Institute of Medical Systems Biology, Ulm University, 89069 Ulm, Germany.
Department of Internal Medicine II, Ulm University, 89081 Ulm, Germany.
Biomolecules. 2018 Nov 26;8(4):158. doi: 10.3390/biom8040158.
Genetic model organisms have the potential of removing blind spots from the underlying gene regulatory networks of human diseases. Allowing analyses under experimental conditions they complement the insights gained from observational data. An inevitable requirement for a successful trans-species transfer is an abstract but precise high-level characterization of experimental findings. In this work, we provide a large-scale analysis of seven weak contractility/heart failure genotypes of the model organism zebrafish which all share a weak contractility phenotype. In supervised classification experiments, we screen for discriminative patterns that distinguish between observable phenotypes (homozygous mutant individuals) as well as wild-type (homozygous wild-types) and carriers (heterozygous individuals). As the method of choice we use semantic multi-classifier systems, a knowledge-based approach which constructs hypotheses from a predefined vocabulary of high-level terms (e.g., Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways or Gene Ontology (GO) terms). Evaluating these models leads to a compact description of the underlying processes and guides the screening for new molecular markers of heart failure. Furthermore, we were able to independently corroborate the identified processes in Wistar rats.
遗传模式生物有可能消除人类疾病相关基因调控网络中的盲点。通过在实验条件下进行分析，可以补充从观察性数据中获得的见解。成功进行跨物种转移的一个必然要求是对实验结果进行抽象但精确的高层描述。在这项工作中，我们对具有弱收缩力/心力衰竭表型的模式生物斑马鱼的七种弱收缩力/心力衰竭基因型进行了大规模分析。在有监督的分类实验中，我们筛选出可区分可观察表型（纯合突变个体）与野生型（纯合野生型）和携带者（杂合个体）的有区别的模式。作为首选方法，我们使用语义多分类器系统，这是一种基于知识的方法，它从预定义的高级术语词汇（例如京都基因与基因组百科全书 (KEGG) 途径或基因本体论 (GO) 术语）构建假设。评估这些模型可以对潜在过程进行简洁描述，并指导筛选心力衰竭的新分子标志物。此外，我们还能够在 Wistar 大鼠中独立证实所确定的过程。
