Deletion of Ultraconserved Elements Yields Viable Mice

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Abstract
Ultraconserved elements have been suggested to retain extended perfect sequence identity between the human, mouse, and rat genomes due to essential functional properties. To investigate the necessities of these elements in vivo, we removed four noncoding ultraconserved elements (ranging in length from 222 to 731 base pairs) from the mouse genome. To maximize the likelihood of observing a phenotype, we chose to delete elements that function as enhancers in a mouse transgenic assay and that are near genes that exhibit marked phenotypes both when completely inactivated in the mouse and when their expression is altered due to other genomic modifications. Remarkably, all four resulting lines of mice lacking these ultraconserved elements were viable and fertile, and failed to reveal any critical abnormalities when assayed for a variety of phenotypes including growth, longevity, pathology, and metabolism. In addition, more targeted screens, informed by the abnormalities observed in mice in which genes in proximity to the investigated elements had been altered, also failed to reveal notable abnormalities. These results, while not inclusive of all the possible phenotypic impact of the deleted sequences, indicate that extreme sequence constraint does not necessarily reflect crucial functions required for viability. It is widely believed that the most evolutionarily conserved DNA sequences in the human genome have been preserved because of their functional importance and that their removal would thus have a devastating effect on the organism. To ascertain this we removed from the mouse genome four ultraconserved elements—sequences of 200 base pairs or longer that are 100% identical among human, mouse, and rat. To our surprise, we found that the mice lacking these elements are viable, fertile, and show no apparent abnormalities. This completely unexpected finding indicates that extreme levels of DNA sequence conservation are not necessarily indicative of an indispensable functional nature.