Sat, 26 Jul 2008 13:36:36 BST CiteULike: emptyhbs Shoukry http://www.citeulike.org/user/emptyhb/author/Shoukry CiteULike.org en-gb Copyright © 2004-2008 citeulike.org http://www.citeulike.org/user/emptyhb/article/698675 <i>Genome Res (12 June 2006)</i><br /><br />Cross-species DNA sequence comparison is the primary method used to identify functional noncoding elements in human and other large genomes. However, little is known about the relative merits of evolutionarily close and distant sequence comparisons. To address this problem, we identified evolutionarily conserved noncoding regions in primate, mammalian, and more distant comparisons using a uniform approach (Gumby) that facilitates unbiased assessment of the impact of evolutionary distance on predictive power. We benchmarked computational predictions against previously identified cis-regulatory elements at diverse genomic loci and also tested numerous extremely conserved human-rodent sequences for transcriptional enhancer activity using an in vivo enhancer assay in transgenic mice. Human regulatory elements were identified with acceptable sensitivity (53%-80%) and true-positive rate (27%-67%) by comparison with one to five other eutherian mammals or six other simian primates. More distant comparisons (marsupial, avian, amphibian, and fish) failed to identify many of the empirically defined functional noncoding elements. Our results highlight the practical utility of close sequence comparisons, and the loss of sensitivity entailed by more distant comparisons. We derived an intuitive relationship between ancient and recent noncoding sequence conservation from whole-genome comparative analysis that explains most of the observations from empirical benchmarking. Lastly, we determined that, in addition to strength of conservation, genomic location and/or density of surrounding conserved elements must also be considered in selecting candidate enhancers for in vivo testing at embryonic time points. Close sequence comparisons are sufficient to identify human cis-regulatory elements. Shyam Prabhakar Francis Poulin Malak Shoukry Veena Afzal Edward M Rubin Olivier Couronne Len A Pennacchio doi:10.1101/gr.4717506 Genome Res (12 June 2006) 2006-06-16T19:46:25-00:00 2006 Genome Res 1088-9051 cis_regulatory_elements cis_regulatory_evolution motif_searching http://www.citeulike.org/user/emptyhb/article/2211514 <i>Nat Genet (6 January 2008)</i><br /><br />Extended perfect human-rodent sequence identity of at least 200 base pairs (ultraconservation) is potentially indicative of evolutionary or functional uniqueness. We used a transgenic mouse assay to compare the embryonic enhancer activity of 231 noncoding ultraconserved human genome regions with that of 206 extremely conserved regions lacking ultraconservation. Developmental enhancers were equally prevalent in both populations, suggesting instead that ultraconservation identifies a small, functionally indistinct subset of similarly constrained cis-regulatory elements. Ultraconservation identifies a small subset of extremely constrained developmental enhancers. Axel Visel Shyam Prabhakar Jennifer A Akiyama Malak Shoukry Keith D Lewis Amy Holt Ingrid Plajzer-Frick Veena Afzal Edward M Rubin Len A Pennacchio doi:10.1038/ng.2007.55 Nat Genet (6 January 2008) 2008-01-09T17:38:56-00:00 2008 Nat Genet 1546-1718 cis_regulatory_elements