Phadnis Nitin, Fry James D
Department of Biology, University of Rochester, Rochester, New York 14627-0211, USA.
Genetics. 2005 Sep;171(1):385-92. doi: 10.1534/genetics.104.039016. Epub 2005 Jun 21.
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.
有害突变的显性对于诸如近亲繁殖衰退、二倍体进化和自然遗传变异水平等现象具有重要影响。凯瑟和伯恩斯的代谢理论为为何大多数大效应突变是隐性的提供了一个典范性解释。根据代谢理论,大效应突变的隐性是代谢途径通量与该途径中任何一步的酶活性之间收益递减关系的结果,而这又是长代谢途径的必然结果。该理论的一个主要支持证据是在果蝇中证明了纯合效应与突变显性之间存在负相关,这与代谢理论的一个核心预测一致。利用酵母基因缺失的数据,我们表明,对于所分析的所有主要基因类别,而非仅仅是那些编码酶的基因,纯合效应与突变显性之间都存在负相关。对于重复基因和单拷贝基因,以及其产物是蛋白质复合物成员的基因和非此类成员的基因,显性与纯合效应之间的关系是相似的。因此,对显性的完整解释要么需要将凯瑟和伯恩斯的理论推广到非酶基因,要么需要一个新理论。