西亚试剂：Deletion of Ultraconserved Elements Yields Viable Mice

Deletion of Ultraconserved Elements Yields Viable Mice

Nadav Ahituv1,2¤, Yiwen Zhu1, Axel Visel1, Amy Holt1, Veena Afzal1, Len A. Pennacchio1,2, Edward M. Rubin1,2*

1 Genomics Division, Lawrence Berkeley National Laboratory, Berkeley, California, United States of America, 2 United States Department of Energy Joint Genome Institute, Walnut Creek, California, United States of America

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.

Received: May 15, 2007; Accepted: July 3, 2007; Published: September 4, 2007

 Figure 1.Schematic of the Human Genomic Locations of the Four Ultraconserved Elements That Were Deleted

(A) uc248 region; (B) uc329 region; (C) uc467 region; (D) uc482 region. A black oval represents each ultraconserved element, while the embryos above the schematics represent observed positive enhancer activities captured through transgenic mouse testing at e11.5 for that element [6]. Stained embryos in boxes represent whole-mount in situ hybridizations of the specific gene at e11.5 (genes without stained embryos were negative for this assay at this time point). Exons and noncoding elements not shown to scale.

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