Researchers at the Icahn School of Medicine at Mount Sinai have unveiled a game-changing computational tool called LoGoFunc, designed to predict pathogenic gain- and loss-of-function variants within the human genome. Unlike existing methods that primarily focus on loss of function, LoGoFunc’s revolutionary approach distinguishes between different harmful mutations, promising crucial insights into diverse disease outcomes.
Genetic variations can profoundly impact protein function. Some mutations can increase activity or introduce new functions (gain of function), while others can diminish or eliminate function (loss of function). Understanding these changes is paramount to human health and disease treatment.
LoGoFunc addresses a critical gap in existing tools. Co-senior author Yuval Itan, PhD, Associate Professor of Genetics and Genomic Sciences at Icahn Mount Sinai, emphasizes, “Tools presently available fall short in differentiating between gain and loss of function. This matters because these variants impact protein activity differently, influencing disease outcomes.”
Harnessing machine learning for precision
LoGoFunc leverages the power of machine learning, trained on a comprehensive database of known pathogenic gain-of-function and loss-of-function mutations found in the scientific literature. What sets it apart is considering a wide array of biological features, including data from protein structures predicted by AlphaFold2 and network features reflecting human protein interactions.
In rigorous testing using datasets from the Human Gene Mutation Database and ClinVar, LoGoFunc demonstrated remarkable accuracy in predicting gain-of-function, loss-of-function, and neutral variants. This accuracy positions LoGoFunc as a formidable tool in genetic research and analysis.
“Beyond personalized medicine,” says co-senior corresponding author Avner Schlessinger, Ph.D., Professor of Pharmacological Sciences and Associate Director of the Mount Sinai Center for Therapeutics Discovery, “LoGoFunc has implications for drug discovery, genetic counseling, and accelerating genetic research. Its accessibility promotes collaboration and offers a comprehensive view of variant impact across the human genome.”
Paving the way for precision medicine
Perhaps most excitingly, LoGoFunc’s potential in precision medicine is undeniable. It opens the door to the possibility of treatments tailored to an individual’s genetic makeup, potentially revolutionizing the healthcare landscape.
However, the researchers caution that while these findings represent a significant leap forward, translating them into clinical applications necessitates further validation and integration with other medical information. Ongoing validation efforts are crucial to ensure reliable outcomes.
A bridge to the future
As genetic data continues to expand rapidly, LoGoFunc’s capabilities will be refined and its scope extended. This commitment to evolution positions the tool as a crucial element in deciphering the functional consequences of genetic variations.
David Stein, a Ph.D. candidate at Icahn Mount Sinai and the study’s first author, underscores the tool’s importance: “By bridging the gaps, the tool enhances our understanding of genetic variations that contribute to diseases, paving the way for personalized treatment strategies and drug discovery. We believe that LoGoFunc will be a powerful tool for deciphering the functional consequences of genetic variations. While its potential applications are vast, ongoing validation efforts will ensure its real-world impact.”
