Differences in behavior and activity associated with a poly(a) expansion in the dopamine transporter in Belgian Malinois.

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.

Characterization of a dopamine transporter polymorphism and behavior in Belgian Malinois.

BACKGROUND: The Belgian Malinois dog breed (MAL) is frequently used in law enforcement and military environments. Owners have reported seizures and unpredictable behavioral changes including dogs' eyes "glazing over," dogs' lack of response to environmental stimuli, and loss of behavioral inhibition including owner-directed biting behavior. Dogs with severe behavioral changes may be euthanized as they can represent a danger to humans and other dogs. In the dog, the dopamine transporter gene (DAT) contains a 38-base pair variable number tandem repeat (DAT-VNTR); alleles have either one or two copies of the 38-base pair sequence. The objective of this study was to assess frequency of DAT-VNTR alleles, and characterize the association between DAT-VNTR alleles and behavior in MAL and other breeds. RESULTS: In an American sample of 280 dogs comprising 26 breeds, most breeds are predominantly homozygous for the DAT-VNTR two-tandem-repeat allele (2/2). The one-tandem-repeat allele is over-represented in American MAL (AM-MAL) (n = 144), both as heterozygotes (1/2) and homozygotes (1/1). All AM-MAL with reported seizures (n = 5) were 1/1 genotype. For AM-MAL with at least one "1" allele (1/1 or 1/2 genotype, n = 121), owners reported higher levels of attention, increased frequency of episodic aggression, and increased frequency of loss of responsiveness to environmental stimuli. In behavior observations, Belgian Military Working Dogs (MWD) with 1/1 or 1/2 genotypes displayed fewer distracted behaviors and more stress-related behaviors such as lower posture and increased yawning. Handlers' treatment of MWD varied with DAT-VNTR genotype as did dogs' responses to handlers' behavior. For 1/1 or 1/2 genotype MWD, 1) lower posture after the first aversive stimulus given by handlers was associated with poorer obedience performance; 2) increased aversive stimuli during protection exercises were associated with decreased performance; 3) more aversive stimuli during obedience were associated with more aversive stimuli during protection; and 4) handlers used more aversive stimuli in protection compared with obedience exercises. CONCLUSIONS: The single copy allele of DAT-VNTR is associated with owner-reported seizures, loss of responsiveness to environmental stimuli, episodic aggression, and hyper-vigilance in MAL. Behavioral changes are associated with differential treatment by handlers. Findings should be considered preliminary until replicated in a larger sample.