Quantitative trait locus mapping and analysis of heritable variation in affiliative social behavior and co‐occurring traits

Abstract

Humans exhibit broad heterogeneity in affiliative social behavior. Twin and family studies show that individual differences in core dimensions of social behavior are heritable, yet there are knowledge gaps in understanding the underlying genetic and neurobiological mechanisms. Animal genetic reference panels (GRPs) provide a tractable strategy for examining the behavioral and genetic architecture of complex traits. Here, using males from 50 mouse strains from the BXD GRP, 4 domains of affiliative social behavior—social approach, social recognition, direct social interaction (DSI) (partner sniffing) and vocal communication—were examined in 2 widely used behavioral tasks—the 3‐chamber and DSI tasks. There was continuous and broad variation in social and nonsocial traits, with moderate to high heritability of social approach sniff preference (0.31), ultrasonic vocalization (USV) count (0.39), partner sniffing (0.51), locomotor activity (0.54‐0.66) and anxiety‐like behavior (0.36). Principal component analysis shows that variation in social and nonsocial traits are attributable to 5 independent factors. Genome‐wide mapping identified significant quantitative trait loci for USV count on chromosome (Chr) 18 and locomotor activity on Chr X, with suggestive loci and candidate quantitative trait genes identified for all traits with one notable exception—partner sniffing in the DSI task. The results show heritable variation in sociability, which is independent of variation in activity and anxiety‐like traits. In addition, a highly heritable and ethological domain of affiliative sociability—partner sniffing—appears highly polygenic. These findings establish a basis for identifying functional natural variants, leading to a new understanding typical and atypical sociability.

Gtf2i and Gtf2ird1 mutation are not sufficient to reproduce mouse phenotypes caused by the Williams Syndrome critical region

“…The three-chamber social approach assay has come under recent criticism due to how dependent it is on activity levels of mice and its lower heritability compared to tests of direct social interaction (53). The CD animals had not previously been tested in this procedure excatly, but have been tested in a modified social approach where the time spent investigating a mouse in a cup is measured but with no competing non-social stimulus (28, 46, 47).…”

“…Direct social tasks have higher heritability than the three-chamber social approach and offer a more natural social experience (53), which may make them a more sensitive assay for testing social behaviors. Direct tasks have shown that Gtf2i models have increased nose-to-nose investigation time (36), mouse models lacking the proximal end of the region have increased investigation frequency (29), and Gtf2ird1 mutants make fewer aggressive actions but show increased following time (30).…”

Individual variation in the attribution of incentive salience to social cues

“…Finally, this study is the first to demonstrate individual variation in social behaviors in an outbred rodent population. Previously, it has been demonstrated that there are strain differences in conditioned place preference/aversion, social interaction, and social novelty-seeking in rodents (Knoll et al, 2018, Moy et al, 2009, Pinheiro et al, 2016, Ryan et al, 2008; however, all these studies were performed in inbred populations.…”

Using a mouse model to gain insights into developmental coordination disorder

“…To overcome the limitations of the single gene approach, Molenhuis et al proposed that animal models should evaluate the clinical impact of etiological factors on continuous behavioral traits across varying genetics backgrounds. This is done through a classical approach using genetic mapping of quantitative traits in inbred lines of mice . This approach has been used in the context of autistic‐like phenotypes to identify quantitative trait loci (QTLs) underlying social interaction differences between C57BL/6J and the BTBR mouse model …”