The dominance of deleterious mutations has important consequences for phenomena such as inbreeding depression, the evolution of diploidy, and levels of natural genetic variation. Kacser and Burns' metabolic theory provides a paradigmatic explanation for why most large-effect mutations are recessive. According to the metabolic theory, the recessivity of large-effect mutations is a consequence of a diminishing-returns relationship between flux through a metabolic pathway and enzymatic activity at any step in the pathway, which in turn is an inevitable consequence of long metabolic pathways. A major line of support for this theory was the demonstration of a negative correlation between homozygous effects and dominance of mutations in Drosophila, consistent with a central prediction of the metabolic theory. Using data on gene deletions in yeast, we show that a negative correlation between homozygous effects and dominance of mutations exists for all major categories of genes analyzed, not just those encoding enzymes. The relationship between dominance and homozygous effects is similar for duplicated and single-copy genes and for genes whose products are members of protein complexes and those that are not. A complete explanation of dominance therefore requires either a generalization of Kacser and Burns' theory to nonenzyme genes or a new theory.
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机译:有害突变的优势对近亲衰退,二倍体进化和自然遗传变异水平等现象具有重要影响。 Kacser and Burns的代谢理论为大多数大效应突变是隐性的提供了范式解释。根据代谢理论,有效突变的隐性是通过代谢途径的通量与途径中任何一步的酶活性之间递减-回归关系的结果,而这又是长代谢途径的必然结果。支持该理论的主要思路是证明果蝇纯合效应与突变优势之间呈负相关,这与代谢理论的中心预测一致。使用有关酵母中基因缺失的数据,我们表明,所分析的所有主要基因类型(不仅是编码酶的基因)都存在纯合效应和突变优势之间的负相关。对于重复和单拷贝基因,以及其产物是蛋白质复合物成员而非蛋白质复合物的基因,优势和纯合效应之间的关系相似。因此,要完全掌握支配地位,就需要将Kacser和Burns的理论推广到非酶基因,或者需要新的理论。
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