-kDa protein that is required for translation of picornavirus RNA by internal ribosomal entry is identical to the nuclear pyrimidine tract-binding protein.

Initiation of translation of the RNA genomes of picornaviruses such as poliovirus and encephalomyocarditis virus is cap-independent and results from interaction of ribosomes with a segment of the 5' noncoding region of these mRNAs termed the internal ribosomal entry site. Genetic and biochemical studies have previously shown that a 57-kDa cytoplasmic RNA-binding protein (p57) plays an essential role in this translation mechanism. We have now found that p57 shares physical, biochemical, and antigenic properties with the pyrimidine tract-binding protein (PTB), a nuclear protein that has been implicated in various processes involving pre-mRNA. These data indicate that p57 and PTB are the same protein. Purified recombinant PTB bound specifically to a bulged hairpin within the internal ribosomal entry site of encephalomyocarditis virus and had a much lower affinity for a mutated derivative of this hairpin and for unrelated RNAs. Immunodepletion of p57/PTB from a HeLa cell-free lysate inhibited translation of poliovirus and encephalomyocarditis virus mRNAs but had no effect on translation of beta-globin mRNA, confirming the essential role of p57 in translation by internal ribosomal entry.

Base Sequence↗

PubMed2004

Heterogeneous patterns of variation among multiple human x-linked Loci: the possible role of diversity-reducing selection in non-africans.

Studies of human DNA sequence polymorphism reveal a range of diversity patterns throughout the genome. This variation among loci may be due to natural selection, demographic influences, and/or different sampling strategies. Here we build on a continuing study of noncoding regions on the X chromosome in a panel of 41 globally sampled humans representing African and non-African populations by examining patterns of DNA sequence variation at four loci (APXL, AMELX, TNFSF5, and RRM2P4) and comparing these patterns with those previously reported at six loci in the same panel of 41 individuals. We also include comparisons with patterns of noncoding variation seen at five additional X-linked loci that were sequenced in similar global panels. We find that, while almost all loci show a reduction in non-African diversity, the magnitude of the reduction varies substantially across loci. The large observed variance in non-African levels of diversity results in the rejection of a neutral model of molecular evolution with a multi-locus HKA test under both a constant size and a bottleneck model. In non-Africans, some loci harbor an excess of rare mutations over neutral equilibrium predictions, while other loci show no such deviation in the distribution of mutation frequencies. We also observe a positive relationship between recombination rate and frequency spectra in our non-African, but not in our African, sample. These results indicate that a simple out-of-Africa bottleneck model is not sufficient to explain the observed patterns of sequence variation and that diversity-reducing selection acting at a subset of loci and/or a more complex neutral model must be invoked.

Black or African American↗

PubMed1990

Structure of the human smooth muscle alpha-actin gene. Analysis of a cDNA and 5' upstream region.

The structures of a cDNA and the 5' upstream region of the human smooth muscle alpha-actin gene have been characterized. Transcriptional start sites and the non-coding first exon were mapped by primer extension analysis and by comparing cDNA and genomic sequences. The deduced human smooth muscle alpha-actin protein sequence is identical to the corresponding bovine protein sequence, and thus confirms that the previously determined human genomic sequence contained a mutation at codon 312. Human smooth muscle cells express only a single, 1.4-kilobase smooth muscle alpha-actin transcript. 5' Noncoding sequences that have the greatest similarity to the chicken gene are located in five noncontiguous segments, extending from approximately 250 base pairs upstream of the cap site through the first exon. Conserved sequences encompass a region required for expression and tissue-specific regulation of chicken smooth muscle alpha-actin and therefore are probably also important for expression of the human gene.

Actins↗

PubMed1995

Diversity of Ig light chain clusters in the sandbar shark (Carcharhinus plumbeus).

