Mathematical Sciences: Chromosome Geometry and Chromosome Aberrations

研究者在活的哺乳动物细胞中模拟染色体畸变，强调对大规模染色体几何和电离辐射损伤生物学的影响。他利用DNA几何、运动和大分子水平反应的概率模型，分析了细胞周期间期辐射诱导DNA双链断裂后染色体畸变的形成。例如，一个领域涉及非法重组的组合学和动力学，涉及几个不同染色体之间片段的交换。聚合物模型用于大规模的染色体结构和运动。当通过现代荧光原位杂交技术获得关于特定个体染色体的非常详细的实验信息时，就会出现统计问题；他通过扩展已经开发的蒙特卡洛模拟来解决这些问题。这项研究包括开发计算机算法，明确求解随机过程模型，以及与实验组合作。电离辐射对染色体的损害正在用数学方法进行研究。当电离辐射击中细胞时，例如在肿瘤放疗或辐射事故中发生的情况，DNA分子会被破坏和大规模重组。由此产生的染色体畸变被认为是大多数主要放射生物学效应的症状或原因。它们在生物剂量学中尤其重要，通过观察残余细胞损伤来估计过去暴露于辐射剂量。它们也是基础生物学的一个窗口，因为它们受到染色体几何和运动的影响，并且是它们的症状。最近的发展，即特定的人类染色体可以被“涂上”不同的颜色，极大地增加了从畸变研究中获得的信息量。现在可以观察到非常丰富多彩的各种像差。试图理解一个人所看到的重组的数量和类型会导致数学上的重大问题，这些问题可以通过计算机模拟或“纸笔”计算来解决。模拟和计算是在赠款下进行的。结果允许系统比较不同实验室使用不同的染色体绘制方案观察到的细胞辐射损伤效应。此外，染色体畸变如何随时间演变的机制建模有助于解决放射生物学的主要谜团：如何从统计上显著的实验结果所需的大剂量推断到与受环境或人为源辐射的大量人口的风险估计有关的小得多的剂量。

Sachs 9532055 The investigator models chromosome aberrations in live mammalian cells, emphasizing implications for large-scale chromosome geometry and for the biology of ionizing radiation damage. He analyzes formation of chromosome aberrations after induction of DNA double strand breaks by radiation during the interphase part of the cell cycle, using probabilistic models for DNA geometry, motion, and reactions at the macromolecular level. For example, one area concerns the combinatorics and kinetics of illegitimate recombinations, involving the exchange of fragments between several different chromosomes. Polymer models are used for large-scale chromosome structure and motion. Statistical questions arise when very detailed experimental information about specific individual chromosomes is made available by modern fluorescent in situ hybridization techniques; these he addresses by extending already developed Monte-Carlo simulations. The study involves developing computer algorithms, explicitly solving stochastic process models, and collaborating with experimental groups. Ionizing radiation damage to chromosomes is being studied mathematically. When ionizing radiation hits cells, as occurs for example in tumor radiotherapy or radiation accidents, one gets breakage and large-scale reshuffling of DNA molecules. The resulting chromosome aberrations have been implicated as symptoms or causes of most major radiobiological effects. They are especially important in biodosimetry, the estimation of past exposure to radiation dose by looking at residual cellular damage. They are also a window on fundamental biology because they are influenced by, and symptomatic of, chromosome geometry and motion. Recent developments, whereby specific human chromosomes can be "painted" different colors, have dramatically increased the amount of information obtained from aberration studies. A very rich and colorful variety of aberrations can now be observed. Trying to und erstand the number and kind of reshufflings one sees leads to mathematically nontrivial problems, amenable to computer simulations or "pen and paper" calculations. The simulations and calculations are being carried out under the grant. The results allow systematic comparisons of cellular radiation damage effects observed by different laboratories using different chromosome painting schemes. In addition, mechanistic modeling of how chromosome aberrations evolve in time is helping to attack the main mystery of radiobiology: how to extrapolate from the larger doses needed for statistically significant experimental results to the much smaller doses relevant to risk estimates for large human populations subjected to radiation from environmental or man-made sources.