Date of Graduation
5-2026
Document Type
UAF Access Only - Thesis
Degree Name
Bachelor of Science in Biomedical Engineering
Degree Level
Undergraduate
Department
Biomedical Engineering
Advisor/Mentor
Harris, Leonard
Abstract
Fanconi anemia (FA) is a rare genetic disorder characterized by flawed DNA repair, genomic instability, and an increased risk of developing cancer. Phenotypically, FA-affected individuals are more prone to growth deficiencies, skeletal malformations, and hearing loss. One of the key components of the condition is the dysfunction of the FA DNA damage repair pathway, a complex network of proteins responsible for identifying and fixing DNA interstrand crosslinks that stall replication and threaten cell viability. Prior studies utilized computational models to capture the complex biochemical processes involved in the FA DNA damage repair pathway and predict outcomes of various perturbations. In particular, a previously proposed Boolean model utilized “synchronous updating” to identify stable system states for numerous gain-of-function (GoF) and loss-of-function (LoF) pathway mutations. In this work, we utilize a more biologically realistic “asynchronous updating” method to account for the stochasticity of biological environments. Using this method, we analyzed the existing Boolean network model by performing thousands of stochastic simulations and quantified the effects of all possible GoF and LoF mutations on the efficiency of DNA damage repair. Mutations were introduced at key regulatory nodes, such as proteins involved in damage recognition, signal transduction, and downstream repair processes. Simulation results indicated an activation of DNA damage markers and impaired repair mechanisms when LoF mutations occurred, whereas GoF mutations generally resulted in accelerated pathway activation. Overall, this study provides a perspective on the impact of genetic disorders on DNA damage response pathways and highlights the utility of stochastic simulation approaches in studying complex biological pathways.
Keywords
Fanconi Anemia; Stochastic Modeling; Systems Biology; DNA Interstrand Crosslinks; Boolean Networks; PySB
Citation
Basler, M. (2026). Stochastic Simulations of Gain- and Loss-of-Function Mutations in the Fanconi Anemia DNA Damage Repair Pathway. Biomedical Engineering Undergraduate Honors Theses Retrieved from https://scholarworks.uark.edu/bmeguht/170
