We use Drosophila to facilitate the diagnoses of rare human diseases. Developments in sequencing human genomes using whole exome (WES) or whole genome sequencing (WGS) have completely changed the landscape of human genetics. It is estimated that there are approximately 30 million people in the US and 400 million worldwide with a rare disease. Many of these are genetic in nature and patients with these diseases often undergo a diagnostic odyssey and remain undiagnosed for many years. By sequencing their genomes and those of their relatives, human geneticists can now discover genetic variations that are rare or ultra-rare. However, considering that there are many polymorphisms in each genome, assessing which variant(s) are related to the observed symptoms remains a significant challenge. This is precisely where model organisms can contribute and Drosophila is now playing a prominent in this venture (Splinter et al., 2018).
The NIH launched the Undiagnosed Diseases Network (UDN) to solicit patients with undiagnosed diseases and try to determine their cause. The patients who are enrolled are some of the most challenging cases in medicine. Eighteen clinical sites, a sequencing center, a metabolomics core, and three Model Organisms Screening Centers (MOSC) are supported by the UDN to develop a diagnosis for as many of these patients as possible. To date, over 7,000 patients have applied (about 40% have been accepted, and about 30% of the accepted patients have been diagnosed), some by performing functional studies in flies, worms or zebrafish. The MOSC Drosophila Core has played a prominent role in this venture and has provided critical data for more than 50 new human diseases (Yamamoto et al., 2024). We have also collaborated with the Centers for Mendelian Genomics (now known as the GREGoR Consortium) to assess variant function using Drosophila and facilitate the discovery of new human disease-causing genes (Yamamoto et al., 2014).
Due to the overwhelming success of our strategies, we have been approached by human geneticists from around the world to help in the diagnosis of rare diseases. We are now collaborating with teams in Canada, Pakistan, Belgium, Netherlands, Germany, Switzerland, Korea, Australia, New Zealand, China and several non-UDN participating clinical sites in the USA. Given the quickly expanding number of WES and WGS that are being performed in clinical diagnostic laboratories around the world and the vast number of VUS (variants of unknown significance in genes) as well as variants in genes of unknown significance that are accumulating, there is a strong need to encourage model organism researchers to participate in collaborative research with clinicians. We are working closely with leadership teams for the Canadian Rare Disease Models and Mechanisms Network (RDMM) and related initiatives in Japan (J-RDMM) and the European Union (SolveRD). These publicly funded consortia promote the use of model organisms in rare disease research to engage more model organism researchers around the world to join in this endeavor.
Due to the success of our strategies, we have been approached by human geneticists from around the world to help in the diagnosis of rare diseases. We are now collaborating with teams in Canada, Netherlands, Germany, Switzerland, Korea, Australia, New Zealand, China and several non-UDN affiliated clinical sites in the USA. Given the quickly expanding number of WES and WGS that are being performed in clinical diagnostic laboratories around the world and the vast number of VUS (variants of unknown significance) in disease-associated genes as well as variants in genes of unknown significance that are accumulating, there is a strong need to encourage model organism researchers to participate in collaborative research with clinicians. We are therefore working closely with leadership teams for the Canadian Rare Disease Models and Mechanisms Network (RDMM) and related initiatives in Japan (J-RDMM), the European Union (SolveRD) and Australia (AFGN). These publicly funded consortia promote the use of model organisms in rare disease research to engage more model organism researchers around the world to join in this endeavor.
We also developed bioinformatic approaches to facilitate collaborations between clinicians and basic scientists. These include MARRVEL (Wang et al., 2017), AI-MARRVEL (Mao et al., 2024), and ModelMatcher (Harnish et al., 2022). MARRVEL is a meta-search engine that allows anyone to mine various human and model organism data that are useful for rare disease research. AI-MARRVEL is a knowledge driven artificial intelligence system to prioritize candidate genetic variants that are found through WES and WGS in patients. ModelMatcher is a matchmaking tool that connects scientists and clinicians that are interested in orthologous genes in different model organisms. These tools have been designed to break down barriers and hurdles to facilitate interdisciplinary collaborations.
