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Nature Conserves Its Most Vital DNA by Multitasking

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    In evolutionary biology, the most vital genomic elements necessary for survival are typically those that are held on most dearly throughout the history of life on Earth.

    In a study published in the advanced online edition of Molecular Biology and Evolution, Professor Claudio Alonso and colleagues at the University of Sussex (UK) investigated these treasured genomic keepsakes, called ultraconserved elements (UCEs), which have been found to span the tree of life, from plants to yeast to mice to humans. They used the trusted fruit fly model Drosophila melanogaster together with other species where they applied a variety of bioinformatics tools to get at the heart of this poorly understood phenomenon.

    The scientists explored this idea in a paper—“Combinatorial Gene Regulatory Functions Underlie Ultraconserved Elements (UCEs) in Drosophila”—that appeared May 31 in the journal Molecular Biology and Evolution. In this paper, the authors describe and define “ultraconserved” as 50-base-pair-long DNA elements found in the 12 fruit fly Drosophila species they studied. Most important, the authors show that UCEs are the “multitaskers” of the genome, involved in numerous biological processes simultaneously, and this multilayered function may be responsible for the extreme DNA sequence conservation observed.

    Overall, they identified more than 1500 UCEs in the fruit fly genome. These UCEs where found next to genes critical to animal development, suggesting that they act like hubs to allow genome access for an array of proteins. And similar to the real estate market, location is everything. They showed that the exact roles of UCEs vary depending on whether a UCE is found within a gene, between genes, or controlling a gene from a vast distance.

    “…gene regulatory roles of intronic and intergenic UCEs (iUCEs) are distinct from those found in exonic UCEs (eUCEs),” wrote the paper’s authors. “In iUCEs, transcription factor (TF) and epigenetic factor binding data strongly support iUCE roles in transcriptional and epigenetic regulation. In contrast, analyses of eUCEs indicate that they are two orders of magnitude more likely than expected to simultaneously include protein-coding sequence, TF binding sites, splice sites and RNA editing sites but have reduced roles in transcriptional or epigenetic regulation.”

    For one protein, called Cad, the scientists demonstrated dynamic binding with UCEs during development. This analysis showed that in young embryos, Cad binding was significantly enriched within a gene, whereas in adult flies there was a depletion of Cad binding. These results suggest that Drosophila UCEs might be implicated in the establishment and maintenance of genome packaging that is necessary for the precise control of gene expression throughout development.

    “…we use a Drosophila cell culture system and transgenic Drosophila embryos to validate the notion of UCE combinatorial regulatory roles using an eUCE within the Hox gene Ultrabithorax and show that its protein-coding region also contains alternative splicing regulatory information,” detailed the authors. “Taken together our experiments indicate that UCEs emerge as a result of combinatorial gene regulatory roles and highlight common features in mammalian and insect UCEs implying that similar processes might underlie ultraconservation in diverse animal taxa.”

    “As a molecular biologist these elements always intrigued me because no single known molecular mechanism can explain the retention of exact DNA sequences of this length for such long evolutionary periods,” concluded Claudio Alonso, a professor of developmental neurobiology at the University of Sussex. “Our computational work…strongly suggests that UCEs achieve their invariance due to their multitasking roles in several molecular mechanisms involved in gene control.”

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