TY - CHAP
T1 - Gain-of-Function Variomics and Multi-omics Network Biology for Precision Medicine
AU - Li, Mark M.
AU - Awasthi, Sharad
AU - Ghosh, Sumanta
AU - Bisht, Deepa
AU - Coban Akdemir, Zeynep H.
AU - Sheynkman, Gloria M.
AU - Sahni, Nidhi
AU - Yi, S. Stephen
N1 - Publisher Copyright:
© 2023, The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.
PY - 2023
Y1 - 2023
N2 - Traditionally, disease causal mutations were thought to disrupt gene function. However, it becomes more clear that many deleterious mutations could exhibit a “gain-of-function” (GOF) behavior. Systematic investigation of such mutations has been lacking and largely overlooked. Advances in next-generation sequencing have identified thousands of genomic variants that perturb the normal functions of proteins, further contributing to diverse phenotypic consequences in disease. Elucidating the functional pathways rewired by GOF mutations will be crucial for prioritizing disease-causing variants and their resultant therapeutic liabilities. In distinct cell types (with varying genotypes), precise signal transduction controls cell decision, including gene regulation and phenotypic output. When signal transduction goes awry due to GOF mutations, it would give rise to various disease types. Quantitative and molecular understanding of network perturbations by GOF mutations may provide explanations for ‘missing heritability” in previous genome-wide association studies. We envision that it will be instrumental to push current paradigm toward a thorough functional and quantitative modeling of all GOF mutations and their mechanistic molecular events involved in disease development and progression. Many fundamental questions pertaining to genotype–phenotype relationships remain unresolved. For example, which GOF mutations are key for gene regulation and cellular decisions? What are the GOF mechanisms at various regulation levels? How do interaction networks undergo rewiring upon GOF mutations? Is it possible to leverage GOF mutations to reprogram signal transduction in cells, aiming to cure disease? To begin to address these questions, we will cover a wide range of topics regarding GOF disease mutations and their characterization by multi-omic networks. We highlight the fundamental function of GOF mutations and discuss the potential mechanistic effects in the context of signaling networks. We also discuss advances in bioinformatic and computational resources, which will dramatically help with studies on the functional and phenotypic consequences of GOF mutations.
AB - Traditionally, disease causal mutations were thought to disrupt gene function. However, it becomes more clear that many deleterious mutations could exhibit a “gain-of-function” (GOF) behavior. Systematic investigation of such mutations has been lacking and largely overlooked. Advances in next-generation sequencing have identified thousands of genomic variants that perturb the normal functions of proteins, further contributing to diverse phenotypic consequences in disease. Elucidating the functional pathways rewired by GOF mutations will be crucial for prioritizing disease-causing variants and their resultant therapeutic liabilities. In distinct cell types (with varying genotypes), precise signal transduction controls cell decision, including gene regulation and phenotypic output. When signal transduction goes awry due to GOF mutations, it would give rise to various disease types. Quantitative and molecular understanding of network perturbations by GOF mutations may provide explanations for ‘missing heritability” in previous genome-wide association studies. We envision that it will be instrumental to push current paradigm toward a thorough functional and quantitative modeling of all GOF mutations and their mechanistic molecular events involved in disease development and progression. Many fundamental questions pertaining to genotype–phenotype relationships remain unresolved. For example, which GOF mutations are key for gene regulation and cellular decisions? What are the GOF mechanisms at various regulation levels? How do interaction networks undergo rewiring upon GOF mutations? Is it possible to leverage GOF mutations to reprogram signal transduction in cells, aiming to cure disease? To begin to address these questions, we will cover a wide range of topics regarding GOF disease mutations and their characterization by multi-omic networks. We highlight the fundamental function of GOF mutations and discuss the potential mechanistic effects in the context of signaling networks. We also discuss advances in bioinformatic and computational resources, which will dramatically help with studies on the functional and phenotypic consequences of GOF mutations.
KW - Coding and noncoding variants
KW - Computational mutation annotation
KW - Gain-of-Function mutations
KW - Liquid-liquid phase separation
KW - Post-translational regulation
KW - Protein-protein interactions
UR - http://www.scopus.com/inward/record.url?scp=85159739749&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85159739749&partnerID=8YFLogxK
U2 - 10.1007/978-1-0716-3163-8_24
DO - 10.1007/978-1-0716-3163-8_24
M3 - Chapter
C2 - 37191809
AN - SCOPUS:85159739749
T3 - Methods in Molecular Biology
SP - 357
EP - 372
BT - Methods in Molecular Biology
PB - Humana Press Inc.
ER -