Tetrasomy 16 in the mouse: a more severe condition than the corresponding trisomy

Although an understanding of the phenotypic similarities and differences between individuals trisomic and tetrasomic for the same chromosome or chromosome segment is of considerable theoretical interest with regard to the relationship of the phenotypic features of aneuploid states to changes in the dosage of specific genes, the data obtainable from human cases of tetrasomy do not permit firm conclusions to be drawn. However, a mouse model system based on the intercrossing of animals doubly heterozygous for two Robertsonian translocation (metacentric) chromosomes with monobrachial homology can be used to generate both tetrasomic and trisomic embryos simultaneously. With mice carrying the two metacentric chromosomes, Rb(11.16)2H and Rb(16.17)32Lub, which share chromosome 16 in common, embryos with tetrasomy 16 and trisomy 16 have been generated. The rate of non-disjunction in both males and females was 34 to 36%, and the observed overall frequency of tetrasomics in embryos up to 10 days of age was 3.3%, very close to the expected 3.1%. Although trisomy 16 and tetrasomy 16 embryos could not be distinguished by size from one another or from diploid embryos at the sixth day of gestation, the tetrasomy 16 embryos were very small and delayed in development at day 10 and clearly distinguishable from the trisomics. Fusion of the anterior neuropore had not occurred, rotation of the embryo was incomplete, and somite formation was retarded. By day 12, all of the tetrasomy 16 embryos were either dead or dying. By contrast, virtually all trisomy 16 embryos were alive at day 10, although about 60% were retarded in development. The same was also the case on day 12 for trisomy 16 embryos obtained from mothers that were naturally mated. However, superovulation of the mothers, which caused a doubling of the number of implants, resulted in a significant decrease in the frequency of trisomy 16 embryos and possibly of tetrasomy 16 embryos as well. This finding is consistent with the suggestion that the viability of aneuploid embryos, which may be at a proliferative disadvantage, is highly dependent upon intrauterine conditions. These exogenous factors notwithstanding, it is clear that tetrasomy 16 has much more deleterious effects on embryonic development than does trisomy 16 and that four doses of the genes on chromosome 16 result in developmental derangements greater than are produced by three doses of the same genes.