A complicated genetic insult

Trisomy for human chromosome 21 produces dosage imbalance for 200–250 genes, resulting in Down’s syndrome. Some features arise in nearly all individuals with the disease, including the characteristic facies, Alzheimer disease-like histopathology, and various structural anomalies of the brain that correspond to a consistent, though variable, cognitive deficit. Trisomy 21 raises the risk of many other traits seen in patients with Down’s syndrome, including cardiac anomalies of septation, leukaemia, and Hirschsprung’s disease. Jerome LeJeune discovered, in 1959, that Down’s syndrome is caused by trisomy, and since then investigation has been focused on correlation of the actions of specific genes with specific aspects of the disorder. For a particular phenotype of Down’s syndrome, dosage imbalance of some genes will contribute and others will have little effect. However, which genes these are, and whether their effects are amplified by the small perturbations of hundreds of genes at dosage imbalance are unknown. The finished sequence of chromosome 21 contains all of the possible genes that contribute primarily to anomalous development in Down’s syndrome. Predictions about the contributions of individual genes to the disease phenotypes can be tested in animals. Comparative mapping in the mouse has identified candidate orthologs for about 150 human chromosome 21 genes. These genes map to the same relative positions in three highly conserved segments on mouse chromosomes 16, 17, and 10. Transgenic mice have extra copies of one or several genes, and segmental trisomy or inclusion of a human chromosome 21 in a mouse produces dosage imbalance for hundreds of the same genes that contribute to Down’s syndrome. Genetic models have led to a focus on the degree to which phenotypes of patients can be modelled in other organisms. Models are relevant where conserved, genetically regulated processes are disrupted in the same way. Development of the skull and craniofacial skeleton provides an example. The skull is an ancient structure, readily identifiable in all vertebrates. The genetic programme that creates this complex structure certainly arose only once in evolution, with modifications to the details of this plan accounting for differences in form among species. The structural conservation of mammalian skulls is such that all corresponding bones can be identified. Almost every individual with Down’s syndrome has immediately recognisable facial features, caused by anomalous development of the underlying craniofacial skeleton. These alterations in craniofacial structure have been measured in individuals with the disease, and changes in specific bones have been documented. Studies show that the same changes arise in the same bones in the craniofacial skeleton and neurocranium of two strains of mice with different degrees of segmental trisomy 16—the same complex genetic insult has disrupted what we presume to be essentially the same network of gene expression to produce a corresponding phenotype in people and in mice (figure). The characteristic reduction in size of the cerebellum of patients relative to the rest of the brain is recapitulated in mice. Mice with segmental trisomy also show a reduction in the density of cerebellar granule neurons, a characteristic which had never been examined in Down’s syndrome. Assessment of the cerebellum of patients showed the same reduction in density—ie, this phenotype was correctly predicted by the mouse model. This precise parallel in adults raised the question, what is the earliest point in development when no difference can be detected between euploid and trisomic individuals? A simple histological analysis shows that the cerebellum of a trisomic mouse is indistinguishable at the day of birth but significantly smaller and hypocellular 6 days later when compared with a healthy brain. This result focuses investigation of the specific cellular and molecular events arising in this small and obviously important time frame. By supporting quantitative assessment of conserved phenotypes at any developmental stage, and by providing the basis for defining subsets of chromosome 21 genes that produce those phenotypes, mouse models provide a means for translating genomic information into biology. These models bring us to a new set of questions about Down’s syndrome, and provide an opportunity to focus research questions in areas most relevant to human beings. This area would arguably be that of cognitive impairment. Mouse models can be used to ask whether there are inherent defects in neurons with three copies of chromosome 21 that prevent them from working properly, or whether they are functionally normal but present in insufficient numbers or are improperly organised because of an early developmental problem. Therapeutic approaches would be quite different in form and in time for these situations. A complete ontogeny of Down’s syndrome phenotypes will ultimately allow intercession at an early and fundamental stage, and will provide insights into development in euploid individuals and those with other genetic anomalies. Smallest region of overlap for effects on skull and craniofacial skeleton