Some dogs display unpredictable aggression. This type of aggression often does not have a cause or trigger. It can appear suddenly and out of nowhere. While any dog can have this type of aggression, there are certain breeds of dogs that are more prone to it. The majority of these breeds fall in the fighting breed category. It is recommended that dogs displaying this type of aggression be humanely euthanized. Owning a dog that has unpredictable aggression is a personal and public safety risk, especially if the dog is large enough to inflict serious injury or death to a person or other animal.
Behavioral Variation
Perhaps the most striking behavioral variation observed in dogs is that observed across breeds.5,42,51,53–55,58 In their now classic study, Scott and Fuller58 examined interbreed differences in behavior in the American cocker spaniel, basenji, beagle, Shetland sheepdog, and wire-haired fox terrier. In general, dogs were reared in a standardized environment, although a subset was also cross fostered (across breed) to study the effect of maternal environment and some were reared in private homes to ensure that the performance of the laboratory animals was comparable to dogs in natural social settings.
The study revealed several interesting results. Specifically, the authors found that the cocker spaniel and Shetland sheepdog have much lower reactivity than the beagle, basenji, or wire-haired fox terrier. Reactivity relates to dogs' response to sudden changes in stimuli, such as a doorbell ring. They also found differences in trainability, depending on the specific task. One training task was learning the sit-stay command, which the cocker spaniel and wire-haired fox terrier learned much more quickly than the basenji, with the performance of the beagle and Shetland sheepdog falling in the middle. Breeds were also tested for problem-solving abilities with mazes, manipulation, spatial-orientation, detour, and trailing tests. Interestingly, no breed universally outperformed all the other breeds on all of the tests. Not surprisingly given the tasks, the beagle ranked first for speed of trailing a scent. The basenji ranked first for all the various manipulation tests of pulling strings and moving objects to reveal food items. Because of differences on a number of phenotypic axes, American cocker spaniels and basenjis were crossed to generate experimental, reciprocal backcross populations. F1 and F2 hybrids showed a strong tendency to be intermediate in performance on behavioral tests. Similarly, backcross progeny were intermediate relative to F1 and parental animals. In summary, although a limited number of breeds were characterized, the results of this work represents direct empirical evidence of the pronounced and reproducible behavioral diversity of the dog as well as the existence of genetic components of behavior.
Candidate Genes
As with human behavior, the candidate-gene approach has also been applied to the study of dog genetics, but with very limited success. Studies involving putative behavioral genes, such as those involved in serotonergic, catecholaminergic, and glutamatergic pathways,59–61 have failed to find variants of certain significance, largely because of a small number of study subjects and a lack of functional assays. Screening the coding sequences and intron and exon boundaries of three serotonergic genes in the hopes of understanding aggression in golden retrievers62 has been similarly frustrating. Although interbreed differences in allele frequency are found for some SNPs,59–62 none of the studies clearly defined phenotypes with which to contextualize results and none included sufficiently large numbers of animals to achieve statistical significance.
Whole-Genome Association Studies
Whole-genome association studies (WGASs) can bypass many of the weaknesses associated with candidate-gene studies because WGASs take an unbiased approach to assessing the entire genome. Two studies suggest that WGAS studies in the dog will require significantly fewer SNPs than similar studies in humans because linkage disequilibrium (LD) extends for megabases in the dog, whereas it extends for only kilobases in humans.8,63 In an initial set of experiments, Sutter and colleagues examined five breeds of dog at five unlinked loci and reported a 10-fold range in LD in breeds that ranged from popular to rare and whose individual histories differed in key features such as use of popular sires and occurrence of population bottlenecks. In addition, they showed that, on average, LD extends for about 2 Mb in dogs compared with the frequently quoted number of 0.28 Mb for humans.64,65 These differences reflect not only the breed barrier that defines dog breeds, but also the fact that many breeds originated from small numbers of founders, thus restricting genetic diversity. In addition, the gene pool of many breeds suffers from overrepresentation of popular sires—that is, dogs who do well at performance events and from whom frozen sperm has been collected, producing theoretically hundreds of progeny. Finally, the fact that dog breeds wax and wane in popularity, sometimes increasing or decreasing by as much as 100,000 new registrations per year in less then two decades, as was the case with the rottweiller, affects the gene pool as well. The length of LD in any region will ultimately reflect the alleles that passed through the bottlenecks. The implications of these findings are important for experimental design and suggest that a WGAS in the dog would require as few as 10,000–30,000 SNPs, compared to the 500,000 required for human studies.66,67
These results were validated and expanded in a much larger study by Lindblad-Toh and colleagues as part of the boxer sequencing effort.8 These investigators reported that the dog genome consists of megabase-size regions that are alternatively homozygous and heterozygous. In addition, they reported on characteristics of over 2.1 million SNPs in the dog. Finally, as did Sutter et al.,63 Lindblad-Toh and colleagues highlighted the fact that haplotype sharing between breeds was a common occurrence, although haplotype diversity was more rare then expected.8This important result suggests that a single SNP chip could be developed and used for mapping in all breeds of dogs. As a result, several such resources have been or are being produced, including the now widely available Affymetrix chip that contains nearly 127,000 SNPs.
