Evolutionary Discrimination of Mammalian Conserved Non-Genic Sequences (CNGs)

Dermitzakis, Emmanouil T.; Reymond, Alexandre; Scamuffa, Nathalie; Ucla, Catherine; Kirkness, Ewen F.; Rossier, Colette; Antonarakis, Stylianos E.

doi:10.1126/science.1087047

Cited by 180 publications

(144 citation statements)

References 22 publications

(27 reference statements)

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“…The indications are, however, that we have much to learn about the complex functions of non-coding regions of the genome. 44 A striking feature of the organisation of the immune system is the relatively large number of molecules with classical and non-classical inhibitory signalling motifs, including CTLA-4 and PD-1, on the one hand, 45 and its active dependence on limited self-reactivity as a source of survival signals on the other (reviewed in Freitas and Rocha 46 ). The need to sustain overall responsiveness while constraining autoreactivity may favour a degree of redundancy among the large number of inhibitory molecules that allows the accumulation of alleles that only weakly compromise the functions of individual inhibitory proteins.…”

Section: Discussionmentioning

confidence: 99%

PDCD1: a tissue-specific susceptibility locus for inherited inflammatory disorders

et al. 2005

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Variation in genes encoding costimulatory molecules expressed on lymphocytes has been expected to contribute to the genetic component of inflammatory disease, but only the gene encoding the inhibitory protein, CTLA-4, seems consistently to confer disease susceptibility. Studies in murine models implicate the inhibitory product of the pd1 gene, programmed death-1, in the maintenance of peripheral tolerance to self-antigens. We identify 22 single-nucleotide polymorphisms (SNPs) in the equivalent human gene, PDCD1, a number of which show significant associations with the specific immunoglobulin E response to grass allergens in atopic individuals. Stepwise analyses indicate that four of the disease-associated SNPs have independent effects. The two most common haplotypes show positive and negative associations but rarer haplotypes are also likely to be of influence. In a case-control study, multiple regression analysis of genotypic data implies that PDCD1 also confers susceptibility to rheumatoid arthritis. Along with work linking PDCD1 with susceptibility to another autoimmune condition, systemic lupus erythematosus, our data identify PDCD1 as a second immunomodulatory gene with pleiotropic effects in human disease. Genes encoding negative regulators may generally confer a significant fraction of the genetic risk associated with inherited inflammatory disorders.

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Section: Discussionmentioning

confidence: 99%

PDCD1: a tissue-specific susceptibility locus for inherited inflammatory disorders

et al. 2005

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“…One very highly conserved SNP (rs7113868) was located in a nongenic region on chromosome 11. Furthermore, the high conservation across species may indicate a functional protein binding and regulatory region [52] important in cytotoxicity.…”

Section: Discussionmentioning

confidence: 99%

Susceptibility loci involved in cisplatin-induced cytotoxicity and apoptosis

Shukla

Duan²,

Badner³

et al. 2008

Pharmacogenetics and Genomics

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Objectives-Cisplatin is a widely used chemotherapeutic agent; however, nephrotoxicity and neuropathy are obstacles for drug efficacy. Little is known about the genes or genetic variants contributing to the risk of developing these toxicities or chemotherapeutic response. Thus, we have applied a cell-based model to identify and characterize previously unknown genes that may be involved in cellular susceptibility to cisplatin.Methods-Lymphoblastoid cell lines from 27 large Centre d'Etude du Polymorphisme Humain pedigrees were used to elucidate the genetic contribution to cisplatin-induced cytotoxicity. Phenotype was defined as cell growth inhibition following exposure of cell lines to increasing concentrations of cisplatin for 48 h.Results-Significant heritability, ranging from 0.32 to 0.43 (P < 10 −7 ), was found for the cytotoxic effects of each concentration (1, 2.5, 5, 10, and 20 μmol/l) and IC50, the concentration required for 50% cell growth inhibition. Linkage analysis revealed 11 genomic regions on six chromosomes with logarithm of odds (LOD) scores above 1.5 for cytotoxic phenotypes. The highest LOD score was found on chromosome 4q21.3−q35.2 (LOD = 2.65, P = 2.4 × 10 −4 ) for 5 μmol/l cisplatin. Quantitative transmission disequilibrium tests were performed using 191 973 nonredundant single nucleotide polymorphisms (SNPs) located in the 1 LOD confidence interval of these 11 regions. Twenty SNPs, with 10 SNPs located in five genes, were significantly associated with cisplatin-induced cytotoxicity (P ≤ 1 × 10 −4 ). Four of these 20 SNPs were found to explain over 10% of the variation in cisplatininduced apoptosis.Conclusions-Our results suggest that genetic factors involved in cytotoxicity also contribute to cisplatin-induced apoptosis. These cell lines provide a paradigm to identify previously unknown pharmacogenetic variants associated with drug cytotoxicity.

