Updating Chromosome Aberration Simulator (CAS) Software

描述（由申请人提供）：在细胞周期的G0/G1期，电离辐射诱导的DNA损伤的酶促错误修复会产生染色体畸变，如易位和双中心。染色体畸变会导致主要的功能破坏，包括细胞死亡、突变和肿瘤。放射基因畸变在生物剂量学、致癌风险评估和肿瘤放射治疗计划中具有重要意义。它们与用于表征特定肿瘤类型的畸变和现代比较基因组学中考虑的大规模基因组重排密切相关。最近的研究表明，放射性基因交换型畸变通常是复杂的，涉及两个以上DNA双链断裂之间的相互作用。为了充分表征和分析复杂像差的光谱，计算机模拟是必要的，并且现在被广泛使用。由伯克利/哈佛团队开发的开创性软件是CAS（染色体畸变模拟器），这是一个通过蒙特卡罗实现畸变形成的基本生物物理模型的软件包，马尔可夫链计算断裂错误重新连接，考虑到间期细胞核中的染色体几何形状。CAS开源软件已成功应用于全球多个研究小组的联合工作中，并得到辐射细胞遗传学家对互联网生物信息学理念的广泛支持。建议的项目如下：1)利用早期版本的经验和畸变理论的最新进展对CAS进行重构；2)使CAS作为一个开源的互联网资源更加人性化；3)通过多种方式扩展CAS，以跟上当前快速的实验进展，例如像差检测技术。这个项目已经组建了一个跨学科的团队。拨款将确保对辐射细胞遗传学社区重要的计算机资源保持最新和随时可用。

DESCRIPTION (provided by applicant): 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.