University of Texas MD Anderson Cancer Center in Houston researchers have developed a new diagnostic tool, in collaboration with scientists from the University of Utah (U of U), to quickly and more precisely identify disease-causing mutations in families.
The tool, known as the “pedigree Variant Annotation, Analysis and Search Tool” (pVAAST), combines linkage examination with case control association. A study about the tool’s features and efficacy was recently published in Nature Biotechnology.
“Linkage analysis and case control association traditionally have been used to find gene mutations,” said Chad Huff, Ph.D., a corresponding author on the study, an assistant professor of epidemiology at the MD Anderson Cancer Center, and a 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 tool works by searching DNA sequenced genomes in a family in order to locate shared mutations and identify the gene with the highest probability of causing a disease. There are already other gene-finding tools, but this is the first one that recognizes family relationships. Another innovation is the ability to simultaneously search multiple families with the same disease for mutations, which can reduce time and effort spent on the analysis of a common disease-causing variant.
“The issue with whole genome sequences has been that sequencing one person’s genome to find a single disease-causing gene is difficult,” stress the researchers, adding that “if you can sequence the whole family it gives a fuller picture of the sequence and variations potentially involved in disease.”
The human body contains two healthy copies of each gene, which can suffer mutations and consequently lead to disease. Gene mutations are random and rare, but once they occur, the mutations are likely to be passed down to other subsequent generations.
“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,” said Huff.
Dr. Huff’s team had previously created a gene-finding tool, called Phenotype Driven Variant Ontological Re-ranking tool (Phevor), which improved the results of individual and small family sequencing. Phevor works by combining the probabilities of mutations involved with a disease with databases of phenotypes and information on gene functions.
The combinations of both instruments may increase the precision and magnitude of the results, compared to other tools, researchers believe.