In 1998, the International Molecular Genetic Study of Autism Consortium set the stagefor autism genetics research by conducting a comprehensive screen for genes linked to thedisorder. Working with 99 families from different countries, IMGSAC was able to amplify theDNA extracted from their
blood samples (or buccal swabs, in limited cases) usingPolymerase Chain Reaction (PCR). The researchers then screened the pool of DNA for differentmicrosatellite markers, using statistical software to classify the inheritance of differences inspecific loci and the linkage with the disorder. In doing so, the researchers identifiedchromosome 16p as a potential predisposing gene for autism. Their results showed that 16preturned the second-largest rate of linkage with ASD, having a multipoint maximum LOD scoreof greater than 1 (IMGSAC, 1998), for a region whose markers correspond to locus 16p13(Lucarelli et al, 2003). This chromosome
prevalence in multiple cases of autistic patients wasreconfirmed by genetic screens following IM
original project (Philippe et al, 1999;IMGSAC, 2001; Lamb et al, 2005).Building on this research, in April of 2007, Sebat et al honed in on the specific locus16p11.2 in relation to autism. The goal of their study was to specifically check the associationbetween de novo CNVs and autism (Method of analysis outlined in
. Through usinghigh-resolution genomic microarray analysis, it was the first of its kind to study this association(Sebat et al, 2007).The results showed 14 out of 195 ASD patients exhibiting de novo CNVs, as opposed toonly 2 out of the 196 normally-developing control individuals. This demonstrated that thesevariations in genes are indeed linked to the disorder. The loss of locus 16p11.2 was found in onefemale subject, the only member of her family diagnosed with Aspergers. This and other CNVsdiscovered in this study varied from subject to subject, causing Sebat et al. to suggest the geneticcause behind autism to be lesions of different gene regions combined into one disorder. Theresearchers stated that the
“Lack of recurrence
[of any of the mutations] may in fact reflect an
underlying reality that autistic behavior can result from many different genetic defects”
) (Sebat et al, 2007).
Following Sebat et al’s
project, multiple studies have researched the microdeletion of locus 16p11.2, guided by the same questions: what causes the linkage to autism in so manycases, and why do carriers of the deletion exhibit such different phenotypes? Each studyconfirmed the potential linkage and documented new cases of phenotypic results in regards to theCNV (Kumar et al, 2007; Weiss et al, 2008 ; Shimojima et al, 2008; Schaaf et al, 2010; Bijslmaet al, 2009 ; Rosenfeld et al, 2010 ; Shinawi et al, 2010)This research has begun to uncover possible pathways for the genetic barrier to thedisorder. Nonetheless, the results of neither of these two papers can clearly validate causality,potential mechanism of effect, nor even direct influence of the gene candidates identified onautism (Sebat et al, 2007). These last two points are especially important when thinking aboutthe CNV this assay focuses on, as discussed by Horev, et al. (2011).
Mouse Modeling Approach
After having identified a candidate for the genetic basis of autism in humans, the limits of
research in that realm was limited. For this reason, Horev et al (2011), decided to test the gene’s
effects further by creating CNV mutations in mice models, in order to both observe the