Identifying the Genetic Drivers of 3q29 Deletion-Associated Phenotypes Open Access

Abstract

The 3q29 deletion is a 1.6 Mb, heterozygous deletion that confers a greater than 40-fold increased risk for schizophrenia. This deletion also confers increased risk for other neurodevelopmental disorders, including autism spectrum disorder and intellectual disability. To interrogate the biological consequences of the 3q29 deletion, the Emory 3q29 project mouse team generated a mouse model harboring a heterozygous deletion of the syntenic region on mouse chromosome 16. These mice display social interaction and growth deficits similar to phenotypes observed in humans with the 3q29 deletion. The FVB mouse genetic background altered the observed growth deficits suggesting that genetic background can modulate the genotype-phenotype relationship. Given the attention that DLG1 has received as a candidate gene, we used Dlg1+/- mice to determine if DLG1 is the causal gene for the observed phenotypes. We saw minor growth deficits in the Dlg+/- mice but did not observe behavioral deficits. To narrow the critical region of distinct phenotypes identified in the full deletion mice, I used CRISPR/cas9 to generate two additional mouse models harboring heterozygous sub deletions of the 3q29 interval. Taken together, we show that the 3q29 deletion mouse model is a tractable entry point to understanding the biological mechanisms underlying complex deletion-associated phenotypes, including neurodevelopment disorders. 

Table of Contents

Introduction …………………………………………………………. 1 

Methods …………………………………………………………..…. 9 

Results ………………………………………………………………. 14 

Discussion …………………………………………………………… 20 

Table 1 ………………………………………………………………. 27 

Table 2 ………………………………………………………………. 28 

Table 3 ………………………………………………………………. 29 

Figure 1 ……………………………………………………………… 30 

Figure 2 ……………………………………………………………… 31 

Figure 3 ……………………………………………………………… 32 

Figure 4 ……………………………………………………………… 33 

Figure 5 ……………………………………………………………… 34 

Figure 6 ……………………………………………………………… 35 

References …………………………………………………………… 36 

About this Master's Thesis

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School	Laney Graduate School
Department	Biological and Biomedical Sciences
Subfield / Discipline	Genetics and Molecular Biology
Degree	M.S.
Submission	Master's Thesis
Language	English
Research Field	Biology, Genetics
Keyword	3q29
Committee Chair / Thesis Advisor	Tamara Caspary, PhD, Emory University
Committee Members	Andrew Escayg, PhD, Emory University Jennifer G Mulle, PhD, Emory University

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