Ultraconserved Elements: Analyses of Dosage Sensitivity, Motifs and Boundaries

By Chiang, Charleston W. K.; Derti, Adnan et al. | Genetics, December 2008 | Go to article overview

Ultraconserved Elements: Analyses of Dosage Sensitivity, Motifs and Boundaries


Chiang, Charleston W. K., Derti, Adnan, Schwartz, Daniel, Chou, Michael F., Hirschhorn, Joel N., Wu, C-ting, Genetics


ABSTRACT

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 + T frequency.

ALIGNMENTS of reference genomes representing distantly related species have identified thousands of ultraconserved elements (UCEs) that are 100% identical (Bejerano et al. 2004; Derti et al. 2006; Stephen et al. 2008), of which many are ≥200 bp in length. These UCEs, which can be intergenic, intronic, or exonic, are under negative selection (Drake et al. 2006; Chen et al. 2007; Katzman et al. 2007) and enriched in or near specific classes of genes (Bejerano et al. 2004). They are therefore likely to encode important functions, including the regulation of gene expression (Pennacchio et al. 2006; Paparidis et al. 2007; Visel et al. 2008). A number of laboratories have indeed demonstrated the ability of nonexonic (intergenic and intronic) UCEs to direct tissue-specific expression, and thus their capacity to act as enhancers (Pennacchio et al. 2006; Ahituv et al. 2007; Paparidis et al. 2007; Visel et al. 2008). What remains puzzling is the ultraconservation of these UCEs, since enhancers appear to be quite tolerant of sequence changes (Ludwig et al. 2005; Fisher et al. 2006; Li et al. 2008;McGaughey et al. 2008; Rastegar et al. 2008). The ultraconservation of nonexonic UCEs may therefore reflect a multiplicity of constraints, such as dual regulatory roles at the DNA and RNA levels (Feng et al. 2006) or a superimposition of binding sites formultiple transcription factors [Bejerano et al. 2004; Boffelli et al. 2004; De La Calle-Mustienes et al. 2005; Siepel et al. 2005; Derti et al. 2006; Pennacchio et al. 2006; Vavouri et al. 2007; also see related arguments for exonic UCEs (Derti et al. 2006)]. The latter explanation is consistent with the putative enhancer-like activity of nonexonic UCEs as well as other highly conserved noncoding elements (CNEs) (Woolfe et al. 2005; McEwen et al. 2006; Pennacchio et al. 2006; Ahituv et al. 2007; Paparidis et al. 2007; Visel et al. 2008) and has also been hypothesized for invertebrate highly conserved elements (Siepel et al. 2005; Vavouri et al. 2007). In support of these proposals, multiple transcription factor binding sites have been observed in an intronic UCE at the GLI3 locus (Paparidis et al. 2007). However, an explanation involving overlapping binding sites for transcription factors would likely require a large number of such sites to maintain ultraconservation at all or most positions within a UCE. Alternatively, in conjunction with their enhancer activities, nonexonic UCEs may embody a separate function that constrains them at the sequence level.

Our earlier study asked whether the ultraconservation of UCEs might reflect an evolutionary constraint in addition to enhancer and/or other functions. …

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