Population genetic consequences of the fragile-X syndrome, based on the X-inactivation imprinting model

We have examined the population genetic consequences of the model of Laird (Genetics 117:587-599, 1987) in which the fragile-X syndrome is caused by "imprinting" of a mutant chromosome. The imprinting event in this model results from a block to reactivation of an inactive X chromosome prior to oogenesis. If it is assumed that males carrying the imprinted chromosome never reproduce, the frequencies of females and males carrying the imprinted chromosome are expected to be equal. When a mutation-selection balance is established, there are expected to be somewhat more than twice as many females carrying the nonimprinted fragile X as carry the imprinted fragile-X chromosome, the excess depending on the fertility of fragile-X females. Nonpenetrant (transmitting) males, i.e., those with the nonimprinted fragile-X chromosome, are expected to be present at about the same frequency as are males with the syndrome. More than one-third of the nonimprinted chromosomes in the population are expected to be newly arisen in each generation. We have considered possible alternatives to the model of a mutation-selection balance. Nonimprinted carrier females would need to have 100% fertility excess to avoid postulating a high mutation rate to account for the very high prevalence of the syndrome.