Biology's next top model

Anyone who loves dogs and makes a living studying genomes is sure to enjoy a new collection of reviews entitled ‘The Dog and Its Genome’. A wide range of topics is covered, from the role of dogs in a modern military to clinical trials for gene therapy, and from genetic dissection of congenital hip dysplasia to selection on cognitive function in silver foxes. The question is, though, whether or not someone not so enamored with dogs is likely to find the subject matter interesting and compelling. This question is at the heart of the matter of whether the recent completion of the canine genome sequence will see the domestic dog take its place alongside the laboratory mouse as an indispensable model for human disease.I put this question to one of my own shelties, Paddington. He looked me straight in the eye and firmly expressed his opinion that the real question is whether the human is a useful model for canine disease? There are many indications that it is, but certain deficiencies of the human system limit their utility for identification of susceptibility factors for complex disease. The first generation of the canine haplotype map and increasing interest in canine genetics suggest that much progress is to be expected from direct study of a wide range of breeds.The primary advantage of the dog for mapping complex diseases is that the two-phase recent history of the species, involving initial domestication out-of-Asia approximately 40,000 years ago, followed by very recent selection of over 200 breeds, has left a very convenient haplotype block structure. Within most breeds, it appears that the genome can be regarded as a mosaic of just ten thousand segments, and this number of tagging polymorphisms (SNPs) should be sufficient to conduct a whole genome scan for association between genotype and disease. That is about one tenth the number required for humans, though it remains to be seen whether the density is as comprehensive as theory suggests. Subsequently, more focused sampling across regions in a collection of breeds promises to refine 5 Mb intervals to individual candidate genes, as the boundaries of haplotype blocks are thought to vary among breeds. This scheme is outlined nicely in the book, in the chapter authored by Lindblad-Toh and coworkers, who also provide a more detailed description of the 7.6X assembly of the genome of a boxer as well as initial observations of the canine hapmap in a recent Nature paper [1xGenome sequence, comparative analysis, and haplotype structure of the domestic dog. Lindblad-Toh, K., Wade, C.M., Mikkelsen, T.S., Karlsson, E.K., Jaffe, D.B., Kamal, M., Clamp, M., Chang, J.L., Kulbokas, E.J. 3rd, Zody, M.C. et al. Nature. 2005; 438: 803–819CrossRef | PubMed | Scopus (1185)See all References1].It is becoming apparent that the alleles that promote disease susceptibility are often unevenly distributed across human populations. This presents a considerable drawback for association mapping in humans, because of the so-called population stratification problem, and considerably reduces their utility relative to Canis familiaris. The breed structure of domestic dogs not only provides a framework for study designs that are relatively unaffected by admixture, but also takes advantage of the hypothesis that most common disease alleles have been captured by the inbreeding process. The biggest uncertainty, common to both dogs and humans, is genetic heterogeneity: if different polymorphisms contribute to disease in different populations or breeds, comparisons across these groups are not informative. But many of the alleles of interest likely arose prior to recent breed formation, and the well-known tendency of particular maladies to show breed-specificity can be used to infer likely sharing of descent of the causative alleles. As made clear in the volume under review, this is as true of major-gene diseases such as copper toxicosis and various retinopathies, as it is of the more complex and more prevalent cardiomyopathies, cancers, and dermatitis.Conduction of clinical trials is also much more difficult in humans. Human healthcare is expensive, and members of this species show a predilection toward law suits when things don't go quite right. By contrast, dog trials can be relatively quick to perform, study populations are fairly easily recruited, and it turns out the physiology and endocrinology of disease is often strikingly similar between the large mammals. Though not discussed in the volume, pharmacogenetics may get a boost from dogs, as refractoriness to drugs often displays similar levels as observed in humans — for example, veterinarians will tell you that approximately ten percent of epileptics are non-responsive to the commonly used pharmacological agents — and there is less of the litigious downside to mis-prediction. Gene therapy, too, has definite upsides in canines as various gene delivery approaches can be assessed in dogs for many treatable rare disorders that can actually be bred in study colonies.Why not mice? The simple answer is that most of the complex diseases we see in dogs are naturally occurring, as opposed to having been engineered into caged animals. Our pets share our toxicological and, to some extent, nutritional environment, and the similarities in the time of onset and etiology of so many of the major diseases is striking. It turns out, too, that our genomes are more similar at the level of gene content and sequence than those of rodents, even though rodents share a more recent common ancestor with Homo sapiens than do dogs. This is because of an accelerated rate of divergence in the smaller mammals.Nevertheless, many biomedical researchers, particularly those who serve on study sections, will point out that there are few remaining limits to gene discovery in humans, and what we really need is a model organism that we can manipulate genetically in order to test specific hypotheses. Transgenic dogs expressing GFP-tagged proteins aren't likely to be running around any time soon — though a dog with fluorescent green eyes may go down well with children — while biochemistry and molecular cell biology lag well behind the mouse. Dogs are unlikely ever to become a model for the annotation of gene function.Which brings us back to the reason why there are dogs in the first place: they are physically diverse and attractive, and behaviorally fascinating and useful. Another reason to buy The Dog and its Genome is for the superb 28-page appendix of paintings of 145 breeds. It is remarkable given the variety of shapes and sizes how little attention evolutionary developmental biologists have given to the species. Aside from a few groups performing quantitative trait loci (QTL) mapping within breeds, there is little data on the genetic basis of allometric differentiation, despite the fact that such studies are likely to provide a perspective quite distinct from the one derived from comparison of invertebrate development [2xEndless Forms Most Beautiful: The New Science of Evo Devo and the Making of the Animal Kingdom. Carroll, S.B. See all References2]. Regarding behavior, dogs are even more compelling. Whether it is herding tendencies or separation anxiety, the neurochemistry of seizures, or simply the biology of unconditional love, dogs present opportunities for study that are second to none.