Friday, September 07, 2007

Are highly conserved sequences what we think they are?

By the way, the elements they deleted are noncoding sequences, but likely play a role in gene regulation, but from Liza's Gross summary:

Mutations in genes near each of the other ultraconserved elements revealed a range of similarly lethal or severe abnormalities, ranging from neurological and sexual disorders to defective eye and kidney development. But in no case did the researchers find comparable aberrations in mice lacking the adjacent ultraconserved elements.

These results challenge the prevailing notion that highly conserved elements necessarily encode essential functions. Still, the researchers acknowledge that their experimental setup could have missed phenotypic changes that may have emerged under other conditions (in the wild, for example, or over multiple generations). Since all the ultraconserved elements were chosen based on their ability to promote transcription in lab tests—ensuring that the elements were capable of function—it's possible that deleting them produced no obvious effects because other elements stepped in to perform their job. Future studies can explore these possibilities and continue to probe the mechanisms that gave rise to such extreme evolutionary conservation. But for researchers relying on sequence constraint to shed light on the function of billions of noncoding base pairs in the human genome, the question remains: Why would evolution preserve these noncoding elements if their loss has no significant effect on the viability, fertility, and function of the organism?

Deletion of Ultraconserved Elements Yields Viable Mice

Nadav Ahituv, Yiwen Zhu, Axel Visel, Amy Holt, Veena Afzal, Len A. Pennacchio, Edward M. Rubin

PLoS Biol 5(9): e234
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.

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