Enzymatic misrepair of DNA damage induced by ionizing radiation during the G0/G1 phase of the cell cycle produces chromosome aberrations, such as translocations and dicentrics. Chromosome aberrations can cause major disruptions of function, including cell death, mutation and neoplasia. Radiogenic aberrations are important in biodosimetry, carcinogenesis risk estimation, and tumor radiotherapy treatment planning. They are closely related to aberrations used in characterizing specific tumor types and to large-scale genome rearrangements considered in modern comparative genomics. Recent work has shown that radiogenic exchange-type aberrations are often complex, involving interactions between more than two DNA double strand breaks. To characterize and analyze spectra of complex aberrations adequately, computer simulations are needed, and are now commonly used. The pioneering software, developed by a Berkeley/Harvard team, is CAS (chromosome aberration simulator), a package implementing basic biophysical models of aberration formation via Monte Carlo, Markov chain calculations of break misrejoining, taking into account chromosome geometry in an interphase cell nucleus. The CAS open source software has been successfully applied in joint work with many groups worldwide, and broad support among radiation cytogeneticists for the idea of internet bioinformatics has been identified. The proposed project is the following: 1) reengineer CAS to take advantage of experience with earlier versions and recent progress in aberration theory; 2) make CAS more user-friendly as an open source internet resource; and 3), extend CAS in various ways to keep up with current rapid experimental advances, e.g. in aberration detection technology. An interdisciplinary team has been assembled for this project. The grant would ensure that a computer resource important to the radiation cytogenetics community is kept fully current and readily available.
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