Differences in Behavior and Activity Associated with a Poly(A) Expansion in the Dopamine Transporter in Belgian Malinois

Makoto Sato,Lisa Lit,Janelle M Belanger,Anita M Oberbauer,Debby Boehm,Nathan Lybarger

doi:10.1371/journal.pone.0082948

Makoto Sato, Lisa Lit + Show 4 more

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https://doi.org/10.1371/journal.pone.0082948

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Abstract

In Belgian Malinois dogs, a 38-base pair variable number tandem repeat in the dopamine transporter gene (SLC6A3) is associated with behavior changes in Malinois. By additional sequencing in SLC6A3, we identified an intronic 12-nucleotide poly(A) insertion (“PolyA(22)”) before the terminal exon that was associated with seizure, “glazing over” behaviors, and episodic biting behaviors in a sample of 138 Malinois. We next investigated whether PolyA(22) was associated with 1) increased locomotor activity and 2) response to novelty. Using a sample of 22 Malinois and 25 dogs of other breeds, dogs’ activity was monitored in a novel and non-novel environment while wearing activity monitoring collars. All dogs were more active in novel compared with non-novel environments, and Malinois were more active overall than other breeds. There was an effect of PolyA(22) genotype on activity levels, and this effect appeared to underlie the difference detected between Malinois and other breeds. There was no effect of PolyA(22) genotype on the relative decrease in activity between novel and non-novel environments for either group or all dogs considered together. In addition to an association between PolyA(22) and owner reports of seizure, “glazing over” behaviors, and episodic biting behaviors, these findings support an effect of PolyA(22) on dopamine transporter function related to activity. Further investigation is required to confirm mechanistic effects of PolyA(22) on SLC6A3. The complex polygenic nature of behavior and the range of behaviors associated with this insertion predict that effects are likely also modified by additional genetic and environmental factors.

Highlights

The neurotransmitter dopamine has been implicated in pathogenesis of a wide range of behaviors, including aggression, in part due to its wide-ranging role as a neuromodulator
The complex polygenic nature of aggression suggests that the same genetic polymorphism combined with different environmental or genetic backgrounds may result in a wide array of expressions of behavior, including the display of aggression associated with that polymorphism (e.g. [4])
We report on two novel alleles identified through additional fine mapping: an 18-nucleotide deletion found in most breeds we evaluated, and a 12-nucleotide poly(A) insertion found primarily in Belgian Malinois [‘‘PolyA(22)’’] that, like the variable number tandem repeat (VNTR) previously described [12] is associated with owner reports of episodic behavioral changes in dogs, but we hypothesize may be more likely to result in mechanistic changes to SLC6A3 than the VNTR previously described

Summary

Introduction

The neurotransmitter dopamine has been implicated in pathogenesis of a wide range of behaviors, including aggression, in part due to its wide-ranging role as a neuromodulator (reviewed in [1]). The complex polygenic nature of aggression suggests that the same genetic polymorphism combined with different environmental or genetic backgrounds may result in a wide array of expressions of behavior, including the display of aggression associated with that polymorphism A dopaminergic gene that is relevant to aggression and other behavioral changes across species is the dopamine transporter (SLC6A3). In humans SLC6A3 has been associated with aggression [7], hyperactivity [8], and response to novelty [9]. Findings in SLC6A3 knockout mice of differences in aggressive and other social behaviors [10], hyper-locomotion [10], and response to a novel environment [11] further demonstrate a mechanistic link between SLC6A3 and a range of behavioral phenotypes

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