Genetic background modulates phenotypes of serotonin transporter Ala56 knock-in mice

Travis M Kerr,Rita Pfeiffer,Randy D Blakely,Nicole Baganz,Jeremy Veenstra-Vanderweele,Christopher S Jetter,Mahfuzur Miah,Christopher L Muller,George M Anderson,Charisma Shah,James S Sutcliffe,Jacqueline N Crawley

doi:10.1186/2040-2392-4-35

Abstract

BackgroundPreviously, we identified multiple, rare serotonin (5-HT) transporter (SERT) variants in children with autism spectrum disorder (ASD). Although in our study the SERT Ala56 variant was over-transmitted to ASD probands, it was also seen in some unaffected individuals, suggesting that associated ASD risk is influenced by the epistatic effects of other genetic variation. Subsequently, we established that mice expressing the SERT Ala56 variant on a 129S6/S4 genetic background display multiple biochemical, physiological and behavioral changes, including hyperserotonemia, altered 5-HT receptor sensitivity, and altered social, communication, and repetitive behavior. Here we explore the effects of genetic background on SERT Ala56 knock-in phenotypes.MethodsTo explore the effects of genetic background, we backcrossed SERT Ala56 mice on the 129 background into a C57BL/6 (B6) background to achieve congenic B6 SERT Ala56 mice, and assessed autism-relevant behavior, including sociability, ultrasonic vocalizations, and repetitive behavior in the home cage, as well as serotonergic phenotypes, including whole blood serotonin levels and serotonin receptor sensitivity.ResultsOne consistent phenotype between the two strains was performance in the tube test for dominance, where mutant mice displayed a greater tendency to withdraw from a social encounter in a narrow tube as compared to wildtype littermate controls. On the B6 background, mutant pup ultrasonic vocalizations were significantly increased, in contrast to decreased vocalizations seen previously on the 129 background. Several phenotypes seen on the 129 background were reduced or absent when the mutation was placed on the B6 background, including hyperserotonemia, 5-HT receptor hypersensivity, and repetitive behavior.ConclusionsOur findings provide a cogent example of how epistatic interactions can modulate the impact of functional genetic variation and suggest that some aspects of social behavior may be especially sensitive to changes in SERT function. Finally, these results provide a platform for the identification of genes that may modulate the risk of ASD in humans.

Highlights

We identified multiple, rare serotonin (5-HT) transporter (SERT) variants in children with autism spectrum disorder (ASD)
Some variant carriers were unaffected by ASD, and a case–control study has reported no association of ASD with rare SERT amino acid variants in the absence of linkage [22], indicating that other genetic or non-genetic risk factors likely impact the resulting phenotype
Our findings reveal a striking influence of genetic background on the impact of the SERT Ala56 variant, suggesting that further dissection of strain differences could illuminate other genes modulating risk of ASD

Summary

Introduction

We identified multiple, rare serotonin (5-HT) transporter (SERT) variants in children with autism spectrum disorder (ASD). In our study the SERT Ala variant was over-transmitted to ASD probands, it was seen in some unaffected individuals, suggesting that associated ASD risk is influenced by the epistatic effects of other genetic variation. In contrast to linkage studies, multiple groups have found, at most, modest association between common SLC6A4 variants and ASD [16,17,18]. Rare SERT coding variants in ASD families with evidence of linkage to 17q. Some variant carriers were unaffected by ASD, and a case–control study has reported no association of ASD with rare SERT amino acid variants in the absence of linkage [22], indicating that other genetic or non-genetic risk factors likely impact the resulting phenotype

Methods

Results

Discussion

Conclusion