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Some genetic research is best done close to the evolutionary home

ther a gene is switched on or off -- but until now, the relative merits of comparing species as diverse as humans and fish were not known.

"To address this problem, we identified evolutionarily conserved non-coding regions in primate, mammalian and more distant species using a uniform approach that facilitates an unbiased assessment of the impact of evolutionary distance on predictive power," said Pennacchio. "We benchmarked computational predictions against previously identified regulatory elements at diverse genomic loci, and also tested numerous extremely conserved sequences in humans and rodents for enhancer activity."

The computational algorithm, which is used to provide a uniform evaluation of the benefits and limitations of DNA sequence comparisons between close versus distant species, was developed by Prabhakar. He dubbed this program "Gumby," after a mathematical concept called the Gumbel distribution. Prabhakar's Gumby program has now been incorporated into VISTA, the comprehensive suite of programs and databases for comparative analysis of genomic sequences that was developed and is maintained at Berkeley Lab.

Using the Gumby program, Prabhakar, Pennacchio and their colleagues were able to identify human regulatory DNA sequences with a sensitivity that ranged from 53 to 80 percent, and a true-positive rate that ran as high as 67 percent based on comparisons with primates and other eutherian (placental) mammals. By contrast, comparisons with more distant species, including marsupial, avian, amphibian and fish, failed to identify most of the empirically defined functional non-coding DNA sequences.

Said Prabhakar, "Our results highlight the practical utility of close sequence comparisons, and the loss of sensitivity entailed by more distant comparisons. The intuitive relationship we derived between ancient and recent non-coding sequence conservation from whole-genome comparative analysis explains most of the observations fro
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Contact: Lynn Yarris
lcyarris@lbl.gov
510-486-5375
DOE/Lawrence Berkeley National Laboratory
12-Jun-2006


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