Discovering signals of selection in cancer mutations with Hidden Markov Models

使用隐马尔可夫模型发现癌症突变的选择信号

• 批准号: 219638969
• 负责人: Dr. Andrej Fischer
• 金额: --
• 依托单位: Wellcome Sanger Institute
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2012
• 资助国家: 德国
• 起止时间: 2011-12-31 至 2012-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/219638969?language=en
• 关键词: Discovering; signals; selection; cancer; mutations

What kind of mutation causes cancer? The answer to this important question lies in the correct interpretation of cancer-cell DNA data, which now exists in abundance. This task is complicated by the fact that the actual “driver mutations“ that causally contribute to the development of cancer are disguised by a large pool of random “passenger mutations“. Sometimes, individual driver mutations can be identified when they systematically appear in many independent tumor samples. But such cases are rare, for it seems that the mechanisms of cancer evolution are intricate and not without alternative. It is the aim of this project to devise statistical and computational methods to robustly identify DNA regions that are important to cancer evolution. This can be done by finding signals of selection: when genes are required by the cancer to be in a state that is different from their configuration in healthy cells, they will exhibit a higher rate of genetic reconfiguration in the form of missense mutations. Moreover, in order to alter the gene considerably, these mutations are more likely to appear at locations that usually do not tolerate too much diversity. Combining these two complementary aspects could be the key to quantify the functional effects of cancer mutations in a biologically meaningful and statistically powerful manner. Practically, the detection of signals of selection requires extensive statistical analysis not only of the observed cancer mutations but also of the potential mutation target - the human genome - itself. Only by comparing what was seen to what could have been seen can one assess the significance of findings. The probabilistic method of Hidden Markov Models is ideally suited to perform this task efficiently on large data sets. The goal is to establish a computational framework to implement an evolutionarily informed analysis of cancer sequencing data with the objective to identify genomic regions that can act as drivers for cancer progression.

哪种突变会导致癌症？这个重要问题的答案在于对癌细胞DNA数据的正确解释，这些数据现在已经大量存在。这项任务因以下事实而变得复杂：导致癌症发展的实际“司机突变”被大量随机的“乘客突变”所掩盖。有时，当个体驱动突变系统地出现在许多独立的肿瘤样本中时，就可以识别出它们。但这种情况很少见，因为癌症进化的机制似乎错综复杂，并不是没有其他选择。这个项目的目的是设计统计和计算方法，以强有力地识别对癌症进化至关重要的DNA区域。这可以通过寻找选择信号来实现：当癌症要求基因处于与其在健康细胞中的配置不同的状态时，它们将以错义突变的形式表现出更高的基因重构率。此外，为了显著改变基因，这些突变更有可能出现在通常不能容忍太多多样性的位置。将这两个互补的方面结合起来，可能是以一种具有生物学意义和统计效力的方式量化癌症突变的功能影响的关键。实际上，对选择信号的检测不仅需要对观察到的癌症突变进行广泛的统计分析，还需要对潜在的突变目标--人类基因组--本身进行广泛的统计分析。只有将看到的与可能看到的进行比较，才能评估发现的意义。隐马尔可夫模型的概率方法非常适合于在大数据集上有效地执行这一任务。其目标是建立一个计算框架，对癌症测序数据进行进化知情的分析，目的是确定可以作为癌症进展驱动因素的基因组区域。