Abstract
The development of genetic technologies has led to the identification of several copy number variations (CNVs) in the human genome. Genome rearrangements affect dosage-sensitive gene expression in normal brain development. There is strong evidence associating human psychiatric disorders, especially autism spectrum disorders (ASDs) and schizophrenia to genetic risk factors and accumulated CNV risk loci. Deletions in 1q21, 3q29, 15q13, 17p12, and 22q11, as well as duplications in 16p11, 16p13, and 15q11-13 have been reported as recurrent CNVs in ASD and/or schizophrenia. Chromosome engineering can be a useful technology to reflect human diseases in animal models, especially CNV-based psychiatric disorders. This system, based on the Cre/loxP strategy, uses large chromosome rearrangement such as deletion, duplication, inversion, and translocation. Although it is hard to reflect human pathophysiology in animal models, some aspects of molecular pathways, brain anatomy, cognitive, and behavioral phenotypes can be addressed. Some groups have created animal models of psychiatric disorders, ASD, and schizophrenia, which are based on human CNV. These mouse models display some brain anatomical and behavioral abnormalities, providing insight into human neuropsychiatric disorders that will contribute to novel drug screening for these devastating disorders.
Highlights
Copy number variation (CNV) is a structural genomic variation of the human genome that may either be inherited or caused by de novo mutation
CNVs can range in size from kilobases (Kbs) to several megabases (Mbs) that have not been identified by conventional chromosomal analysis
The DECIPHER database is a Consortium comprised of an international network of more than 100 centers and has uploaded more than 2000 cases [5]
Summary
Copy number variation (CNV) is a structural genomic variation of the human genome that may either be inherited or caused by de novo mutation. A recent report using microarray technology revealed that as much as 12% of the human genome are variable in copy number [4] These known CNVs are available from the interactive web-based database DECIPHER (Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources, http://decipher.sanger.ac.uk/). Several efforts have been made to generate mouse models of psychiatric disorders by conventional gene targeting, conditional gene targeting, and point mutation by chemical mutagens These techniques are not enough to reflect complex human genomic rearrangements, such as large deletions, inversions, and duplications. The Cre/loxP-based chromosome engineering technique is useful to generate this kind of complex genomic rearrangements in the mouse genome By using this chromosome engineering technique, we can accomplish CNV-based unbiased animal models of psychiatric disorders. We focus on animal model of ASD (and schizophrenia) which was generated by chromosome engineering, principle of this technology, and discuss for future directions
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