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Exploration for functional nucleotide sequence candidates within coding regions of mammalian genes.

ABSTRACT: The primary role of a protein coding gene is to encode amino acids. Therefore, synonymous sites of codons, which do not change the encoded amino acid, are regarded as evolving neutrally. However, if a certain region of a protein coding gene contains a functional nucleotide element (e.g. splicing signals), synonymous sites in the region may have selective pressure. The existence of such elements would be detected by searching regions of low nucleotide substitution. We explored invariant nucleotide sequences in 10,790 orthologous genes of six mammalian species (Homo sapiens, Macaca mulatta, Mus musculus, Rattus norvegicus, Bos taurus, and Canis familiaris), and extracted 4150 sequences whose conservation is significantly stronger than other regions of the gene and named them significantly conserved coding sequences (SCCSs). SCCSs are observed in 2273 genes. The genes are mainly involved with development, transcriptional regulation, and the neurons, and are expressed in the nervous system and the head and neck organs. No strong influence of conventional factors that affect synonymous substitution was observed in SCCSs. These results imply that SCCSs may have double function as nucleotide element and protein coding sequence and retained in the course of mammalian evolution.

SUBMITTER: Suzuki R

PROVIDER: S-EPMC3111233 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

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Exploration for functional nucleotide sequence candidates within coding regions of mammalian genes.

Suzuki Rumiko R Saitou Naruya N

DNA research : an international journal for rapid publication of reports on genes and genomes 20110517 3

The primary role of a protein coding gene is to encode amino acids. Therefore, synonymous sites of codons, which do not change the encoded amino acid, are regarded as evolving neutrally. However, if a certain region of a protein coding gene contains a functional nucleotide element (e.g. splicing signals), synonymous sites in the region may have selective pressure. The existence of such elements would be detected by searching regions of low nucleotide substitution. We explored invariant nucleotid ...[more]

PMID: 21586532

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Project description:Background: Long non-coding RNAs (lncRNAs), which are generally less functionally characterized or less annotated, evolve more rapidly than mRNAs and substantially possess fewer sequence conservation patterns than protein-coding genes across divergent species. People assume that the functional inference could be conducted on the evolutionarily conserved long non-coding RNAs as they are most likely to be functional. In the past decades, substantial progress has been made in discussions on the evolutionary conservation of non-coding genomic regions from multiple perspectives. However, understanding their conservation and the functions associated with sequence conservation in relation to further corresponding phenotypic variability or disorders still remains incomplete. Results: Accordingly, we determined a highly conserved region (HCR) to verify the sequence conservation among long non-coding RNAs and systematically profiled homologous long non-coding RNA clusters in humans and mice based on the detection of highly conserved regions. Moreover, according to homolog clustering, we explored the potential function inference via highly conserved regions on representative long non-coding RNAs. On lncRNA XACT, we investigated the potential functional competence between XACT and lncRNA XIST by recruiting miRNA-29a, regulating the downstream target genes. In addition, on lncRNA LINC00461, we examined the interaction relationship between LINC00461 and SND1. This interaction or association may be perturbed during the progression of glioma. In addition, we have constructed a website with user-friendly web interfaces for searching, analyzing, and downloading to present the homologous clusters of humans and mice. Conclusion: Collectively, homolog clustering via the highly conserved region definition and detection on long non-coding RNAs, as well as the functional explorations on representative sequences in our research, would provide new evidence for the potential function of long non-coding RNAs. Our results on the remarkable roles of long non-coding RNAs would presumably provide a new theoretical basis and candidate diagnostic indicators for tumors.

Project description:BackgroundThe mce operons play an important role in the entry of M. tuberculosis into macrophages and non-phagocytic cells. Their non-redundant function as well as complex regulation is implied by the phenotype of mce mutants. Recently, mce1 operon was found to extend over 13 genes, fadD5 (Rv0166) being the first gene of the operon. The presence of a non-coding sequence of 200 base pairs between Rv0166 and Rv0167 is peculiar to mce1 among the four mce operons of M.tuberculosis. We have examined the function of this region.ResultsWe predicted putative promoter activity of the 200 base pairs of non-coding, intergenic region between Rv0166 and Rv0167 in silico using MEME software and designate it as intergenic promoter, IGPr. We demonstrate both promoter activity and a putative negative regulatory function of this fragment by reporter assays carried out in the surrogate host M.smegmatis. We find that the repressive elements not only control the native promoter but also repress a heterologous promoter of M.smegmatis. The higher activity of the intergenic promoter in a clinical isolate in comparison with the wild type sequence from M.tuberculosis H37Rv could be correlated with a point mutation within the negative element. We have mapped two transcription start sites for mce1 operon both of which are utilized in M.tuberculosis H37Rv as well as the clinical isolate VPCI591. Our studies show that the promoter activity in the non-coding region is relevant not only in reporter gene expression but also in the expression of mce1 operon in M. tuberculosis cells grown in synthetic medium.ConclusionThe mce operon of M.tuberculosis H37Rv potentially can be transcribed from two promoters P1 and P2, former mapping upstream of Rv0166 and the latter in the non-coding intergenic region between Rv0166 and Rv0167. The transcription initiation from P1 results in a transcript with Rv0166 while that from P2 will be without it. The sequences between the translation start site of Rv0167 and the promoter P2 have a negative regulatory role, as point mutation within the sequence leads to enhanced activity of P2 as well as a heterologous promoter from M.smegmatis. The mutation detected in the clinical isolate VPCI591 therefore behaves like a gain-of-function mutation.

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Exploration for functional nucleotide sequence candidates within coding regions of mammalian genes.

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Exploration for functional nucleotide sequence candidates within coding regions of mammalian genes.

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