Weinreich Daniel M, Delaney Nigel F, Depristo Mark A, Hartl Daniel L
Department of Organismic and Evolutionary Biology, Harvard University, 16 Divinity Avenue, Cambridge, MA 02138, USA.
Science. 2006 Apr 7;312(5770):111-4. doi: 10.1126/science.1123539.
Five point mutations in a particular beta-lactamase allele jointly increase bacterial resistance to a clinically important antibiotic by a factor of approximately 100,000. In principle, evolution to this high-resistance beta-lactamase might follow any of the 120 mutational trajectories linking these alleles. However, we demonstrate that 102 trajectories are inaccessible to Darwinian selection and that many of the remaining trajectories have negligible probabilities of realization, because four of these five mutations fail to increase drug resistance in some combinations. Pervasive biophysical pleiotropy within the beta-lactamase seems to be responsible, and because such pleiotropy appears to be a general property of missense mutations, we conclude that much protein evolution will be similarly constrained. This implies that the protein tape of life may be largely reproducible and even predictable.
特定β-内酰胺酶等位基因中的五个点突变共同使细菌对一种临床上重要的抗生素的耐药性提高了约100,000倍。原则上，进化到这种高耐药性β-内酰胺酶可能遵循连接这些等位基因的120条突变轨迹中的任何一条。然而，我们证明达尔文选择无法实现102条轨迹，并且其余许多轨迹实现的概率可以忽略不计，因为这五个突变中的四个在某些组合中无法增加耐药性。β-内酰胺酶内普遍存在的生物物理多效性似乎是原因所在，并且由于这种多效性似乎是错义突变的普遍特性，我们得出结论，许多蛋白质进化也将受到类似的限制。这意味着生命的蛋白质磁带在很大程度上可能是可重现的，甚至是可预测的。
