Perhaps the strongest argument for the rare allele model comes from evolutionary theory. Since disease is deleterious to fitness, variants that promote disease should be selected against, and hence disease-promoting variants should not be common3,26,27. The existence of disease-promoting variants reflects the balance between mutation creating new susceptibility variants, and selection preventing them from drifting into the population2,28. Mutation rates are sufficiently large that purifying selection cannot remove all deleterious variants, and those that have a modest effect on fitness (for example, if they influence late-onset diseases 29) may rise to allele frequencies of 1% or occasionally more, particularly if the effect is recessive. But selection is sufficiently efficient that even a fitness reduction of a fraction of a percent will keep allele frequencies from reaching common levels. The argument has been made that relaxed selection in modern humans may favor the accumulation of deleterious rare alleles, greatly increasing the prevalence of disease hundreds of generations into the future30.
