Polygenic Contribution of the Transcription Factors Gtf2i and Gtf2ird1 of the William’s Syndrome Critical Region to Produce Disease Relevant Phenotypes

Thursday, May 11, 2017: 12:00 PM-1:40 PM
Golden Gate Ballroom (Marriott Marquis Hotel)
N. D. Kopp and J. Dougherty, Genetics, Washington University School of Medicine, St. Louis, MO

Chromosome region 7q11.23 contains dosage-sensitive genes that affect social behavior. The duplication of the region is associated with autism spectrum disorders (ASDs), whereas the reciprocal deletion causes William’s syndrome (WS), a neurodevelopmental disorder characterized by increased social motivation but impaired social interactions. There are 28 genes present at the locus making genotype-phenotype correlations difficult to discern, and it is possible that more than one gene in the locus contribute to the social phenotype. Human and mouse studies have highlighted two paralogous transcription factors, GTF2I and GTF2IRD1, as contributing to the social and anxiety phenotypes. However, prior mouse models that studied these genes individually failed to test the impact of epistatic genetic interactions.


Using newly developed mouse models, we aim to test the hypothesis that the two transcription factors, Gtf2i and Gtf2ird1, interact genetically to affect behaviors related to ASD and WS.


We have generated two knockout mouse lines, Gtf2i+/- and Gtf2ird1+/-, using the CRISPR/Cas9 system. Crossing these two lines yields four genotypes in the offspring: wild type, Gtf2i+/-, Gtf2ird1+/-, and Gtf2i+/-/Gtf2ird1+/-  double mutants. A cohort of these animals (n=83) was run through a battery of behavior tests to assess developmental behaviors, such as maternal separation induced ultrasonic vocalization (USV) and juvenile play, and adult behaviors, such as the sensorimotor battery, open-field, social approach, marble burying, object recognition, T-maze, and tube-test of social dominance. This breeding scheme allows us to determine the main effects of each gene as well as test for genetic interaction between the genes on behavioral performance.


We show that each gene has a main effect on certain behaviors, but there also exists behaviors that are affected by the interaction of the two genes. During development we see that Gtf2i mainly affects the pitch at which pups emit USVs, but that Gtf2i and Gtf2ird1 interact to affect the duration of the USVs. Furthermore, in adulthood we see that Gtf2i mutation alone is sufficient to induce hyper-activity, while Gtf2ird1 mutation alone is sufficient for anxiety-like phenotypes in the open field. Interestingly, we see genetic interactions on multiple behaviors including balance of the mice in the ledge task, and the number of marbles buried during a task of repetitive digging behavior. Finally, we see robust interaction in a social phenotype, the tube test, where only the double mutant mice show a subordinate phenotype.


Using newly developed mouse lines we have shown that two transcription factors located within a region that is associated with two developmental disorders (ASDs and WS) contribute individually to specific phenotypes such as anxiety and hyperactivity but also interact to affect social and motor behaviors, suggesting the related human disorders may also be polygenic in etiology.

See more of: Animal Models
See more of: Animal Models