Haldane's dilemma, also known as "the waiting time problem", is a limit on the speed of beneficial evolution, calculated by J. B. S. Haldane in 1957. Before the invention of DNA sequencing technologies, it was not known how much polymorphism DNA harbored, although alloenzymes (variant forms of an enzyme which differ structurally but not functionally from other alloenzymes coded for by different alleles at the same locus) were beginning to make it clear that substantial polymorphism existed. This was puzzling because the amount of polymorphism known to exist seemed to exceed the theoretical limits that Haldane calculated, that is, the limits imposed if polymorphisms present in the population generally influence an organism's fitness. Motoo Kimura's landmark paper on neutral theory in 1968 built on Haldane's work to suggest that most molecular evolution is neutral, resolving the dilemma. Although neutral evolution remains the consensus theory among modern biologists, and thus Kimura's resolution of Haldane's dilemma is widely regarded as correct, some biologists argue that adaptive evolution explains a large fraction of substitutions in protein coding sequence, and they propose alternative solutions to Haldane's dilemma. Substitution cost In the introduction to The Cost of Natural Selection Haldane writes that it is difficult for breeders to simultaneously select all the desired qualities, partly because the required genes may not be found together in the stock; but, he writes, especially in slowly breeding animals such as cattle, one cannot cull even half the females, even though only one in a hundred of them combines the various qualities desired. That is, the problem for the cattle breeder is that keeping only the specimens with the desired qualities will lower the reproductive capability too much to keep a useful breeding stock. Haldane states that this same problem arises with respect to natural selection. Characters that are positively correlated at one time may be negatively correlated at a later time, so simultaneous optimization of more than one character is a problem also in nature. And, as Haldane writes [i]n this paper I shall try to make quantitative the fairly obvious statement that natural selection cannot occur with great intensity for a number of characters at once unless they happen to be controlled by the same genes. In faster breeding species there is less of a problem. Haldane mentions the peppered moth, Biston betularia, whose variation in pigmentation is determined by several alleles at a single gene. One