Cancer and Inflammation Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, National Cancer Institute at Frederick, Frederick, Maryland, United States of America.
Sackler Institute of Molecular Medicine, Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
PLoS Comput Biol. 2019 Jun 20;15(6):e1006648. doi: 10.1371/journal.pcbi.1006648. eCollection 2019 Jun.
Classically, phenotype is what is observed, and genotype is the genetic makeup. Statistical studies aim to project phenotypic likelihoods of genotypic patterns. The traditional genotype-to-phenotype theory embraces the view that the encoded protein shape together with gene expression level largely determines the resulting phenotypic trait. Here, we point out that the molecular biology revolution at the turn of the century explained that the gene encodes not one but ensembles of conformations, which in turn spell all possible gene-associated phenotypes. The significance of a dynamic ensemble view is in understanding the linkage between genetic change and the gained observable physical or biochemical characteristics. Thus, despite the transformative shift in our understanding of the basis of protein structure and function, the literature still commonly relates to the classical genotype-phenotype paradigm. This is important because an ensemble view clarifies how even seemingly small genetic alterations can lead to pleiotropic traits in adaptive evolution and in disease, why cellular pathways can be modified in monogenic and polygenic traits, and how the environment may tweak protein function.
传统上，表型是观察到的，基因型是遗传组成。统计研究旨在预测基因型模式的表型可能性。传统的基因型到表型理论认为，编码蛋白的形状和基因表达水平在很大程度上决定了最终的表型特征。在这里，我们指出，在世纪之交的分子生物学革命解释了基因编码的不是一种而是构象的集合，而构象的集合反过来又决定了所有可能的与基因相关的表型。动态集合视图的意义在于理解遗传变化与获得的可观察的物理或生化特征之间的联系。因此，尽管我们对蛋白质结构和功能基础的理解发生了革命性的转变，但文献仍然普遍与经典的基因型-表型范式相关。这很重要，因为集合视图阐明了即使是看似微小的遗传改变如何在适应性进化和疾病中导致多效性特征，为什么细胞途径可以在单基因和多基因特征中被修饰，以及环境如何调整蛋白质功能。
