Moore Foundation grantees at the Salk Institute have developed an algorithm that makes locating key regions within the genome more precise and accurate than other tools.
Led by senior author Joesph Ecker, a HHMI/Moore Foundation Plant Biology Investigator and director of Salk’s Genomic Analysis Laboratory, the method could help researchers conduct vastly more targeted searches for disease-causing genetic variants in the human genome, such as ones that promote cancer or cause metabolic disorders.
Only about two percent of our DNA is made up of genes, which code for proteins that keep us healthy and functional. For many years, the other 98 percent was thought to be extraneous "junk."
As science has developed ever more sophisticated tools to probe the genome, it has become clear that much of that so-called junk has vital regulatory roles.
For example, sections of DNA called "enhancers" dictate where and when the gene information is read out. Increasingly, mutations or disruption in enhancers have been tied to major causes of human disease, but enhancers have been hard to locate within the genome.
Ecker and his team created a new tool called REPTILE (regulatory-element prediction based on tissue-specific local epigenomic signatures), that recognizes enhancers in mammals by feeding into the algorithm both the locations of known enhancers as well as other genomic areas in the DNA.
In this study, published this week in the Proceedings of the National Academy of Sciences, the algorithm ran on nine mouse and five human cell lines and tissues whose enhancer regions were unknown and pinpointed the locations of potential enhancers.
The Salk team then used data from laboratory experiments to test whether the predictions made by REPTILE corresponded to real regulatory regions. They also tested REPTILE’s predictions against four other commonly used enhancer-finding algorithms.
Overall, REPTILE outperformed each one, finding enhancer regions with greater accuracy and fewer errors.
"The number of genetic variants in the genome is enormous," says Ecker. "So in terms of finding ones that cause disease, you really want to shine a spotlight on the regions you think are most important and identifying enhancers is a critical step in the process."
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