Institute for Computer Science and Department of Biology, Heinrich Heine University, Universitätsstraße 1, Düsseldorf, D-40221, Germany.
Sci Rep. 2018 Nov 22;8(1):17252. doi: 10.1038/s41598-018-35092-1.
A major obstacle to the mapping of genotype-phenotype relationships is pleiotropy, the tendency of mutations to affect seemingly unrelated traits. Pleiotropy has major implications for evolution, development, ageing, and disease. Except for disease data, pleiotropy is almost exclusively estimated from full gene knockouts. However, most deleterious alleles segregating in natural populations do not fully abolish gene function, and the degree to which a polymorphism reduces protein function may influence the number of traits it affects. Utilizing genome-scale metabolic models for Escherichia coli and Saccharomyces cerevisiae, we show that most fitness-reducing full gene knockouts of metabolic genes in these fast-growing microbes have pleiotropic effects, i.e., they compromise the production of multiple biomass components. Alleles of the same metabolic enzyme-encoding gene with increasingly reduced enzymatic function typically affect an increasing number of biomass components. This increasing pleiotropy is often mediated through effects on the generation of currency metabolites such as ATP or NADPH. We conclude that the physiological effects observed in full gene knockouts of metabolic genes will in most cases not be representative for alleles with only partially reduced enzyme capacity or expression level.
基因型-表型关系映射的一个主要障碍是多效性，即突变影响看似不相关特征的趋势。多效性对进化、发育、衰老和疾病都有重大影响。除了疾病数据外，多效性几乎完全是根据完全基因敲除来估计的。然而，在自然种群中分离的大多数有害等位基因并没有完全废除基因功能，并且多态性降低蛋白质功能的程度可能会影响它影响的特征数量。利用大肠杆菌和酿酒酵母的基因组规模代谢模型，我们表明，这些快速生长的微生物中代谢基因的大多数降低适应性的完全基因敲除都具有多效性效应，即它们会损害多种生物量成分的产生。具有越来越低酶功能的同一代谢酶编码基因的等位基因通常会影响越来越多的生物量成分。这种不断增加的多效性通常是通过对货币代谢物（如 ATP 或 NADPH）的生成的影响来介导的。我们得出结论，在代谢基因的完全基因敲除中观察到的生理效应在大多数情况下不会代表只有部分降低酶活性或表达水平的等位基因。
