Grant: Project Grant

DNA sequencing has ushered in a "Golden Age" of disease discovery. The causes of many rare genetic diseases have been found, and the genetic contributions to common diseases are also being solved very quickly. However, digging through multiple human genomes has unearthed thousands of new DNA variants, and often it isn't obvious which ones are the disease-causing mutations that affect health, and which other ones have no health effects. Our lab focuses on rare mutations that cause human overgrowth. Overgrowth syndromes cause tall stature, large head size and medical problems such as obesity, cancer, autism and intellectual disability. Having discovered the overgrowth syndromes that are caused by rare mutations in the "PRC2" group of proteins, we're now trying to understand exactly which DNA variants in PRC2 cause overgrowth and which ones don't. We have also found that some PRC2 mutations cause other medical problems, such as muscle fatigue and even stunted growth (i.e. the opposite of overgrowth). In this project we seek to recruit people who have rare DNA variants in PRC2 members, so we can follow them over time and find out what medical problems they have (if any). Because the human PRC2 genes each have an analogous gene that does pretty much the same thing in fruit flies, we plan to engineer our human mutations into experimental fruit flies. In this way we can figure out which of our variants are true mutations that produce a non-working protein, and which variants produce a protein that works well enough to allow normal function. By taking advantage of the wealth of molecular techniques that exist for fruit flies, we can quickly find out which human variants are likely to be benign with no effects on health, and which human variants are likely to be disease-causing mutations. The data from our study will help diagnostic labs sort out the small number of disease-causing PRC2 variants from the larger number of benign DNA variants in the PRC2 proteins.