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Luo R, Sanders SJ, Tian Y, Voineagu I, Huang N, Chu SH, Klei L, Cai C, Ou J, Lowe JK, Hurles ME, Devlin B, State MW, Geschwind DH. Genome-wide Transcriptome Profiling Reveals the Functional Impact of Rare De Novo and Recurrent CNVs in Autism Spectrum Disorders. Am J Hum Genet. 2012 Jun 21 ; Pubmed Abstract

Comments on News and Primary Papers
Comment by:  Karoly Mirnics, SRF Advisor
Submitted 16 July 2012
Posted 16 July 2012

This is another excellent genomics study from the Geschwind laboratory, challenging us to think in the context of gene networks (rather than single genes). We always knew that genome deletion, duplications, and mutations will have an effect on development and cellular function only if they ultimately affect gene expression, but rarely has this been proven so eloquently as in this study. Knowing a genetic alteration is not sufficient—the consequences are what matter—and establishing the relevance/causality of mutations and CNVs vis--vis a disease process is quite challenging. Combining genetics and genomics can help to achieve this, especially if the expression studies can be performed on peripheral tissues from living patients. Still, even this approach has limitations: the brain has a very different expression profile from peripheral tissues—and the real effect of altered genetic sequence cannot be evaluated if a gene is uniquely expressed in the brain. Furthermore, we know that in schizophrenia, expression events in the periphery and the CNS are only marginally overlapping, and a number of neurotransmitters and phenotype-specific functional proteins are not expressed outside of the brain. In these cases, inhibitory postsynaptic currents (IPSCs) might be very beneficial to study the cause-effect relationship and in evaluating the significance of the genetic alterations. However, the approach of the Geschwind lab is perfectly suited for evaluation of multifunctional, generic developmental gene networks, where the genes are expressed and play a similar role across various tissues. It is also important to expand these studies to many patients across a variety of human brain disorders; otherwise, due to the staggering number of genetic variations, we might not be able to recognize the common patterns that are essential for understanding mental disorders.

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