Mathematical Sciences: Chromosome Geometry and Chromosome Aberrations

9302704萨克斯研究人员对活的哺乳动物细胞中的染色体异常进行建模，强调对大规模染色体几何形状和电离辐射损伤生物学的影响。这项研究需要开发计算机算法，明确求解随机过程模型，并与各种实验小组合作。利用大分子水平的DNA几何、运动和反应的概率模型，特别是大规模染色体结构和运动的聚合物模型，分析了在细胞周期间期部分诱导DNA双链断裂后产生的染色体损伤(例如，非法重组，涉及两个不同染色体之间的片段交换)。比较了与染色体几何和生物剂量学有关的密集电离辐射和稀疏电离辐射的影响。当现代荧光标记技术提供关于特定单个染色体的非常详细的实验信息时，出现的统计问题可以通过扩展基于先前分析的生物模型的已经开发的蒙特卡罗模拟来回答。了解电离辐射是如何损害染色体的，对于了解辐射诱发癌症、了解如何处理辐射事故或浪费以及改进肿瘤放射治疗非常重要。这样的理解需要关于活的人类细胞中染色体的几何信息；相反，关于辐射损伤的信息有助于理解染色体几何，这具有基本的生物学重要性。虽然已经投入了大量的努力来对染色体中的DNA进行测序和对染色体的局部几何形状进行建模，但主要研究人员和其他人正在开发更大规模的定量几何模型，这些模型是分析辐射产生的染色体畸变的主要兴趣。该项目将电离辐射物理学的标准信息与这些新的染色体几何生物学模型结合起来，分析损伤是如何形成的。特别是，初步的数学研究和文献搜索表明，由于几何效应，密集电离辐射，如来自氡子体的阿尔法粒子，比其他类型的染色体损伤剂，包括稀疏电离辐射，如X射线，在某些特定类型的损害(如中心染色体环)中所占比例更大。这种密集电离辐射的“特征”应该有助于对辐射危害的现实评估，并将有助于理解染色体几何形状。***

9302704 Sachs The investigator models chromosome aberrations in live mammalian cells, emphasizing implications for large-scale chromosome geometry and for the biology of ionizing radiation damage. The study entails developing computer algorithms, explicitly solving stochastic process models, and collaborating with various experimental groups. Production of chromosome damage (for example, illegitimate recombinations, involving the exchange of fragments between two different chromosomes) after induction of DNA double strand breaks during the interphase part of the cell cycle is analyzed, using probabilistic models for DNA geometry, motion, and reactions at the macromolecular level, in particular polymer models for large-scale chromosome structure and motion. Comparisons of the effects of densely ionizing radiation to those of sparsely ionizing radiation, relevant to chromosome geometry and to biological dosimetry, are made. Statistical questions that arise when very detailed experimental information about specific individual chromosomes is made available by modern fluorescent labeling techniques are answered by extending already developed Monte-Carlo simulations based on previously analyzed biological models. Understanding how ionizing radiation damages chromosomes is important in understanding cancer induction by radiation, understanding how to cope with radiation accidents or waste, and improving tumor radiotherapy. Such understanding requires geometric information about the chromosomes in a live human cell; conversely, information about radiation damage contributes to understanding chromosome geometry, which is of fundamental biological importance. While much effort has been devoted to sequencing the DNA in chromosomes and to modeling local geometry of chromosomes, quantitative geometric models of the larger scales of main interest in analyzing radiation produced chromosome aberrations are just now being developed, by the principal investig ator and others. The project combines standard information on the physics of ionizing radiation with these new biological models of chromosome geometry to analyze how the damage is formed. In particular, preliminary mathematical investigations and a literature search show that, due to geometric effects, densely ionizing radiations, such as alpha particles from radon daughters, make a larger fraction of certain specific kinds of damage (e.g. centric chromosome rings) than other kinds of chromosome damaging agents, including sparsely ionizing radiations such as x-rays. This "signature" of densely ionizing radiations should help in realistic assessments of radiation hazards and will help in understanding chromosome geometry. ***