  Some argue that N is rarely, if ever, true (e.g., Gillespie 1991), whereas others argue otherwise (e.g., Kimura 1983, Lynch 2007a). An ensemble test involving molecular traits would help resolve this controversy. In addition, the notion of optimality at the molecular level must be made precise. A molecular trait needs to have an identified phenotypic consequence. The endeavor to identify such a consequence will likely always involve a combination of very detailed molecular, biochemical, and phenotypic analyses. However, despite the difficulty of the needed analyses, there are claims as to the optimality of various molecular traits. A canonical example is the claim that triosephosphate isomerase, an enzyme involved in glycolysis in animals, fungi, plants, and some bacteria, is catalytically “perfect” (Albery and Knowles 1976); this is a claim that hypothesis O is true. For molecular traits, the assessment of the influence of natural selection, i.e., distinguishing between hypothesis N and hypotheses U and I, is facilitated by the degeneracy of the genetic code and the existence of non-coding regions in the genome. We expect heterogeneity of the realized influence of natural selection among sites in the genome, and differences in evolutionary rates between sites where a DNA base change alters the protein sequence and those sites that it does not (see examples in Graur and Li 2000, Kreitman and Akashi 1995, Nielsen 2005, and Yang 2006).