A study performed in mice determined that deleting UCEs from the genome did not create obvious deleterious phenotypes, despite deletion of UCEs in proximity to promoters and protein coding genes. Affected mice were fertile and targeted screens of the nearby coding genes showed no altered phenotype. A separate mouse study demonstrated that ultra-conserved enhancers were robust to mutagenesis, concluding that perfect conservation of UCE sequences is not required for their function, which would suggest another reason for the sequence consistency besides evolutionary importance. Computational analysis of human ultra-conserved noncoding elements (UCNEs) found that the regions are enriched for A-T sequences and are generally GC poor. However, the UNCEs were found to be enriched for CpG, or highly methylated. This may indicate that there is some change to DNA structure in these regions favoring their precise retention, but this possibility has not been validated through testing. Function Often, ultra-conserved elements are located near transcriptional regulators or developmental genes performing functions such as gene enhancing and splicing regulation. A study comparing ultra-conserved elements between humans and the Japanese puffer fish Takifugu rubripes proposed an importance in vertebrate development. Double-knockouts of UCEs near the ARX gene in mice caused a shrunken hippocampus in the brain, though the effect was not lethal. Some UCEs are not transcribed, and are referred to as ultra-conserved noncoding elements. However, many UCRs in humans are extensively transcribed. A small number of those which are transcribed, known as transcribed UTRs (T-UTRs), have been connected with human carcinomas and leukemias. For example, TUC338 is strongly upregulated in human hepatocellular carcinoma cells. Indeed, UCEs are often affected by copy number variation in cancer cells much more than in healthy contexts, suggesting that altering the copy number of T-UCEs may be deleterious. Role in Human Disease Research has demonstrated that T-UCRs have a tissue-specific expression, and a differential expression profile between tumors and other diseases. The tables below highlight transcripts and polymorphisms within UCRs that have been shown to contribute to human diseases. For example, UCRs tend to accumulate less mutations than flanking segments, in both neoplastic and non-neoplastic samples from persons with hereditary non-polyposis colorectal cancer. Regulation Mechanisms of Disease Related Ultra-conserved Element Transcripts Phenotype-Associated Polymorphisms within Ultra-conserved Elements See also Human accelerated regions Synteny References DNA