The genes encoding Ig chains in elasmobranchs are arranged in clusters or cassettes, an organizational pattern dramatically different from the mammalian translocon gene arrangement. Cluster gene arrangements, which have now been found in non-elasmobranchs as well, pose interesting dilemmas for understanding the mechanisms of Ig gene expression and regulation in terms of allelic exclusion and clonal selection. We have sequenced five lambda genomic clones encoding complete sandbar shark (Carcharhinus plumbeus) lambda L chain gene loci. While the coding regions among all five clones are highly homologous, the noncoding regions have significant differences that allowed us to identify two types of lambda L chain clusters. The noncoding regions are < 60% identical between groups, while the three clones belonging to the first group share > 95% identity in their noncoding regions. The second group is more diverse and may be comprised of several related subgroups. The two clones in this group share approximately 85% identity in the noncoding regions. Variations in the promoter region, including octamer and TATA box orientation and position, are identified between the two groups and may have implications for the molecular regulation of Ab production. Our results show the sandbar shark lambda L chain family to be a complex and diverse system.

Amino Acid Sequence↗

PubMed2001

[Reconstruction of hepatitis D virus ribozymes and their ability to trans-cleave hepatitis C virus RNA].

OBJECTIVE: To study whether reconstructed hepatitis D virus (HDV) ribozymes have the ability to trans-cleave hepatitis C virus (HCV) RNA. METHODS: We reconstructed the stem IV and substrate-binding region of HDV genomic ribozymes, thus obtained three HDV ribozymes named RzC1, RzC2 and RzC3 expected to be able to trans-cleave HCV RNA at predicted sites. The substrate containing HCV RNA 5'-noncoding region (5'-NCR) and 5'-fragment of C region (HCV RNA 5'-NCR-C) was synthesized by transcription in vitro, then radiolabelled at its 5'-end. Under certain pH and appropriate concentration of Mg(2+) with or without deionized formamide, the ribozymes and their substrate were mixed at mol ratio of 100 : 1 and reacted for two hours. Trans-cleaved products were shown by denatured polyacrylamide gel electrophoresis and autoradiography, and the percentage of trans-cleaved substrate was calculated as the activity indicator of these ribozymes. RESULTS: RzC1 and RzC2 were able to trans-cleave HCV RNA 5'-NCR-C site specifically, and their activity could be enhanced by certain concentration of deionized formamide. RzC3 could not trans-cleave the substrate. CONCLUSIONS: Optimized HDV genomic ribozymes can trans-cleave HCV RNA.

5' Untranslated Regions↗

PubMed1993

Sequence analysis of the nucleocapsid protein gene of rat coronavirus SDAV-681.

The nucleotide sequence of the 3'-end of the genomic RNA of sialodacryoadenitis virus strain 681 (SDAV-681) was determined. A large open reading frame encoding a 454-amino-acid protein was identified as the nucleocapsid protein (N) gene, since the predicted protein is similar in size, chemical properties, and amino acid sequence to the N proteins of other coronaviruses. The amino acid variance of the N proteins between SDAV and mouse hepatitis virus (MHV) is not markedly different from that among MHV strains. A high degree of genetic relatedness between SDAV and MHV was revealed in the intergenic and 3'-noncoding sequences as well as in the N gene.

Amino Acid Sequence↗

PubMed2000

New approaches for genotyping of Helicobacter pylori based on amplification of polymorphisms in intergenic DNA regions and at the insertion site of the cag pathogenicity island.