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“…Recently, high levels of sequence conservation of non-coding DNA regions have been reported 13,14 . Here we screen the complete collection of conserved non-coding DNA sequences from mammalian genomes and provide a first annotation of the complement of structurally conserved RNAs in the human genome.…”

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confidence: 99%

Mapping of conserved RNA secondary structures predicts thousands of functional noncoding RNAs in the human genome

et al. 2005

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In contrast to the fairly reliable and complete annotation of the protein coding genes in the human genome, comparable information is lacking for non-coding RNAs. We present a comparative screen of vertebrate genomes for structural non-coding RNAs, which evaluates sequence conservation, secondary structure conservation, and thermodynamic stability of putative RNA structures. We predict more than 30 000 structured RNA elements in the human genome, almost 1000 of which are conserved across all vertebrates. Roughly a third is found in introns of known genes, a sixth are potential regulatory elements in untranslated regions, about half are located far away of any known gene. Only a small fraction of these sequences has been described previously. EST data demonstrate, however, that the majority of them is at least transcribed. The widespread conservation of secondary structure points to a large number of functional ncRNAs in the human genome, which we estimate to be comparable to the number of protein-coding genes. The recent finishing of the human genome sequence emphasizes the "need for reliable experimental and computational methods for comprehensive identification of non-coding RNAs" 1 . A variety of experimental techniques have been used to uncover the human and mouse transcriptomes, in particular tiling arrays 2-4 , cDNA sequencing 5,6 , and unbiased mapping of transcription factor binding sites 7 . All these studies agree that a substantial fraction of the genome is transcribed and that a large fraction of the transcriptome consists of non-coding RNAs. It is unclear, however, which fraction are functional non-coding RNAs (ncRNAs), and which constitutes "transcriptional noise" 8 .Genome-wide computational surveys of ncRNAs, on the other hand, have been impossible until recently, because ncRNAs do not share common signals that could be detected at the sequence level. A large class of ncRNAs, however, has characteristic structures that are functional and hence are well conserved over evolutionary timescales: most of the "classical" ncRNAs, including rRNAs, tRNAs, snRNAs, snoRNAs, as well as the RNA components of RNAse P and the signal recognition particle, are of this type. The stabilizing selection acting on the secondary structure causes characteristic substitution patterns in the underlying sequences: Consistent and compensatory mutations replace one type of base-pair by another one in the paired regions (helices) of the molecule. In addition, loop regions are more variable than helices. These patterns can be ex-1 ploited in comparative computational approaches 9-12 to discriminate functional RNAs from other types of conserved sequence. Recently, high levels of sequence conservation of non-coding DNA regions have been reported 13, 14 . Here we screen the complete collection of conserved non-coding DNA sequences from mammalian genomes and provide a first annotation of the complement of structurally conserved RNAs in the human genome. ResultsSelection of conserved sequences and screening for structural RNAs We s...

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Evolutionary Discrimination of Mammalian Conserved Non-Genic Sequences (CNGs)

Cited by 180 publications

References 22 publications

PDCD1: a tissue-specific susceptibility locus for inherited inflammatory disorders

PDCD1: a tissue-specific susceptibility locus for inherited inflammatory disorders

Susceptibility loci involved in cisplatin-induced cytotoxicity and apoptosis

Mapping of conserved RNA secondary structures predicts thousands of functional noncoding RNAs in the human genome

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