"usually involves a number of deaths equal to about 10 or 20 times the number in a generation" – the minimum being the population size (= "the number in a generation") and rarely being 100 times that number. Haldane assumes 30 to be the mean value. Assuming substitution of genes to take place slowly, one gene at a time over n generations, the fitness of the species will fall below the optimum (achieved when the substitution is complete) by a factor of about 30/n, so long as this is small – small enough to prevent extinction. Haldane doubts that high intensities – such as in the case of the peppered moth – have occurred frequently and estimates that a value of n = 300 is a probable number of generations. This gives a selection intensity of . Haldane then continues: The number of loci in a vertebrate species has been estimated at about 40,000. 'Good' species, even when closely related, may differ at several thousand loci, even if the differences at most of them are very slight. But it takes as many deaths, or their equivalents, to replace a gene by one producing a barely distinguishable phenotype as by one producing a very different one. If two species differ at 1000 loci, and the mean rate of gene substitution, as has been suggested, is one per 300 generations, it will take 300,000 generations to generate an interspecific difference. It may take a good deal more, for if an allele a1 is replaced by a10, the population may pass through stages where the commonest genotype is a1a1, a2a2, a3a3, and so on, successively, the various alleles in turn giving maximal fitness in the existing environment and the residual environment. The number 300 of generations is a conservative estimate for a slowly evolving species not at the brink of extinction by Haldane's calculation. For a difference of at least 1,000 genes, 300,000 generations might be needed – maybe more, if some gene runs through more than one optimisation. Origin of the term "Haldane's dilemma" Apparently the first use of the term "Haldane's dilemma" was by paleontologist Leigh Van Valen in his 1963 paper "Haldane's Dilemma, Evolutionary Rates, and Heterosis". Van Valen writes: Haldane (1957 [= The Cost of Natural Selection]) drew attention to the fact that in the process of the evolutionary substitution of one allele for another, at any intensity of