Scientists at the University of Utah (U of U), the University of Texas MD Anderson Cancer Center in Houston and colleagues have developed a powerful tool called pVAAST that combines linkage analysis with case control association to help researchers and clinicians identify disease-causing mutations in families faster and more precisely than ever before.
In a study in Nature Biotechnology, the researchersdescribe cases in which pVAAST (the pedigree Variant Annotation, Analysis and Search Tool) identified mutations in two families with separate diseases and a de novo or new variation in a 12-year-old who was the only one in his family to suffer from a mysterious and life threatening intestinal problem.
Mark Yandell, Ph.D.
“Linkage analysis and case control association traditionally have been used to find gene mutations,” says Chad Huff, Ph.D., corresponding author on the study, assistant professor of epidemiology at the MD Anderson Cancer Center and former postdoctoral fellow in human genetics at the U of U. “Bringing those methods together provides a strong increase in the power to find gene variations that cause disease.”
The advent of genome sequencing has allowed researchers to search for disease-causing mutations in the genomes of individual patients, larger groups of unrelated people or small and large families. The researchers in this study believe the most powerful way to identify these variants is by sequencing the genomes of families that experience unusually high occurrences of a particular illness. By identifying gene variations that family members share, it’s possible to identify mutations in a gene that causes the disease, according to Mark Yandell, Ph.D., U of U professor of human genetics and a senior author on the paper.
“The issue with whole genome sequences has been that sequencing one person’s genome to find a single disease-causing gene is difficult,” Yandell says. “If you can sequence the whole family it gives a fuller picture of the sequence and variations potentially involved in disease.”
Humans carry two healthy copies of each gene in the body. But mutations in a gene can cause disease or other health problems. These mutations occur randomly and rarely, but once they happen in a family member, they are often passed down to subsequent generations.
pVAAST was designed to search the sequenced genomes of families to find shared mutations and thus identify the gene with the highest probability of causing disease. Unlike other gene-finding tools, pVAAST accounts for people being related as it searches for gene variations that have the highest probabilities of causing disease. A big advantage of pVAAST, according to Huff and Yandell, is its ability to simultaneously search multiple families with the same disease to find mutations; this reduces the amount of time and effort to find a disease-causing variant. For example, if three families have the same disease, two might have different mutations damaging the same gene, while the third family might have a different damaged gene. “pVAAST has the power to determine the true disease-causing mutations across all those families in one analysis,” Yandell says.
In related work, Yandell, Huff, and their colleagues vastly improved the results of individual and small family sequencing by developing another gene-finding tool, Phevor (Phenotype Driven Variant Ontological Re-ranking tool), which combines the probabilities of mutations being involved with a disease with databases of phenotypes and information on gene functions. In doing this Phevor and pVAAST in combination can identify disease genes with much greater precision than other tools.
Sequencing genomes of unrelated patients with the same disease also increases the ability to find gene variations, and a third software tool Yandell and colleagues developed, VAAST (Variant Annotation, Analysis and Search Tool), has greatly advanced the speed and precision of doing that.
If VAAST or pVAAST can’t identify the mutation most likely to cause a disease, Phevor can take the results from those tools and combine them with a description of the patients’ disease called a ‘phenotype’ to find the most likely causative gene.
“We hope that in developing pVAAST, we and other researchers can more rapidly identify genetic variations influencing disease risk by increasing the statistical power of familial genome sequencing,” Huff says.
This study is a collaboration of several institutions in the United States and one in Europe. Lynn B. Jorde, Ph.D., U of U professor and chair of human genetics and Martin Reese, Ph.D., CEO of Oakland, Calif.-based Omicia Inc., are senior authors. Leroy Hood, M.D., Ph.D., of the Institute for Systems Biology in Seattle, is a co-author as is Stephen L. Guthery, M.D., U of U professor of pediatrics who referred a patient and his family for the study, and Hilary Coon, Ph.D., research professor of psychiatry at the University of Utah School of Medicine.
Office of Public Affairs
Phone: (801) 581-2517
Phil Sahm | Eurek Alert!
Great apes communicate cooperatively
25.05.2016 | Max-Planck-Institut für Ornithologie
Rice study decodes genetic circuitry for bacterial spore formation
24.05.2016 | Rice University
Permanent magnets are very important for technologies of the future like electromobility and renewable energy, and rare earth elements (REE) are necessary for their manufacture. The Fraunhofer Institute for Mechanics of Materials IWM in Freiburg, Germany, has now succeeded in identifying promising approaches and materials for new permanent magnets through use of an in-house simulation process based on high-throughput screening (HTS). The team was able to improve magnetic properties this way and at the same time replaced REE with elements that are less expensive and readily available. The results were published in the online technical journal “Scientific Reports”.
The starting point for IWM researchers Wolfgang Körner, Georg Krugel, and Christian Elsässer was a neodymium-iron-nitrogen compound based on a type of...
In the Beyond EUV project, the Fraunhofer Institutes for Laser Technology ILT in Aachen and for Applied Optics and Precision Engineering IOF in Jena are developing key technologies for the manufacture of a new generation of microchips using EUV radiation at a wavelength of 6.7 nm. The resulting structures are barely thicker than single atoms, and they make it possible to produce extremely integrated circuits for such items as wearables or mind-controlled prosthetic limbs.
In 1965 Gordon Moore formulated the law that came to be named after him, which states that the complexity of integrated circuits doubles every one to two...
Characterization of high-quality material reveals important details relevant to next generation nanoelectronic devices
Quantum mechanics is the field of physics governing the behavior of things on atomic scales, where things work very differently from our everyday world.
When current comes in discrete packages: Viennese scientists unravel the quantum properties of the carbon material graphene
In 2010 the Nobel Prize in physics was awarded for the discovery of the exceptional material graphene, which consists of a single layer of carbon atoms...
The trend-forward world of display technology relies on innovative materials and novel approaches to steadily advance the visual experience, for example through higher pixel densities, better contrast, larger formats or user-friendler design. Fraunhofer ISC’s newly developed materials for optics and electronics now broaden the application potential of next generation displays. Learn about lower cost-effective wet-chemical printing procedures and the new materials at the Fraunhofer ISC booth # 1021 in North Hall D during the SID International Symposium on Information Display held from 22 to 27 May 2016 at San Francisco’s Moscone Center.
24.05.2016 | Event News
20.05.2016 | Event News
19.05.2016 | Event News
25.05.2016 | Trade Fair News
25.05.2016 | Life Sciences
25.05.2016 | Power and Electrical Engineering