New Technique Searches ‘Dark Genome’ for Disease Mutations – Lab Manager Magazine

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New York, NY When doctors cant find a diagnosis for a patients disease, they turn to genetic detectives. Equipped with genomic sequencing technologies available for less than 10 years, these sleuths now routinely search through a patients DNA looking for mutations responsible for mysterious diseases.

Despite many successes, the search still comes back empty more often than not. In fact, disease-causing mutations are found in only about one in three to four patients suspected of having a strongly genetic condition.

A big reason why most investigations turn up empty-handed is the dark genome. Only two percent of the human genome is well understood by scientists. This small fraction contains the 20,000 genes that encode instructions for making the cells proteins. The remaining 98 percentthe dark genomeis largely a mystery. Although its known that the dark, non-coding genome regulates genesturning them on and off, for examplethe details remain obscure.

As a consequence, sequencing data from the entire genome is currently considered almost uninterpretable, saysDavid Goldstein, PhD, the John E. Borne Professor of Medical and Surgical Research and director of the Institute for Genomic Medicine at Columbia University Medical Center, and todays genetic detectives restrict their search for disease-causing mutations to the sliver of genome that contains protein-coding genes.

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To help locate pathogenic mutations in the vast non-coding genome, Dr. Goldstein and his colleagues Ayal Gussow and Andrew Allen have developed a new technique called Orion. Orion is designed to flag regions of the non-coding genome that are likely to contain disease-causing genetic changes by identifying parts of the genome that are under selection in the human population.

We anticipate that researchers will immediately start using Orion to help them find pathogenic mutations in patients in which previous sequencing efforts were negative, says Dr. Goldstein. Details about the method were published online Aug. 10 in PLoS One.

Orion was developed by comparing the entire genomes of 1,662 people and identifying stretches of DNA that vary little from person to person. Because these regions are intolerant to change, they are most likely doing something important, says Dr. Goldstein, lead author of the paper.

That means a mutation in an intolerant region is more likely to cause disease than a mutation in a tolerant (read: less important) region. This prediction was confirmed when the researchers mapped the locations of previously identified non-coding mutations: More mutations fell within Orions intolerant regions.

Previous methods to explore the non-coding genome focused on areas of the non-coding genome that have been retained in multiple species over evolutionary time, suggesting they, too, have an important function. However, this approach is not able to identify regions of the genome that have taken on important new functions in humans.

Orion isnt yet a finished product, Dr. Goldstein says. As more genomes are sequenced, the resolution of Orions regions will improve dramatically.

At that point, we are optimistic that Orion will constitute one helpful tool in the effort to identify variants throughout the genome that influence the risk of both rare and common diseases, says Dr. Goldstein.

Thestudyis titled Orion: Detecting Regions of the Human Non-Coding Genome that are Intolerant to Variation Using Population Genetics. Authors are Ayal Gussow (Duke University, Durham, NC, and Columbia University Medical Center, New York, NY), Brett Copeland (CUMC), Ryan Dhindsa (CUMC), Quanli Wang (CUMC), Slave Petrovski (CUMC and University of Melbourne, Victoria, Australia), William Majoros (Duke), Andrew Allen (Duke), and David Goldstein (CUMC).

The study was supported by the National Institutes of Health (1U01MH105670, 1UM1HG00901,F31NS092362,RC2NS070344;U01NS077303;U01NS053998,RC2MH089915,K01MH098126,R01MH097971,U01HG007672, andUM1AI100645); Biogen Inc.; SAIC Fredrick Inc.; the Joseph and Kathleen Bryan Alzheimers Disease Research Center; the Duke Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery; the Bill and Melinda Gates Foundation; the Ellison Medical Foundation; and the Murdock Study Community Registry and Biorepository.

David Goldstein is a founder of and holds equity in Pairnomix and Praxis and receives support from Janssen, Gilead, Biogen, AstraZeneca, and UCB. The authors declare no other conflicts of interest.

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New Technique Searches 'Dark Genome' for Disease Mutations - Lab Manager Magazine