A computational approach to identify genes for functional RNAs in genomic sequences

Carter, Richard J.; Dubchak, Inna; Holbrook, Stephen R.

doi:10.1093/nar/29.19.3928

Cited by 166 publications

(124 citation statements)

References 46 publications

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“…A QRNA screen of E. coli resulted in an estimate of about 200 structural ncRNA genes in this organism (11), a number that is roughly consistent with the results of three other screens (8)(9)(10). Thirty-four different loci identified in these screens have been experimentally shown to express small stable RNAs thus far.…”

Section: Discussionsupporting

confidence: 67%

“…This approach obviously requires the genome sequence of an organism for which transcriptional regulation is well understood. Carter et al (9) used a neural network to classify genomic sequences based on several features, including GC composition. Two other approaches used a comparative genomics approach, requiring genomic sequence from related organisms as well as that of E. coli.…”

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confidence: 99%

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Noncoding RNA genes identified in AT-rich hyperthermophiles

Klein

Misulovin

Eddy

2002

Proc. Natl. Acad. Sci. U.S.A.

160

157

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Noncoding RNA (ncRNA) genes that produce functional RNAs instead of encoding proteins seem to be somewhat more prevalent than previously thought. However, estimating their number and importance is difficult because systematic identification of ncRNA genes remains challenging. Here, we exploit a strong, surprising DNA composition bias in genomes of some hyperthermophilic organisms: simply screening for GC-rich regions in the AT-rich Methanococcus jannaschii and Pyrococcus furiosus genomes efficiently detects both known and new RNA genes with a high degree of secondary structure. A separate screen based on comparative analysis also successfully identifies noncoding RNA genes in P. furiosus. Nine of the 30 new candidate genes predicted by these screens have been verified to produce discrete, apparently noncoding transcripts with sizes ranging from 97 to 277 nucleotides. N oncoding RNA (ncRNA) genes are genes for which RNA, rather than protein, is the functional end product. The number and diversity of ncRNA genes is a subject of active research (1). In principle, the availability of many genome sequences makes it possible to search computationally for novel ncRNA genes. Computational protein gene finders search for ORFs that have certain statistical biases in their nucleotide composition (2-4). Unfortunately, ncRNA genes have neither ORFs nor (generally speaking) nucleotide composition biases, making ncRNA gene-finding a more formidable problem.Hyperthermophiles must stabilize double-stranded DNA and RNA against thermal denaturation (5). The simplest stabilization strategy is increased GC content. However, the GC content of hyperthermophile genomes does not correlate with optimal growth temperature (5-7). Hyperthermophiles use various other mechanisms to stabilize their DNA, including increased intracellular ionic concentrations, cationic proteins, and supercoiling (5, 7). Intramolecular RNA secondary structure, however, seems to be partially stabilized by increased hydrogen bonding, as the GC content of ribosomal RNA and transfer RNA genes in hyperthermophiles shows a strong correlation with optimal growth temperature (6). We reasoned that in an AT-rich extreme hyperthermophile, structural RNA genes (i.e., ncRNA genes with a high degree of secondary structure) might be found just by searching for regions of elevated GC content. Such a gene finder would not be able to be generalized. However, one might use novel ncRNAs identified in these unusual genomes to identify homologous RNAs in a variety of other genomes.Several recent reports describe computationally aided screens for ncRNA genes in Escherichia coli. Argaman et al. (8) searched for strong promoter and terminator signals appropriately spaced over intergenic regions. This approach obviously requires the genome sequence of an organism for which transcriptional regulation is well understood. Carter et al. (9) used a neural network to classify genomic sequences based on several features, including GC composition. Two other approaches used a comparative genomics...

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Section: Discussionsupporting

confidence: 67%

mentioning

confidence: 99%

Noncoding RNA genes identified in AT-rich hyperthermophiles

Klein

Misulovin

Eddy

2002

Proc. Natl. Acad. Sci. U.S.A.

