Modeling Chromosome Aberrations

电离辐射通过染色体断裂和大规模重组产生染色体畸变。使用荧光原位杂交技术将各种染色体涂成不同的颜色，揭示了丰富多样的简单和复杂畸变，每一种畸变都推测表明在一次全面的错误修复反应中涉及两个或更多的dna双链断裂。研究者对当前畸变数据的生物物理含义进行计算，并对沿染色体的DNA双链断裂聚类的脉冲场凝胶电泳数据进行计算，这些数据与畸变形成的早期阶段有关。比较了DNA断裂再连接的三种基本分子模型。这种错误连接的组合可能性是如此之多，以至于需要定理、方程和计算机模拟来系统地解释广泛而复杂的当前数据。主要方法有：(1)适当采用概率论和随机过程理论的标准结果，主要是泊松聚类点过程；(2)扩展CAS （chromosome aberrationsimulator）计算机软件。继续与世界各地许多不同的实验小组合作。假设断裂诱导和错误修复的随机性模型可以合理准确地表征，仅使用两个可调参数，许多不同类型畸变的相对频率及其对相关染色体臂基因组内容的依赖。了解电离辐射对细胞的影响是基础生物学的重要组成部分。染色体畸变是复杂的细胞终点，大量由电离产生，并提供了DNA损伤产生、修复和错误修复的基本机制信息。畸变也与应用放射生物学的主要领域密切相关，包括癌症风险评估、放射治疗期间细胞杀伤估计和生物剂量学（即判断个体过去的辐射暴露，例如在辐射事故或宇航员任务之后）。由于当前研究兴趣的增加和实验技术的改进，有大量关于辐射引起的像差的新数据。研究者研究染色体畸变形成的潜在生物物理学，使用最先进的数学和计算机方法。他的方法区分了目前的三种分子畸变形成模型，这些模型主要用于预测尚未在实验中测量的情况下的辐射损伤水平，例如剂量过低，在实验室分析中不易处理，但仍可能引起大量人群的关注。数学和计算机建模是一种相对廉价的方法，可以最大限度地从快速增长的数据库中获得生物信息，并帮助指导实验。

Sachs9971169 Ionizing radiation produces chromosome aberrations, throughbreakage and large-scale reshuffling of chromosomes. Usingfluorescent in situ hybridization techniques to paint variouschromosomes different colors reveals a rich variety of simple andcomplex aberrations, each putatively indicative of two or moreDNA double strand breaks involved in one over-all misrepairreaction. The investigator undertakes calculations on thebiophysical implications of current data on aberrations, and ofpulsed-field gel-electrophoresis data on DNA double strand breakclustering along chromosomes, relevant to the early stages ofaberration formation. Three basic molecular models for DNA breakmisrejoining are compared. There are so many combinatorialpossibilities for this misrejoining that theorems, equations, andcomputer simulations are needed for systematically interpretingthe extensive, elaborate current data. The main methods are: (1)suitably adapting standard results of probability theory andstochastic process theory, mainly on Poisson cluster pointprocesses; and (2), extending CAS (chromosome aberrationsimulator) computer software. Collaborations with many differentexperimental groups world-wide are continued. Models that assumerandomness of break induction and misrepair can characterize withreasonable accuracy, using only two adjustable parameters, therelative frequencies of many different types of aberrations andtheir dependence on genomic content of the chromosome armsinvolved. Understanding the effects of ionizing radiation on cells isan important part of fundamental biology. Chromosome aberrationsare complex cellular endpoints, copiously produced by ionizingradiation and informative about basic mechanisms of DNA damageproduction, repair, and misrepair. Aberrations are also robustlyimplicated in the main areas of applied radiobiology, includingcancer risk assessment, estimating cell killing duringradiotherapy, and biodosimetry (i.e. judging past exposure of anindividual to radiation, e.g. after a radiation accident or anastronaut's mission). Due to increased current interest and toimproved experimental techniques, there has been a flood of newdata on radiation-induced aberrations. The investigator studiesthe underlying biophysics of chromosome aberration formation,using state-of-the-art mathematical and computer methods. Hismethods discriminate between the three current molecular modelsof aberration formation, which are needed mainly to predictlevels of radiation damage in situations not yet measuredexperimentally, such as doses too low to be readily tractable inlaboratory analyses but nonetheless of possible concern for largepopulations. Mathematical and computer modeling is acomparatively inexpensive way to maximize biological informationobtainable from the rapidly increasing databases and to helpguide experiments.