The Undiagnosed Diseases Network has been a successful rare disease diagnosis effort. The medical geneticists involved in the seven clinical sites and the DNA sequencing teams turn to the power of next-generation sequencing which has been a powerful diagnostic tool. But like anyone doing exomes and genomes they are increasingly faced with the variant interpretation problem. Every personal genome contains hundreds of exceedingly rare or even personal variants. These variants are essentially “new to the system” and very hard to interpret because they don’t show up on our list of what we’ve seen before. This is a crucial problem when the goal is to diagnose Mendelian single gene disorders with sequencing. More functional studies of genes, including model organism research is essential in improving these annotations.
We’ve been part of an exciting team that brings together model organisms, clinical medicine and human genome research. In order to have such teams we need a diverse biomedical research environment with different experts, and human geneticists interfacing with a robust model organism research environment. We published a perspective in GENETICS in which we brought up the current funding situation for model organism research. We were concerned that there has been a disproportionate reduction in model organism support, something that hurts basic science and ultimately also the ability to use model organisms in translational work. The NIH heard the concern, Francis Collins discussed our article and did a more in depth analysis of all grant support for all model organism developed with sophisticated portfolio analysis. This was followed up with a series of NIH Open Mike pieces. The NIH was eager to show their support for model organism work, partly in response to these concerns we raised.
Why is Drosophila work so important? What is it so useful in the current era of clinical genomics? Our team was funded for the Drosophila component of a Model Organism Screening Center (MOSC) for the Undiagnosed Diseases Network, and we have built in parallel a strong collaboration with the Centers for Mendelian Genomics at Baylor College of Medicine, work that came out of the Bellen lab X-chromosome screen and it's work with the CMG. These two strong rare disease projects provide us with a seemingly endless stream of gene function questions in patients. Post-doctoral fellows, graduate students and other scientists who have been studying fruitfly wade into the confusing nomenclature of clinical medicine. Meanwhile clinicians and human geneticists push flies and learn how to integrate and understand fly biology. Variants are examined not only in the human genome, but model organism data is brought in for each variant.
Then a unique and novel approach is used for candidates. In this approach a versatile intronic cassette is selected or inserted into the fly genome into the homolog of the gene of interest allowing functional replacement of fly gene with human and with variants of interest. This past week, two papers came out showing our team’s approach. In one paper, an in depth biological study of a mitochondrial co-chaperone revealed a novel mechanism, and two genes implicated in neurodegeneration. In a second study a novel neurodevelopmental disorder was validated in a Drosophila model. These studies are only the beginning of model organism work on these genes, and they are only the first of many studies merging a Drosophila variant functional screening pipeline with human genomic studies.
These studies have provided new diagnoses for the patient’s involved, and linked the biology in Drosophila with these disease mechanisms. But the other key is team science. Clinicians, human geneticists and Drosophila geneticists consider genetics differently, they ask different questions and they bring different skills to the ultimate goal of understanding the patient and their genetics better. It’s an exciting direction for model organism research and well worth the investment.