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Physiol Rev. 2009 Jul;89(3):887-920. doi: 10.1152/physrev.00032.2007.

Aneuploidy: from a physiological mechanism of variance to Down syndrome.

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Genes and Disease Program, Genomic Regulation Center-CRG, Pompeu Fabra University, Barcelona Biomedical Research Park, Dr Aiguader 88, PRBB building E, Barcelona 08003, Catalonia, Spain.


Quantitative differences in gene expression emerge as a significant source of variation in natural populations, representing an important substrate for evolution and accounting for a considerable fraction of phenotypic diversity. However, perturbation of gene expression is also the main factor in determining the molecular pathogenesis of numerous aneuploid disorders. In this review, we focus on Down syndrome (DS) as the prototype of "genomic disorder" induced by copy number change. The understanding of the pathogenicity of the extra genomic material in trisomy 21 has accelerated in the last years due to the recent advances in genome sequencing, comparative genome analysis, functional genome exploration, and the use of model organisms. We present recent data on the role of genome-altering processes in the generation of diversity in DS neural phenotypes focusing on the impact of trisomy on brain structure and mental retardation and on biological pathways and cell types in target brain regions (including prefrontal cortex, hippocampus, cerebellum, and basal ganglia). We also review the potential that genetically engineered mouse models of DS bring into the understanding of the molecular biology of human learning disorders.

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