TRANSLOCATION BREAKPOINT POSSIBLY PREDISPOSES TO NONRANDOM X-CHROMOSOME INACTIVATION IN MOUSE EMBRYOS BEARING SEARLE T(X-16)16H TRANSLOCATION

To clarify the sequence of events that ultimately achieves the nonrand om inactivation of the paternally inherited X chromosome in postpartum female mice heterozygous for T(X;16)16H, we set out to examine the ex pression of Xist alleles and the X-linked HMG-lacZ transgene in embryo s recovered at the egg cylinder stage. Lack of expression of the Xist( b) allele on the 16(x) translocation chromosome in the embryonic regio n of 7.5 d postcoitum (dpc) X-16/X(n)Xist(a);16(x)Xist(b)/ 16 embryos strongly suggested the occurrence of nonrandom inactivation in favor o f the normal X chromosome, The simplest explanation would be biased ch oice, followed by postinactivation selection against genetically unbal anced cells. However, the frequency and distribution of beta-galactosi dase-positive cells in X-16/X(n)lacZ; 16(x)/16 embryos at 6.5 and 7.5 dpc, together with earlier cytogenetic data, raised an intriguing poss ibility that :he majority of 16(x) chromosomes were prevented from com pleting the inactivation process, when they had been chosen to be sile nced. Phenotypes of female mice carrying a spontaneous recombination b etween X-n and 16(x) in the segment defined by the T16H breakpoint and the X-linked Ta locus suggested that the nonrandomness was brought ab out by disruption of an X-chromosomal sequence or structure at the tra nslocation breakpoint.