基于层次化系统模型研究复杂疾病表型的遗传调控机制

Understanding the hereditary basis of disease susceptibility is alongstanding goal of genetics research, and it is essential for diagnosis and therapy of complex diseases. Here we propose a hierarchical system model to study the mechanistic links from the measured genotypes to the observed complex phenotypes. By integrating SNPgenotype profiling, gene expression, molecular network and disease phenotype data, we constructed the model and apply it to dissect how genetic variations may affect phenotype through a series of hierarchical levels, with genetic variation at the base of this hierarchy affecting higher processes, such as gene expression change, molecular interactions rearrangement, pathway and network reorganization, and cell function disordering. We then assessed the effectiveness of our model based on model organisms, and implemented an integrative data analysis platform, including data from multiple species and tissues. This comprehensive model provides insight into genetic regulation mechanism of common diseases and supports complex phenotype research in both data and analysis methodologies.

遗传因素在疾病发生和发展中的作用机制一直是科学研究的前沿和热点，对于复杂疾病的诊断和治疗具有重要指导意义。这里我们提出层次化的系统模型来研究从基因型到疾病等复杂表型的遗传调控问题。通过整合SNP基因型谱、基因表达谱、分子互作网络和疾病表型数据等多层面信息，来构建遗传变异->基因表达变异->分子间互作改变->通路或网络扰动->细胞功能失调->表型变异的层次化系统模型。基于模式生物进行模型有效性的验证，并构建包括多个物种和组织的整合数据分析平台，为人类常见疾病等复杂表型的遗传调控机制研究提供有益的探索和启示，并给予一定的数据和方法支持。

遗传和表观遗传因素在疾病发生和发展中的作用是当前研究的热点，对于复杂疾病的诊断和治疗具有重要指导意义。这里我们提出层次化的系统模型来研究从基因型到疾病等复杂表型的遗传及表观遗传调控问题。通过整合多维分子谱数据,分子互作网络和疾病表型数据等多层面信息，来构建遗传及表观遗传变异->基因表达变异->分子间互作改变->通路或网络扰动->细胞功能失调->表型变异的层次化系统模型。利用此层次化模型来研究模式生物酵母对小分子药物的反应,我们发现了染色体不同区域的遗传变异会影响分子网络的特定模块，并且找到了对100种不同小分子药物进行响应的子网。我们进一步将此层次化系统模型延伸到多种人类常见癌症的分子机制研究, 通过整合拷贝数变异，基因表达，DNA甲基化以及microRNA的表达数据，来研究在多种遗传及表观遗传变异的扰动下，生物分子网络模块的动态变化,并识别了多种癌症相关通路，为人类常见疾病等复杂表型的分子调控机制研究提供有益的探索和启示，并给予一定的数据和方法支持。