Molecular Evolvability In Theory And In A Bacterial Drug-Resistence Gene

基因突变是生物体基因组的随机变化。它们几乎总是对个体有害，但也会发生罕见的有益突变。后者的常见例子包括细菌的抗生素耐药性突变、流感病毒的疫苗耐药性突变和昆虫的杀虫剂耐药性突变。尽管有益的突变在医学和农业上具有重要意义，但由于它们非常罕见，人们还没有很好地了解它们。一个关键的问题是，两个或更多的有益突变相互作用是否会产生比单个效应预期的更大的影响。Drs。Weinreich和Hartl将在大肠杆菌中研究这个问题，使用一种对广泛使用的抗生素头孢噻肟具有耐药性的基因。该基因中有五种不同的突变与耐药性有关。为了研究它们之间的相互作用，研究人员将对这些突变进行所有可能的组合，并研究它们对头孢噻肟耐药性的影响。拟议的研究可能会带来广泛的好处。许多传染病是由病毒或微生物引起的，这些病毒或微生物对临床使用的药物治疗作出反应，迅速演变出有益的突变，以至于在开发出新的药物之前，即使是最新的药物也会失效。对耐药性的研究将有助于更好地了解这些“超级细菌”的起源以及艾滋病毒等病毒的耐药性。这项研究还解决了进化论的几个一般性问题。

Genetic mutations are random changes in an organism's genome. They are almost always harmful to the individual, but rare beneficial mutations do occur. Familiar examples of the latter include mutations for antibiotic resistance in bacteria, vaccine resistance in influenza viruses, and insecticide resistance in insects. In spite of their great medical and agricultural importance, beneficial mutations are not well understood because they are so rare. One critical issue is whether two or more beneficial mutations interact to produce greater effects than would be expected from their individual effects. Drs. Weinreich and Hartl will study this issue in the bacterium Escherichia coli, using a gene for resistance to the widely used antibiotic cefotaxime. Five different mutations in that gene have been associated with resistance. To investigate their interactions, the researchers will make all possible combinations of those mutations and study their effects on cefotaxime resistance.Broad benefits are likely to flow from the proposed research. Many infectious diseases are caused by viruses or microorganisms that, in response to clinical use of drug therapy, evolve beneficial mutations so rapidly that even the newest drugs become ineffective before still newer drugs can be developed. Research on drug resistance will lead to a better understanding of the origin of these "super bugs" and of drug resistance in viruses such as HIV. The study also addresses several general questions of evolutionary theory.