Ultraconserved Elements: Analyses of Dosage Sensitivity, Motifs and Boundaries

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 1 T frequency.

Common genetic variation in Neuregulin 3 ( NRG3 ) influences risk for schizophrenia and impacts NRG3 expression in human brain

“…Computational biology (MatInspector software; Genomatix), reveals that rs10748842 is centrally located within a classic homeodomain binding module (TAATTA), a core binding sequence for a family of transcription factors (TFs) including Hox, LIM, POU, and PAX domains. Consistently, there is a high degree of species conservation at this SNP locus, coherent with the observation that TAATTA binding modules are recognized ultraconserved genomic elements (UCEs) (19). The alleles of rs10748842 are predicted to differentially bind TFs; specifically, the common allele (T) is predicted to be associated with positive binding potential for at least 10 homeodomain TFs, including Pax6, compared with the nonrisk minor allele, which has no predicted TF binding potential.…”

Ultraconserved Elements in the Human Genome: Association and Transmission Analyses of Highly Constrained Single-Nucleotide Polymorphisms

“…The lack of transmission bias ruled out an immediately and strongly deleterious effect due to the rare derived alleles, consistent with the observation that mice homozygous for the deletion of ultraconserved elements showed no overt phenotype. Our study also illustrated the importance of carefully modeling potential technical confounders when analyzing genotype data of rare variants.R EFERENCE genome alignments of multiple distantly related species have identified thousands of elements that are 98-100% identical (Bejerano et al 2004;Derti et al 2006;Chiang et al 2008;Stephen et al 2008). These ultraconserved or nearly ultraconserved elements are expected to harbor important biological functions as they are dosage sensitive (Derti et al 2006;Chiang et al 2008), are enriched in or near specific classes of genes (Bejerano et al…”

“…R EFERENCE genome alignments of multiple distantly related species have identified thousands of elements that are 98-100% identical (Bejerano et al 2004;Derti et al 2006;Chiang et al 2008;Stephen et al 2008). These ultraconserved or nearly ultraconserved elements are expected to harbor important biological functions as they are dosage sensitive (Derti et al 2006;Chiang et al 2008), are enriched in or near specific classes of genes (Bejerano et al…”

“…These ultraconserved or nearly ultraconserved elements are expected to harbor important biological functions as they are dosage sensitive (Derti et al 2006;Chiang et al 2008), are enriched in or near specific classes of genes (Bejerano et al…”

“…These ultraconserved or nearly ultraconserved elements are expected to harbor important biological functions as they are dosage sensitive (Derti et al 2006;Chiang et al 2008), are enriched in or near specific classes of genes (Bejerano et al 2004), and are under purifying selection (Drake et al 2006;Chen et al 2007;Katzman et al 2007;Sakuraba et al 2008). Indeed, a number of reports have demonstrated the ability of intergenic and intronic highly conserved elements to direct tissue-specific expression (Woolfe et al 2005;McEwen et al 2006;Pennacchio et al 2006;Ahituv et al 2007;Paparidis et al 2007;Visel et al 2008).…”