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Finding a Genetic tie to Autism: A Review of the Identification of CNV for 16p11.2

Finding a Genetic tie to Autism: A Review of the Identification of CNV for 16p11.2

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An essay for the 2012 Undergraduate Awards (International Programme) Competition by Maya Ayoub. Originally submitted for Open prompt; a review of a topic affecting "genes and behavior" which interested the student. at Harvard University, with lecturer Yun Zhang in the category of Life Sciences
An essay for the 2012 Undergraduate Awards (International Programme) Competition by Maya Ayoub. Originally submitted for Open prompt; a review of a topic affecting "genes and behavior" which interested the student. at Harvard University, with lecturer Yun Zhang in the category of Life Sciences

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Published by: Undergraduate Awards on Aug 31, 2012
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10/27/2013

 
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Finding a Genetic tie to Autism: A Review of the Identification of CNV for 16p11.2
ABSTRACT.
Currently, the prevalence of Autism Spectrum Disorders (ASD) in Americaaverages to 1 in 88 infants (CDC, 2012). As classified by the
 DSM-IV 
, ASD
s are mainly
exhibited by “the presence of markedly abnormal or impaired development in social interaction
and
communication and a markedly restricted repertoire of activity and interests” (DSM
-IV,2000). The broad classification of the disease and the unavoidably subjective form of diagnosishas caused many researchers to wonder whether the rates of autism vary per country based onvariations in the method for diagnosis, over-diagnosis (attempting to reach resources), or truevariations in frequency (DSM-IV, 2000; Sahin Lecture, 4-7-11). The search for a geneticlinkage is vital to the continued study of the disorders, and thus two methods for identifyingpotential links for ASD will be reviewed and critiqued through this paper. The case study hererevolves around a discovered Copy Number Variation relating to the human 16p11.2 gene.Although methods utilizing clinical research identified evidence for this gene
s linkage to casesof autism (IMGSAC, 1998; Sebat et al, 2007), the importance of mice model research comes inwith the need to accurately study the potential mechanism or pathway of causality (Sebat et al,2007; Horev et al, 2011). Gene 16p11.2 in humans was hypothesized to be located onchromosome 7 region F4 in the mouse genome; this was seen to affect both brain volume andmice behavior in parallel to the changes observed in patients with ASD (Horev et al, 2011). Oneexample is in stereotyped and repetitive behavior in mice engineered with a defect to this region.The largest puzzle still holds in identifying potential mechanisms, as expression patterns of thisgene
s products returned many possibilities (Horev et al, 2011). Both human and mice researchtechniques present their own limitations, however the combination of methods to study onecandidate gene may be key to uncovering the underlying factors to the prevalent AutismSpectrum Disorders.
 
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I. Introduction
Autism Spectrum Disorders (ASD), as classified by the
 DSM IV 
, are mainly exhibited by
“the presence of markedly abnormal or impaired devel
opment in social interaction and
communication and a markedly restricted repertoire of activity and interests” (DSM
-IV, 2000).The diagnosis of the Autistic Disorder, as the definition is laid out, can only occur if symptomsare present before the child is 3 years of age. The diagnosis is also based solely on theobservation of behavioral symptoms; there are no current diagnostic methods which hold true forall cases based on associated research findings or physical exams, although certain cases havebeen observed in different patients (DSM-IV, 2000).The broad classification of the disease and the unavoidably subjective form of diagnosishas caused many researchers to wonder whether the rates of autism vary per country based onvariations in the method for diagnosis, over-diagnosis (attempting to reach resources), or truevariations in frequency (DSM-IV, 2000; Sahin Lecture, 4-7-11). Currently, the autismprevalence in America averages to 1 in 88 infants (CDC, 2012; CDC, 2010; CDC, 2009), makingthis topic one that concerns many families and healthcare providers, and in high demand forresearch advances.Despite the lack of clarity in the cause of the disorder, there has been much evidencepointing researchers to identify a genetic basis for autism. The majority of this evidence hascome from twin studies which have focused on the effect of environment in determining the fateof individuals with identical genomes. In addition to infant-sibling studies, which have shownthat a child is placed at higher risk for autism by virtue of having an elder sibling with autism,these twin studies strongly confirm the existence of a genetic linkage for autism (Folstein &Rutter, 1977; Steffenberg et al, 1989; Bailey et al, 1995; Bailey et al, 1998; Zhao et al, 2007Rogers, 2009; Ozonoff et al, 2011).With this evidence confirming the existence of genetic association with autism, the fieldhas seen many attempts to subsequently locate the connecting factor. There are two overallmethods through which the genetic linkage for autism can be (and has been) researched; the firstreflects the possibility of non-invasively studying human genetic components, either throughgenetic screenings or through pedigree and statistical analyses (Sebat et al, 2007; Zhao et al,2007). The second method is to create an animal model for the potential genetic candidate andstudy the resulting effects on brain and behavior (Horev et al, 2011; Moy et al, 2006)This paper will discuss methods for identifying potential genetic links for autism, throughthe review of select research relating to one potential genetic link: that of Copy NumberVariations, specifically for the human 16p11.2 gene.
II. Characterizing One Gene Candidate: CNV of 16p11.2
Chromosome 16p has been a much-studied candidate for genetic linkage to autism.Although the research on this subject began over ten years ago, the identification of the specificlocus at 11.2 is much more recent. The newest study on the subject, (Horev et al, 2011
 — 
discussed below), has worked towards developing adequate mice models for the Copy NumberVariant strains analogous to 16p11.2 in humans; this study hopes to continue the research in amuch more comprehensive scope of experiments.
A.
 Human Gene Screening Approaches
 
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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
subjects’
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
’s
prevalence in multiple cases of autistic patients wasreconfirmed by genetic screens following IM
GSAC’s
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
Figure 1)
. 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”
(
Figure2
) (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).
B.
 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

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