The population of the gastric pathogen Helicobacter pylori shows a high degree of genetic diversity. It is well established that heterogeneity at the isolate level is caused by nucleotide transitions within genes, differences in the gene order, and by genetic instability of single genes as well as of a large virulence-associated genomic DNA region, the cag pathogenicity island (PAI). Analysis of intergenic regions with specific PCR-assays developed in this study, revealed that DNA polymorphisms in the noncoding DNA localized in front of the genes ribA and vacA and at the insertion site of the cag PAI contribute to the genetic diversity of H. pylori and are useful for differentiation of individual isolates. Thirteen individual genotypes were identified by PCR analysis of these polymorphic loci in 487, 241, and 182 clinical H. pylori isolates. Sequence analysis revealed that genetic variability in front of genes ribA and vacA, and in the intergenic region at the PAI insertion site is caused by insertion and deletions of so-far-unknown DNA sequences as well as by parts of the H. pylori IS elements IS605 and IS606, respectively. The new genotypes identified could be used to differentiate antrum and corpus isolates from the same patients. Their combination with vacA allele subtypes and with the cagA status allowed to differentiate 140 isolates in 51 subtypes. In 36 cases the corresponding genotype patterns were isolate specific. In summary, the results confirm that DNA polymorphisms in intergenic regions contribute to the genetic diversity of H. pylori. Although individual H. pylori genotypes were not associated with peptic ulcer disease, the PCR-based approaches for their detection developed here should be of use for further investigation of genetic diversity in H. pylori and for epidemiological purposes.

Adult↗

PubMed2003

Multispecies comparative analysis of a mammalian-specific genomic domain encoding secretory proteins.

The mammalian-specific casein gene cluster comprises 3 or 4 evolutionarily related genes and 1 physically linked gene with a functional association. To gain a better understanding of the mechanisms regulating the entire casein cluster at the genomic level we initiated a multispecies comparative sequence analysis. Despite the high level of divergence at the coding level, these studies have identified uncharacterized family members within two species and the presence at orthologous positions of previously uncharacterized genes. Also the previous suggestion that the histatin/statherin gene family, located in this region, was primate specific was ruled out. All 11 genes identified in this region appear to encode secretory proteins. Conservation of a number of noncoding regions was observed; one coincides with an element previously suggested to be important for beta-casein gene expression in human and cow. The conserved regions might have biological importance for the regulation of genes in this genomic "neighborhood."

Amino Acid Sequence↗

PubMed1985

A 78-kilobase region of mouse chromosome 3 contains salivary and pancreatic amylase genes and a pseudogene.

Genetic studies have demonstrated that salivary and pancreatic amylase genes are closely linked in human and mouse. To analyze the arrangement of genes within the amylase cluster, a library of YBR mouse genomic DNA was cloned in the cosmid vector pJB8. Clones containing amylase genes were identified by hybridization with amylase cDNA probes. Salivary and pancreatic amylase genes were isolated on separate cosmid clones, but no overlapping clones were evident from the initial screening. A strategy for the rapid isolation of terminal noncoding fragments from the cosmid clones was developed. By using these terminal fragments for chromosome "walking," a map of 78 kilobases of the amylase gene region was constructed. The salivary and pancreatic amylase genes are present within this region in the same 5'-to-3' orientation, separated by 22 kilobases of genomic DNA. A truncated amylase pseudogene is located 10 kilobases downstream from the pancreatic amylase gene.

Amylases↗

PubMed2001

Complete genome analysis of enterovirus 71 isolated from an outbreak in Taiwan and rapid identification of enterovirus 71 and coxsackievirus A16 by RT-PCR.

Hand, foot, and mouth disease (HFMD) and encephalomyelitis were two major clinical manifestations during the 1998 enterovirus 71 (EV71) epidemic in Taiwan. To investigate whether different clinical patterns were caused by alterations in EV71 genomes, the complete nucleotide sequences of four EV71 strains associated with HFMD or encephalomyelitis were compared. Among these viral strains, two or three nucleotide differences were found within the 5'-noncoding region, and two or four amino acid differences were found within the regions encoding viral polyproteins; however, none of these differences were correlated with either clinical manifestation. Because coxsackievirus A16 was another major causative agent of HFMD, a reverse transcription-polymerase chain reaction assay, with high sensitivity and specificity for identification of EV71 (both 100%) and coxsackievirus A16 (100 and 98.8%), was developed for the rapid differential identification of these two viruses in HFMD patients.

5' Untranslated Regions↗

PubMed2001

Noncoding RNA gene detection using comparative sequence analysis.

