Transmission ratio distortion in offspring of heterozygous female carriersof Robertsonian translocations

Robertsonian translocations are the most common structural rearrangements o f human chromosomes. Although segregation of Robertsonian chromosomes has b een examined in many families, there is little consensus on whether inherit ance in the balanced progeny conforms to Mendelian ratios. To address this question, we have compiled previously reported segregation data, by sex of parent, for 677 balanced offspring of Robertsonian carriers from 82 informa tive families and from a prenatal diagnosis study on the risk of unbalanced offspring in carriers of chromosome rearrangements. Care was taken to avoi d any source of ascertainment bias. Our analysis supports the following con clusions: (1)the transmission ratio is not independent of the sex of the ca rrier; (2) the transmission ratio distortion is observed consistently only among the offspring of carrier females; (3) the transmission ratio distorti on does not appear to be dependent on the presence of a specific acrocentri c chromosome in the rearrangement. The sex-of-parent-specific origin of the non-Mendelian inheritance, the finding that the rearranged ("mutant") chro mosomes are recovered at significantly higher frequency than the acrocentri c ("normal") chromosomes, and the similarities between these observations a nd the segregation of analogous rearrangements through female meiosis in ot her vertebrates strongly support the hypothesis that the transmission ratio distortion in favor of Robertsonian translocations in the human results fr om the preferential segregation of chromosomes during the first meiotic div ision. This non-Mendelian inheritance will result in increased overall risk of aneuploidies in the families of Robertsonian translocation carriers, in dependently of the origin of the transmission ratio distortion.