While a precise molecular diagnosis provides a degree of relief and hope to patients who have undergone a diagnostic odyssey, it is just the beginning. Identification of the cellular and biochemical pathways that are at the root of the phenotypes is the most straightforward way to reveal possible therapeutic targets. The fruit fly offers unmatched tools to dissect the molecular pathogenic mechanisms. By rapidly assessing the precise expression pattern and subcellular protein distribution and dynamics, identifying the physical and genetic interactors of the protein/gene of interest, Drosophila researchers can quickly identify potential therapeutic targets. Furthermore, unravelling the molecular players in flies, scientists can potentially identify FDA approved drugs which can then be quickly tested for repurposing. These discoveries have already led to changes in therapeutic approaches in patients, and physicians have applied for compassionate use when appropriate. Discoveries initiated in flies have already altered the treatment for diseases (Chung et al., 2020; 2023). Hence Drosophila is capable of providing a platform to test existing drugs and develop novel therapeutic approaches.
An important theme that has emerged from functional studies of rare genetic disease is that genes that are affected in pediatric neurological cases (more than 60% of the submitted cases of the UDN) often can provide probing insights into neurodegenerative diseases like Alzheimer's Disease, Parkinson's Disease and Multiple Sclerosis. The observations related to AD and PD are discussed in the previous section.
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Harnish JM, Li LK, Rogic S, Piorier-Morency G, Kim SY, Undiagnosed Diseases Network (UDN), Boycott KM, Wangler MF, Bellen HJ , Hieter P, Pavlidis P, Liu Z, Yamamoto S (2022) ModelMatcher: A scientist-centric online platform to facilitate collaborations between stakeholders of rare and undiagnosed disease research. Human Mutation 43(6):743-759. PMCID: PMC9133126.
Mao D, Liu C, Wang L, AI-Ouran R, Deisseroth C, Pasupuleti S, Kim SK, Li L, Rosenfeld JA, Meng L, Burrage LC, Wangler M, Yamamoto S, Undiagnosed Diseases Network, Santana M, Perez V, Shukla P, Eng C, Lee B, Yuan B, Xia F, Bellen HJ, Liu P, and Liu Z (2024) AI-MARRVEL-A Knowledge-Driven AI System for Diagnosing Mendelian Disorders. NEJMAI 1(5). PMCID: PMC11221788.
Splinter K, Adams DR, Bacino CA, Bellen HJ, Bernstein JA, Cheatle-Jarvela AM, Eng CM, Esteves C, Gahl WA, Hamid R, Jacob HJ, Kikani B, Koeller DM, Kohane IS, Lee BH, Loscalzo J, Luo X, McCray AT, Metz TO, Mulvihill JJ, Nelson SF, Palmer CGS, Phillips JA, 3rd, Pick L, Postlethwait JH, Reuter C, Shashi V, Sweetser DA, Tifft CJ, Walley NM, Wangler MF, Westerfield M, Wheeler MT, Wise AL, Worthey EA, Yamamoto S, Ashley EA, UDN (2018) Effect of genetic diagnosis on patients with previously undiagnosed disease. New England Journal of Medicine 379:2131-2139. PMCID: PMC6481166. Covered in BMJ 363:k4272, Research News.
Wang J, Al-Ouran R, Hu Y, Kim SY, Wan YW, Wangler MF, Yamamoto S, Chao HT, Comjean A, Mohr SE, UDN, Perrimon N, Liu Z*, Bellen HJ* (2017) MARRVEL: integration of human and model organism genetic resources to facilitate functional annotation of the human genome. American Journal of Human Genetics 100:843-853. PMCID: PMC5670038. Selected among Best of AJHG 2016-2017. *Co-Corresponding.
Yamamoto S#, Jaiswal M#, Charng WL, Gambin T, Karaca E, Mirzaa G, Wiszniewski W, Sandoval H, Haelterman NA, Xiong B, Zhang K, Bayat V, David G, Li T, Chen K, Gala U, Harel T, Pehlivan D, Penney S, Vissers LELM, de Ligt J, Jhangiani SN, Xie Y, Tsang SH, Parman Y, Sivaci M, Battaloglu E, Muzny D, Wan YW, Liu Z, Lin-Moore AT, Clark RD, Curry CJ, Link N, Schulze KL, Boerwinkle E, Dobyns WB, Allikmets R, Gibbs RA, Chen R, Lupski JR, Wangler MF*, Bellen HJ* (2014) A Drosophila genetic resource of mutants to study mechanisms underlying human genetic diseases.Cell 159(1):200-214. PMCID: PMC4298142. #Equal Contribution *Co-Corresponding.
Yamamoto S#, Kanca O#, Wangler MF *, Bellen HJ* (2024) Integrating non-mammaliam model organism in the diagnosis of rare genetic human disease. Nature Reviews Genetics 25(1):46-60. PMID: 37491400 . #Equal Contribution *Co-Corresponding.