Genomic Data Analysis Using DNA Structure:  An Analysis of Conserved Nongenic Sequences and Ultraconserved Elements

Gardiner, Eleanor J.; Hirons, Linda; Hunter, Christopher A.; Willett, Peter

doi:10.1021/ci050384i

Cited by 8 publications

(8 citation statements)

References 21 publications

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“…Although transcribed ucRNAs were described several years ago, and sequence conservation across species is highly suggestive of functional roles, elucidation of the potential physiological roles of these ncRNAs has remained elusive. Much of the attention in the field has focused on the evolutionary significance (38,39). Recent Northern blotting analysis for TUC338 and PCBP2 was performed as described in Materials and Methods.…”

Section: Discussionmentioning

confidence: 99%

Expression and functional role of a transcribed noncoding RNA with an ultraconserved element in hepatocellular carcinoma

Braconi¹,

Valeri²,

Kogure³

et al. 2010

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

201

164

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Although expression of non-protein-coding RNA (ncRNA) can be altered in human cancers, their functional relevance is unknown. Ultraconserved regions are noncoding genomic segments that are 100% conserved across humans, mice, and rats. Conservation of gene sequences across species may indicate an essential functional role, and therefore we evaluated the expression of ultraconserved RNAs (ucRNA) in hepatocellular cancer (HCC). The global expression of ucRNAs was analyzed with a custom microarray. Expression was verified in cell lines by real-time PCR or in tissues by in situ hybridization using tissue microarrays. Cellular ucRNA expression was modulated with siRNAs, and the effects on global gene expression and growth of human and murine HCC cells were evaluated. Fifty-six ucRNAs were aberrantly expressed in HepG2 cells compared with nonmalignant hepatocytes. Among these ucRNAs, the greatest change was noted for ultraconserved element 338 (uc.338), which was dramatically increased in human HCC compared with noncancerous adjacent tissues. Although uc.338 is partially located within the poly(rC) binding protein 2 (PCBP2) gene, the transcribed ncRNA encoding uc.338 is expressed independently of PCBP2 and was cloned as a 590-bp RNA gene, termed TUC338. Functional gene annotation analysis indicated predominant effects on genes involved in cell growth. These effects were experimentally demonstrated in both human and murine cells. siRNA to TUC338 decreased both anchorage-dependent and anchorage-independent growth of HCC cells. These studies identify a critical role for TUC338 in regulation of transformed cell growth and of transcribed ultraconserved ncRNA as a unique class of genes involved in the pathobiology of HCC.liver cancer | hepatocarcinoma | exaptation | transposon

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Section: Discussionmentioning

confidence: 99%

Expression and functional role of a transcribed noncoding RNA with an ultraconserved element in hepatocellular carcinoma

Braconi¹,

Valeri²,

Kogure³

et al. 2010

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

201

164

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“…asked whether there may be structural features that distinguish them as discrete entities, distinct from flanking chromosomal regions (e.g., see Gardiner et al 2006). For example, because any chromosomal region in an individual is, barring structural changes, on average $99.9% identical to its homolog (International Hapmap Consortium 2005), a mechanism involving copy counting via comparison would likely have to distinguish a UCE from its flanking regions so that the comparison of the maternal and paternal copies is confined to the UCE.…”

Section: à4mentioning

confidence: 99%

Ultraconserved Elements: Analyses of Dosage Sensitivity, Motifs and Boundaries

et al. 2008

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Ultraconserved elements (UCEs) are sequences that are identical between reference genomes of distantly related species. As they are under negative selection and enriched near or in specific classes of genes, one explanation for their ultraconservation may be their involvement in important functions. Indeed, many UCEs can drive tissue-specific gene expression. We have demonstrated that nonexonic UCEs are depleted among segmental duplications (SDs) and copy number variants (CNVs) and proposed that their ultraconservation may reflect a mechanism of copy counting via comparison. Here, we report that nonexonic UCEs are also depleted among 10 of 11 recent genomewide data sets of human CNVs, including 3 obtained with strategies permitting greater precision in determining the extents of CNVs. We further present observations suggesting that nonexonic UCEs per se may contribute to this depletion and that their apparent dosage sensitivity was in effect when they became fixed in the last common ancestor of mammals, birds, and reptiles, consistent with dosage sensitivity contributing to ultraconservation. Finally, in searching for the mechanism(s) underlying the function of nonexonic UCEs, we have found that they are enriched in TAATTA, which is also the recognition sequence for the homeodomain DNA-binding module, and bounded by a change in A 1 T frequency.

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“…, 2005; Olmo, 2005) differ greatly across amniotes. Other aspects of genome biology, such as the diversity and function of conserved noncoding elements, remain a mystery in the larger context of amniotes (Gardiner et al. , 2006).…”

Section: Introductionmentioning

confidence: 99%

Paleogenomic data suggest mammal‐like genome size in the ancestral amniote and derived large genome size in amphibians

Organ¹,

Canoville²,

Reisz³

et al. 2010

J of Evolutionary Biology

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An unsolved question in evolutionary genomics is whether amniote genomes have been expanding or contracting since the common ancestor of this diverse group. Here, we report on the polarity of amniote genome size evolution using genome size estimates for 14 extinct tetrapod genera from the Paleozoic and early Mesozoic Eras using osteocyte lacunae size as a correlate. We find substantial support for a phylogenetically controlled regression model relating genome size to osteocyte lacunae size (P of slopes < 0.01, r2 = 0.65, phylogenetic signal (λ) = 0.83). Genome size appears to have been homogeneous across Paleozoic crown‐tetrapod lineages (average haploid genome size 2.9–3.7 pg) with values similar to those of extant mammals. The differentiation in genome size and underlying architecture among extant tetrapod lineages likely evolved in the Mesozoic and Cenozoic Eras, with expansion in amphibians, contractions along the diapsid lineage, and no directional change within the synapsid lineage leading to mammals.

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Genomic Data Analysis Using DNA Structure: An Analysis of Conserved Nongenic Sequences and Ultraconserved Elements

Cited by 8 publications

References 21 publications

Expression and functional role of a transcribed noncoding RNA with an ultraconserved element in hepatocellular carcinoma

Expression and functional role of a transcribed noncoding RNA with an ultraconserved element in hepatocellular carcinoma

Ultraconserved Elements: Analyses of Dosage Sensitivity, Motifs and Boundaries

Paleogenomic data suggest mammal‐like genome size in the ancestral amniote and derived large genome size in amphibians

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