New Computational Tool Rapidly Identifies Disease-causing Gene Variations

New Computational Tool Rapidly Identifies Disease-causing Gene Variations

Jun 23, 2011 4:32 PM

SALT LAKE CITY—New software developed by scientists from the University of Utah and Omicia, Inc., will greatly facilitate the ability to find the causes of disease by rapidly identifying gene variations.

In an article published Thursday, June 23, 2011, in Genome Research, the U and Omicia describe VAAST – the Variant Annotation, Analysis and Selection Tool – an algorithm that finds disease-causing gene variations much faster than has been available until now. VAAST is the product of collaboration between Mark Yandell, Ph.D., associate professor of human genetics at the University of Utah School of Medicine, and colleagues, and the Omicia scientific team under the leadership of Martin Reese, Ph.D., the company’s CEO and chief scientific officer.

The dramatic decline in DNA sequencing costs is making personal genome sequencing a reality. Already, significant progress has been made in applying whole genome sequencing to cancer prognosis and early childhood disease. Examples include the 2010 publications on Miller Syndrome in Nature Genetics and Science, and similar studies aimed at identifying the unknown genetic defects responsible for certain early childhood diseases.

However, a bottleneck in interpreting data has limited the utility of personal genome information for medical diagnosis and preventive care. VAAST is designed to address this bottleneck.

“The big challenge in genomic medicine today is how to sift through the millions of variants in a personal genome sequence to identify the disease-relevant variations,” Reese said.  “It’s a classic ‘needle in a haystack’ problem, and VAAST goes a long way toward solving it. We look forward to integrating VAAST into the Omicia Genome Analysis System currently under development for clinical applications.”

VAAST solves many of the practical and theoretical problems that currently plague mutation hunts using personal genome sequences, according to Yandell. “Our results demonstrate that this tool substantially improves upon existing methods with regard to statistical power, flexibility, and scope of use,” he said. “Further, VAAST is automated, fast, works across all variant population frequencies, and is sequencing-platform independent.”

In Genome Research, Yandell and colleagues show that VAAST provides a highly accurate, statistically robust means to rapidly search personal genomes for genes with disease-causing mutations. The authors demonstrate that as few as three genomes from unrelated children, or those of the parents and their two children, are sufficient to identify disease-causing mutations.

In a separate paper published this week in the American Journal of Human Genetics, Gholson Lyon, M.D., Ph.D., previously at the University of Utah and now at the Children’s Hospital of Philadelphia, and colleagues report the use of VAAST as part of an international effort to identify the mutation responsible for a newly discovered childhood disease. This new illness, tentatively called Ogden Syndrome, is characterized by aged appearance, craniofacial abnormalities, cardiac arrhythmias, and other symptoms. The team used X-chromosome exon capture and next-generation sequencing and VAAST to quickly and unambiguously identify the disease-causing mutation in the NAA10 gene that has resulted in this fatal disease in children of two unrelated families.

“VAAST can identify disease-causing mutations with greater accuracy, using far fewer individuals and more rapidly than was previously possible,” Lyon said. “We are now applying VAAST to many other unknown conditions, including rare Mendelian disorders and other common disorders such as ADHD and autism.”

Commenting on the significance of this development, Eric J. Topol, M.D., director of the  Scripps Translational Science Institute and chief academic officer of Scripps Health, said,  “One of the most important and exciting opportunities in genomic medicine is the newfound ability to pinpoint the root cause of an unknown disease in an individual.  The VAAST tool will markedly facilitate this and represents a major advance in the field. It fulfills a significant unmet need of interpreting whole genome sequences and will have a remarkable impact on accurate genomic diagnosis of many individuals going forward.”

The development of VAAST was funded by the National Human Genome Research Institute through an American Recovery and Reinvestment Act Grand Opportunity (GO) grant. GO grants focus on transformative technologies and large, potentially high-impact projects. 

Omicia is a privately held Emeryville, Calif., company developing tools to interpret personal genome sequences.

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