| New bioinformatics tools can be used to filter variants and identify candidate mutations in next generation sequencing studies. There is a very clear need for a rapid system that would enable the functional assessment of candidate mutations, that could provide actionable information for physicians in real time. Novel genome engineering tools in zebrafish (Danio rerio) will facilitate the validation and prioritization of variants, which can be complemented by studies in in vivo and in vitro mammalian models. In this thesis I describe the development of these tools including Transcription Activator-Like Effector Nucleases (TALENs), Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) and CRISPR Associated (CAS) proteins, and examine their utility for genome engineering applications in models of human disease.;The purpose of this two-part thesis is to describe, in detail, case studies in both personalized cancer care in multiple myeloma and undiagnosed inherited liver disorders. In this thesis, I will describe the underlying problems, important observations, and novel strategies that were utilized to study individual patients and arrive at insights concerning the molecular basis of their disease. In addition, I will describe how these insights can be used to shape general strategies and treatment protocols in patients, develop and improve our diagnostic capabilities, and inform our basic understanding of human biology in states of health and disease. |