160

157

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“…Major findings of this analysis are: (1) As many as 2481 pairs of sense-antisense transcript were identified; (2) there is a strong bias in the frequency of the mapping patterns of the sense-antisense transcript pairs (few only on the X chromosome); (3) , predicting noncoding antisense transcripts on the genome sequences by computer programs is almost impossible because virtually all the existing programs are designed to predict protein-coding regions (exons). Recently, trials to predict ncRNA were attempted using computational algorithms (Argaman et al 2001;Carter et al 2001;Rivas et al, 2001;Wassarman et al 2001), but these attempts were possible only for ncRNA that shares structural similarities. The antisense RNA is expected to function through sequence complementarity to the sense strand.…”

Section: Discussionmentioning

confidence: 99%

Antisense Transcripts With FANTOM2 Clone Set and Their Implications for Gene Regulation

Kiyosawa¹,

Yamanaka²,

Osato³

et al. 2003

Genome Res.

235

199

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We have used the FANTOM2 mouse cDNA set (60,770 clones), public mRNA data, and mouse genome sequence data to identify 2481 pairs of sense-antisense transcripts and 899 further pairs of nonantisense bidirectional transcription based upon genomic mapping. The analysis greatly expands the number of known examples of sense-antisense transcript and nonantisense bidirectional transcription pairs in mammals. The FANTOM2 cDNA set appears to contain substantially large numbers of noncoding transcripts suitable for antisense transcript analysis. The average proportion of loci encoding sense-antisense transcript and nonantisense bidirectional transcription pairs on autosomes was 15.1 and 5.4%, respectively. Those on the X chromosome were 6.3 and 4.2%, respectively. Sense-antisense transcript pairs, rather than nonantisense bidirectional transcription pairs, may be less prevalent on the X chromosome, possibly due to X chromosome inactivation. Sense and antisense transcripts tended to be isolated from the same libraries, where nonantisense bidirectional transcription pairs were not apparently coregulated. The existence of large numbers of natural antisense transcripts implies that the regulation of gene expression by antisense transcripts is more common that previously recognized. The viewer showing mapping patterns of sense-antisense transcript pairs and nonantisense bidirectional transcription pairs on the genome and other related statistical data is available on our Web site.

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“…Most identified CNSs have no experimentally defined function (16). There are now several web-based tools that can be used to identify CNSs (17,18) and functional RNAs (19). Very few examples of CNSs have been reported in plants (20,21).…”

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confidence: 99%

Utility and distribution of conserved noncoding sequences in the grasses

Kaplinsky

Braun

Penterman

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

108

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Control of gene expression requires cis-acting regulatory DNA sequences. Historically these sequences have been difficult to identify. Conserved noncoding sequences (CNSs) have recently been identified in mammalian genes through cross-species genomic DNA comparisons, and some have been shown to be regulatory sequences. Using sequence alignment algorithms, we compared genomic noncoding DNA sequences of the liguleless1 (lg1) genes in two grasses, maize and rice, and found several CNSs in lg1. These CNSs are present in multiple grass species that represent phylogenetically disparate lineages. Six other maize͞rice genes were compared and five contained CNSs. Based on nucleotide substitution rates, these CNSs exist because they have biological functions. Our analysis suggests that grass CNSs are smaller and far less frequent than those identified in mammalian genes and that mammalian gene regulation may be more complex than that of grasses. CNSs make excellent pan-grass PCR-based genetic mapping tools. They should be useful as characters in phylogenetic studies and as monitors of gene regulatory complexity.

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A computational approach to identify genes for functional RNAs in genomic sequences

Cited by 166 publications

References 46 publications

Noncoding RNA genes identified in AT-rich hyperthermophiles

Noncoding RNA genes identified in AT-rich hyperthermophiles

Antisense Transcripts With FANTOM2 Clone Set and Their Implications for Gene Regulation

Utility and distribution of conserved noncoding sequences in the grasses

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