Where mutations are not tolerated: a good summary of an outstanding study
/Big datasets pinpoint new regions to explore the genome for disease
A dataset of more than 100,000 individuals allows researchers to identify genetic regions that are intolerant to change and may underlie developmental disorders.
Imagine rain falling on a square of sidewalk. While the raindrops appear to land randomly, over time a patch of sidewalk somehow remains dry. The emerging pattern suggests something special about this region. This analogy is akin to a new method devised by researchers at University of Utah Health. They explored more than 100,000 healthy humans to identify regions of our genes that are intolerant to change. They believe that DNA mutations in these "constrained" regions may cause severe pediatric diseases.
"Instead of focusing on where DNA changes are, we looked for parts of genes where DNA changes are not," said Aaron Quinlan, Ph.D., associate professor of Human Genetics and Biomedical Informatics at U of U Health and associate director of the USTAR Center for Genetic Discovery. "Our model searches for exceptions to the rule of dense genetic variation in this massive dataset to reveal constrained regions of genes that are devoid of variation. We believe these regions may be lethal or cause extreme phenotypes of disease when mutated."
While this approach is conceptually simple, only recently has there been enough human genomes available to make it happen. These new, invariable stretches may reveal new disease-causing genes and can be used to help pinpoint the cause of disease in patients with developmental disorders. The results of this study are available online in the December 10 issue of the journal Nature Genetics.
