Genetic mapping of X-linked loci involved in skewing of X chromosome inactivation in the human

We have analyzed X-chromosome inactivation patterns in lymphocytes of 264 f emales from 38 families not known to have any genetic disease. Quantitative measures of X-inactivation showed strong sister-sister correlation in the degree of departure from equal numbers of cells having each X chromosome ac tive, suggesting heritability of this phenotype. Strong sister-sister corre lation was also observed for the fraction of cells having the same parent's X chromosome active, consistent with the possibility that this trait might be controlled by a cia-acting, X-linked gene. We used a sib-pair approach to determine whether X-inactivation phenotype was linked to loci in any reg ion of the X chromosome. Both quantitative and discrete measures of X-inact ivation phenotype showed evidence of linkage to markers in the region of th e X inactivation center (XIC). The quantitative measure of X-inactivation p henotype used in our study also showed linkage to loci at Xq25-q26. This st udy provides the first evidence for X-linked inheritance of X chromosome in activation phenotype derived from linkage analysis in phenotypically normal human families.