Utah's Role in Developing Technology to Unmask Causes of Genetic Disease

Mark Yandell, PhD professor in Human Genetics at the University of Utah Health, has spent the better part of almost two decades developing new technologies to mine the genome to diagnose genetic disease.

In his recent talk From Bench to the Bedside and Onward to the Market: Commercializing Academic Software, he detailed the many incremental steps he followed to develop two important technologies - the VAAST and PHEVOR - that played an integral role in launching the Utah Genome Project.

Let’s take a moment and roll the clock back to the early 2000s. At that time, geneticists were limited to mining the genome using SNP chips, a small representative set of variants, with the idea that genes responsible for disease were found in similar location on the genome as those in the chip, but this approach missed a lot of information. “Many variants were invisible to the chip-based studies and were lost in the noise,” said Yandell.

Yandell and his team saw the shortcoming of this approach as an opportunity and developed a tool they named VAAST (Variant Annotation, Analysis and Search Tool). This search tool uses probability to identify damaged genes and their disease-causing variants with greater accuracy to explain the burden of disease.  “VAAST is a personalized BLAST search for your own genome sequence,” said Yandell.

PHEVOR was the logical next step following the development of VAAST. PHEVOR (Phenotype Driven Variant Ontological Re-ranking tool) uses algorithms that combine the probabilities of gene mutations of a disease with databases of the outwardly expressed phenotypes and gene functions. “PHEVOR compliments VAAST by applying patient phenotype with VAAST output for improved power,” explains Yandell.

These technologies powered the development of the Utah Genome Project. This large-scale genome sequencing and analysis initiative aims to uncover the molecular basis of human disease. VAAST and PHEVOR enable the rapid, comprehensive searches for genetic variants underlying many common and rare diseases. Once a disease variant is identified, researchers can look for ways to prevent, treat, and diagnose these conditions.

These tools also offer researchers the opportunity to conduct a deep dive on the genome without searching for disease. In 2013, Yandell’s colleagues at the U of U Health used these tools to identify the gene that produced the ruffed crest found on Darwin’s favorite species of pigeon - the rock pigeon. The team was able to sequence the same pigeon species from Darwin’s writings and identified the trait responsible for the crest, which originated early and only once in pigeon evolution, quickly spread through the species.

These accomplishments would not have been possible without careful planning as new technologies are commercialized. Yandell emphasized the importance of Federal funding and scientific publications, especially during the early stages of technology development, to validate the scientific application of the technology to increase success at wooing future venture capital investment.

Ultimately, it will be these and future technologies that will empower researchers to find new approaches to tackle disease. “I've been shocked by how much we have seen medical applications of genomics begin to be realized on a timeframe that I simply would not have predicted when I got involved in this field initially,” said Eric Green, director of the National Human Genome Research Institute. “I'm even more excited about the next generation of biomedical researchers and healthcare professionals who I think are going to be the ones that are going to truly realize genomic medicine.”

About the Author:

Stacy W. Kish