BACKGROUND: Noncoding RNA genes produce transcripts that exert their function without ever producing proteins. Noncoding RNA gene sequences do not have strong statistical signals, unlike protein coding genes. A reliable general purpose computational genefinder for noncoding RNA genes has been elusive. RESULTS: We describe a comparative sequence analysis algorithm for detecting novel structural RNA genes. The key idea is to test the pattern of substitutions observed in a pairwise alignment of two homologous sequences. A conserved coding region tends to show a pattern of synonymous substitutions, whereas a conserved structural RNA tends to show a pattern of compensatory mutations consistent with some base-paired secondary structure. We formalize this intuition using three probabilistic "pair-grammars": a pair stochastic context free grammar modeling alignments constrained by structural RNA evolution, a pair hidden Markov model modeling alignments constrained by coding sequence evolution, and a pair hidden Markov model modeling a null hypothesis of position-independent evolution. Given an input pairwise sequence alignment (e.g. from a BLASTN comparison of two related genomes) we classify the alignment into the coding, RNA, or null class according to the posterior probability of each class. CONCLUSIONS: We have implemented this approach as a program, QRNA, which we consider to be a prototype structural noncoding RNA genefinder. Tests suggest that this approach detects noncoding RNA genes with a fair degree of reliability.

Algorithms↗

PubMed2006

Clusters of internally primed transcripts reveal novel long noncoding RNAs.

Non-protein-coding RNAs (ncRNAs) are increasingly being recognized as having important regulatory roles. Although much recent attention has focused on tiny 22- to 25-nucleotide microRNAs, several functional ncRNAs are orders of magnitude larger in size. Examples of such macro ncRNAs include Xist and Air, which in mouse are 18 and 108 kilobases (Kb), respectively. We surveyed the 102,801 FANTOM3 mouse cDNA clones and found that Air and Xist were present not as single, full-length transcripts but as a cluster of multiple, shorter cDNAs, which were unspliced, had little coding potential, and were most likely primed from internal adenine-rich regions within longer parental transcripts. We therefore conducted a genome-wide search for regional clusters of such cDNAs to find novel macro ncRNA candidates. Sixty-six regions were identified, each of which mapped outside known protein-coding loci and which had a mean length of 92 Kb. We detected several known long ncRNAs within these regions, supporting the basic rationale of our approach. In silico analysis showed that many regions had evidence of imprinting and/or antisense transcription. These regions were significantly associated with microRNAs and transcripts from the central nervous system. We selected eight novel regions for experimental validation by northern blot and RT-PCR and found that the majority represent previously unrecognized noncoding transcripts that are at least 10 Kb in size and predominantly localized in the nucleus. Taken together, the data not only identify multiple new ncRNAs but also suggest the existence of many more macro ncRNAs like Xist and Air.

Animals↗

PubMed1989

Avian retroviral vectors derived from avian defective leukemia virus: role of the translational context of the inserted gene on efficiency of the vectors.

We have constructed retroviral vectors derived from the genome of avian erythroblastosis virus ES4 (AEV ES4). The neo selectable gene was substituted for the original v-erbA or v-erbB oncogenes of AEV, either in the same or in a different reading frames. Recombinant retrovirus were rescued and used to infect chicken embryo fibroblasts or quail QT6 cells. When the neo gene was inserted in the same reading frame as the original oncogene, we obtained (1) a high level of expression of the neo gene, (2) a balanced ration of both genomic and subgenomic RNAs, and (3) high titer recombinant viruses. Conversely, when the neo gene was inserted in a reading frame different from that of the original oncogene, we observed (1) a very low level of expression of the neo protein, (2) a predominance of the viral transcript used as translational template for the neo protein synthesis, and (3) low titer recombinant viruses. One of the vectors was used to transfer a human delta-globin gene into avian cells in culture without detectable rearrangement of this gene, but exhibited a deletion within the conserved noncoding region located between the two original oncogenes. Our data provide information for further construction of double expression vectors. Furthermore, three of the vectors would provide helpful tools to identify genetic elements of the virus genome involved in splicing regulation.

Alpharetrovirus↗