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Molecular Signatures of Strong-effect ASD Genes and 16p11.2 Deletion

Understanding how the genetic defects that cause autism lead to abnormal neurodevelopment is critical both to understanding the disorder and to developing effective treatments. One particularly important question is whether different genetic defects produce autism in completely different ways, or alternatively, whether alterations in quite different genes might trigger a cascade of cellular changes that overlap with each other and ultimately produce autism by the same biochemical mechanism.  A number of autism genes have been discovered whose normal function is to help in the regulation of the timing and level of expression of genes throughout the human genome.  Using sequencing techniques to simultaneously measure the regulation of all genes in the genome, Dr. Gusella’s group explored the consequences on gene expression of each of these autism genes and determined whether these effects were distinct or shared.  They also compared these changes in gene expression with the effects of the common autism-associated chromosome 16p deletion.  Importantly, these comparisons were done in authentic human cells at the immature nerve cell precursor stage and throughout their development into mature nerve cells, a process of fundamental relevance to neurodevelopment in autism.  The results of their analysis tested whether the different autism genes produce the disorder by leading to the same kinds of changes in nerve cell development and whether that biochemical mechanism is also triggered by the 16p deletion mutation.