One caveat to the above is that although long-range LD makes the identification of initial loci less problematic than similar studies in humans, it is likely to make the move from linked marker to gene more challenging. Initial findings of linkage may extend for megabases and span nearly a hundred genes.68Multiple strategies will probably be needed to overcome this problem. The first is the use of cross-breed comparisons. Parker et al. have shown that modern dog breeds can be divided into five major groups, with the members of each groups sharing some common ancestry.9,10 As was demonstrated by the identification of two disease mutations relevant for canine vision disorders9,69 and identification of a gene for body size,70 the analysis of haplotypes from affected dogs belonging to breeds from the same group allows for significant reduction in the region of linkage. The use of samples that are from dog lineages from that same breed but that are either comparatively out bred, or that share few common founders or popular sires between lines, can produce the same results.
Ultimately, however, functional studies will be needed to develop a complete understanding of how any germline variant affects behavior. It has been suggested that the development of cross-bred lines of dogs would be useful in this regard. Although this is theoretically true, the development and maintenance of a behavioral colony of dogs is extremely expensive and, frankly, an unpopular concept because of spiraling animal-care costs, long-term funding worries, and animal-welfare concerns. In addition, it is well recognized that many social behaviors in dogs do not appear in a colony setting and require interaction to develop. Much more likely will be the incorporation of mouse or other behavioral models to test putative behavioral variants.
Where Will the Causative Variants Be?
Many behavioral-mapping studies are likely to reveal a role for changes in noncoding and regulatory regions. Indeed, given that coding regions are typically under the most selective constraint, these sequences typically evolve at a slower rate than noncoding sequences. As a result of the recent divergence of dogs from wolves and the subsequent radiation of the dog, it is likely that substitutions in noncoding regulatory regions that control transcription levels, message stability, and localization, as well as splicing, will be important. Two studies have examined differential gene expression in the canine brain.71,72 In the study of Saetre and colleagues, brain regions thought to be important in emotion and cognition, such as the hypothalamus, amygdala, and frontal cortex, were compared in postmortem brain samples from ten each of dogs and coyotes, and from five wolves, by use of a cDNA microarray containing 7762 genes. Divergence in gene expression in the frontal lobe correlated with the evolutionary distances between species. Expression profiles of the amygdala were differentiated, but did not correlate with evolutionary distance or domestication. In contrast, gene expression in hypothalamus, which controls specific emotional and endocrinological responses, was highly conserved among the wild canids, yet divergent in the dog. Saetre et al.71 have postulated that behavioral selection for domestication may be the result of simple changes in gene regulation by genes in the hypothalamus.
Lindberg and colleagues examined gene expression for three brain regions in tame and unselected foxes from the colony in Noversebirsk, as well as foxes living in the wild.72 Whereas they found large differences between the wild and farm animals, only small differences were seen between the tame and nonselected farm lines. This suggests that the behavioral and physiological changes caused by selection for tameness might be associated with only limited changes in gene expression in the fox brain.
What's Wrong with My Dog?
