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 among 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
NIH