van Opijnen Tim, Boerlijst Maarten C, Berkhout Ben
Department of Human Retrovirology, Academic Medical Centre, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands.
J Virol. 2006 Jul;80(13):6678-85. doi: 10.1128/JVI.02547-05.
A mutation's effect on fitness or phenotype may in part depend on the interaction of the mutation with the environment. The resulting phenotype or fitness is important, since it determines the adaptive potential of a species. To date, most studies have focused on alterations to protein-coding regions of the genome and their consequential fitness effects. Non-protein-coding regulatory regions have been largely neglected, although they make up a large and important part of an organism's genome. Here, we use human immunodeficiency virus type 1 as a model system to investigate fitness effects of random mutations in noncoding DNA-binding sites of the transcriptional promoter. We determined 242 fitness values for 35 viral promoter mutants with one, two, or three mutations across seven distinct cellular environments and identified that (i) all mutants have an effect in at least one cellular environment; (ii) fitness effects are highly dependent on the cellular environment; (iii) disadvantageous and advantageous mutations occur at high and similar frequencies; and (iv) epistatic effects of multiple mutations are rare. Our results underline the evolutionary potential of regulatory regions and indicate that DNA-binding sites evolve under strong selection, while at the same time, they are very plastic to environmental change.
突变对适应性或表型的影响可能部分取决于突变与环境的相互作用。由此产生的表型或适应性很重要，因为它决定了一个物种的适应潜力。迄今为止，大多数研究都集中在基因组蛋白质编码区域的改变及其相应的适应性影响上。非蛋白质编码调控区域在很大程度上被忽视了，尽管它们构成了生物体基因组的一个重要组成部分。在这里，我们以1型人类免疫缺陷病毒为模型系统，研究转录启动子非编码DNA结合位点随机突变的适应性影响。我们测定了35个病毒启动子突变体在七种不同细胞环境中具有一个、两个或三个突变的242个适应性值，并确定：（i）所有突变体在至少一种细胞环境中都有影响；（ii）适应性影响高度依赖于细胞环境；（iii）有害突变和有利突变以高频率且相似的频率出现；（iv）多个突变的上位性效应很少见。我们的结果强调了调控区域的进化潜力，并表明DNA结合位点在强烈选择下进化，同时，它们对环境变化非常具有可塑性。