Questions regarding abnormal behaviors in dogs are among the most frequently asked questions of behaviorists. Although there is little evidence for complex disorders like bipolar disease, dog-behavior experts have long treated dogs for anxiety and depression. Also, as described above, sleep disorders, which are prevalent in humans, occur in dogs.73Indeed, the genetic study of canine narcolepsy is an excellent demonstration of how canine genetics can inform our understanding of common human diseases. Although inherited narcolepsy is rare in both humans and canines, sleep disorders are extremely common in humans. In 1999, long-term studies by Mignot and colleagues revealed that canine narcolepsy, which segregated in a colony of Doberman pinchers, was caused by a mutation in the hypocretin (orexin) receptor 2 gene.34 This important discovery lead to subsequent findings74,75 that regard the molecular biology of sleep modulation and that have proven critical for more general studies of sleep disorders in humans.
The dog is also likely to contribute to our understanding of the pathways involved in obsessive-compulsive disorder (OCD). Although human OCD is often believed to have at least a partial a hereditary component, both candidate-gene and linkage studies have yet to identify causative mutations, genes, or pathways underlying the disorder.76 OCD has been described in several dog breeds, particularly the bull terrier and related breeds.37 Affected dogs display an obsessive tail-chasing behavior that responds to treatment with serotonin-reuptake inhibitors such as clomipramine hydrochloride, suggesting that they are true obsessive-compulsive disorders and not the result of a seizure. Although the gene for this disorder has not yet been found, the fact that the disorder occurs in only a small subset of related terrier breeds (bull terriers, miniature bull terrier, American Staffordshire terrier, and Jack Russell terrier) makes it a good candidate for either a family-based linkage study or a WGAS.
How many other human disorders can we learn about by studying anomalous behavior in dogs? Certainly aggression has been considered at length.62 However, the social and political ramifications of identifying genes that control this complex behavior are not lost on either the companion animal or human-genetics communities. Dog fanciers argue that there are “no bad dogs, only bad dog owners” and that laws that would outlaw so-called “aggressive” dog breeds within city limits are discriminatory to owners of those breeds. In terms of human genetics, the considerations are much more complex. Ethicists will be faced with difficult discussions about both individual and social responsibilities for violent actions on the part of individuals carrying certain mutations. More likely to be palatable to both communities are studies of depression and anxiety, which clearly exist in humans and dogs and for which a genetic understanding would be welcome.
Performance-Enhancing Polymorphisms
Although behavioral studies are often couched in the negative (i.e., what is wrong with my dog?), of equal interest to canine behaviorists are studies of performance genetics. We recently showed that two copies of a protein-truncating mutation in the myostatin gene (MSTN) are found in whippet dogs with a heavily muscled phenotype known as “bully” whippets.77 However of even greater interest is the observation that heterozygotes, who carry only one copy of the mutation and who are, on average, more muscular than the typically lean wild-type, compete more successfully in racing events than individuals who lack the mutation. These results highlight the importance of “performance-enhancing polymorphisms” as well as raise questions about the role of MSTN and similar genes in human athletics.77We found only one report of a human who is a homozygote for mutations in MSTN, a child who is heavily muscled and whose mother was reportedly an Olympic-class swimmer.78 How many athletes are heterozygotes for mutations in this or other performance-enhancing genes? It is difficult to even speculate, but certainly several.
Conclusions
For years the dog has been suggested as an ideal system for studies of behavioral genetics.79 With the genome now mapped and sequenced and tools for building haplotypes and studying expression at hand, it is time to tackle the hard experiments. Why is the basset hound less effective at herding sheep or an Anatolian shepherd less effective as a hunting dog? More importantly, why do Australian shepherd dogs herd and greyhounds chase, both in the absence of instruction? Why did the domestication of dogs lead to a level of loyalty and devotion unrivaled among modern mammals?
For many geneticists, the most interesting behaviors in dogs are those that are highly breed associated, such as herding and pointing. For others, the challenge is to understand the genetic variation that contributes to the individual variation between dogs (personality). Still others see in man's best friend a mirror of our best (loyalty, steadfastness, trainability, strong work ethic) and worst (stubbornness, aggression, and anxiety) qualities. An understanding of the genetics of all of these traits is likely to produce a better understand of not only the canine species, but the human species as well.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2253978/
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