Date of Award

Summer 8-15-2019

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Human & Statistical Genetics)

Degree Name

Doctor of Philosophy (PhD)

Degree Type



Williams syndrome is a neurodevelopmental model caused by the deletion of 26-28 genes on chr7q11.23. The loss of these genes affects multiple organ systems resulting in severe cardiovascular disease, craniofacial dysmorphology, intellectual impairment, a specific Williams syndrome cognitive profile made up of deficits in visual-spatial processing with preserved language skills, and a characteristic hypersocial personality. The reciprocal duplication occurs at a lower frequency and manifests with diametric phenotypes to the deletion. This suggests that this locus harbors dosage sensitive genes that play a role in neurodevelopment. Large efforts have been taken to identify which genes are responsible for causing the different aspects of the disorder. Only the cardiovascular phenotype has been linked to the hemizgosity of the ELN gene. In order to incorporate the complexity of genetic contributions to complex traits, we synthesize genetic and behavioral analyses in both humans and mouse models. We performed whole exome sequencing on 85 individuals with Williams syndrome to test the hypothesis that genetic variation on the remaining chr7q11.23 allele contributes to variation in the social phenotype. We show that the social phenotype consists of deficits in several aspects of social behavior, but social motivation is preserved in Williams syndrome. Whole exome sequencing revealed that there is little common variation contribution to the variability of the social phenotype but did suggest involvement of SNPs in the BAZ1B and GTF2IRD1 genes. Using mouse models, we generated three new mouse lines to test the hypothesis that two genes in the syntenic region, Gtf2i and Gtf2ird1, share overlapping DNA targets and both contribute to overlapping behavioral phenotypes suggesting an oligogenic contribution of these genes to phenotypes relevant to WS. Finally, we show that loss of function mutations in both Gtf2i and Gtf2ird1 are not sufficient to reproduce the full phenotype that is produced by deleting the entire syntenic Williams syndrome critical region in mice. Taken together these data suggest an oligogenic pattern of contribution to the phenotypes seen in WS.


English (en)

Chair and Committee

Joseph D. Dougherty

Committee Members

Yehuda Ben-Shahar, Don Conrad, Harrison Gabel, Christina Gurnett,


Permanent URL: https://doi.org/10.7936/5dc1-td76