Genomic implications of gene dosage imbalance in autosomal trisomy during neural development

Autosomal trisomy is a numerical chromosomal abnormality with an extra single copy of an autosomal chromosome. The most common and important autosomal trisomy at live birth in human is trisomy 21, Down syndrome. Many efforts had been made to identify loci and genes on human chromosome 21 in association with the neurodevelopmental manifestations in Down syndrome through such methods as gene cloning, locus mapping, animal modelling and chromosome sequencing. However, only very few critical genomic regions in the human chromosome 21 can be linked with the cognitive impairment. It is unlikely that these pathology are due to only a few numbers of specific genes. Current working hypothesis of autosomal trisomy is genome-wide dosage imbalance of increased gene products in the additional chromosome. A direct link of the conditions in Down syndrome to the global gene dosage imbalance is very complex because of its multiple underlying genetic causes and the large number of genes affected by the aneuploidy itself. Most studies, unfortunately, were carried out on adult materials, even amniocytes, placental or fibroblast cells. The abnormalities in brain contributing to the phenotypes in autosomal trisomy are likely to arise during neural differentiation and development. Thus, it is critically important to conduct genome-wide investigation at developmental stage. Recently mouse embryonic stem cell lines containing extra human or mouse autosomal chromosome(s) have been used for transcriptomic study. This opens up an milestone in understanding the genomic implications of gene dosage imbalance in autosomal trisomy. The gene dosage imbalance alters global gene expression of both trisomic and disomic genes during early neural differentiation and development. The autosomal imbalance is associated with specific neuronal loss through premature neural apoptosis during differentiation. New candidate genes are identified in responsible for possible causation of the cognitive conditions of Down syndrome through this approach. The technology serves as substrates to understand the functional changes preceding the morphological abnormalities in Down syndrome that are unequivocally apparent following birth.