Two progenitor cells for human oogonia inferred from pedigree data and the X-inactivation imprinting model of the fragile-X syndrome

Abstract

Laird has proposed that the human fragile-X syndrome is caused by abnormal chromosome imprinting. The analysis presented here supports and extends this proposal. Using published pedigrees that include DNA polymorphism (RFLP) data, we establish that the states of the fragile-X mutation termed "imprinted" and "nonimprinted" usually can be distinguished by the level of cytogenetic expression of the fragile-X chromosome. This information is then used to assess the state of the fragile-X allele in carrier progeny of individual women who inherited a nonimprinted fragile-X chromosome. From this assessment, an estimate is made of the frequency, in individual women, of primary oocytes with an imprinted fragile-X chromosome. The results of this analysis provide additional support for the specific model in which chromosome imprinting occurs in a female in, on average, half of her primary oocytes. This is the expected frequency if X-chromosome inactivation is the initial step in the imprinting of the mutant fragile-X allele. Moreover, this analysis suggests a biological explanation for peculiarities of fragile-X inheritance described by others as "clustering" and the "Sherman paradox." We interpret these peculiarities as consequences of a very small number of oogonial progenitor cells. Two progenitor cells for oogonia is the best integer estimate of the number of such cells at the time of the initial event that leads to chromosome imprinting.