The Ivermectin Study
The genetic mutation responsible for a specific reaction to ivermectin marks the emergence of breeds from the collie ancestry.
The people who ran the Ivermectin DNA study wish to thank all of you who participated by sending in DNA samples. A report on this study entitled: Breed distribution and history of canine mdr1-1delta, a pharmacogenetic mutation that marks the emergence of breeds from the collie lineage is available online at http://www.pnas.org/cgi/content/full/101/32/11725
Since much of the report seems to be proving the scientific validity of the process, and it’s difficult for the non-genetics aficionados to understand (it’s above my head), I have tried to hit the high points. I asked a couple of friends who are well versed in genetics to review it to make sure I got it correct.
The introduction to the report says:
“A mutation in the canine multidrug resistance gene, MDR1, has previously been associated with drug sensitivities in two breeds from the collie lineage. We exploited breed phylogeny and reports of drug sensitivity to survey other purebred populations that might be genetically at risk. We found that the same allele, mdr1-1, segregated in seven additional breeds, including two sighthounds that were not expected to share collie ancestry. A mutant haplotype that was conserved among affected breeds indicated that the allele was identical by descent. Based on breed histories and the extent of linkage disequilibrium, we conclude that all dogs carrying mdr1-1 are descendants of a dog that lived in Great Britain before the genetic isolation of breeds by registry (ca. 1873). The breed distribution and frequency of mdr1-1 have applications in veterinary medicine and selective breeding, whereas the allele’s history recounts the emergence of formally recognized breeds from an admixed population of working sheepdogs.”
So in addition to identifying the breeds that are at risk of adverse reactions to certain drugs, and furthering the science of the genome, the study proved that the new breeds of Long Haired Whippets and Silken Windhounds are descended from a Shetland Sheepdog which carries a particular haplotype.
The English Shepherd breed is one of the breeds found to have the mutation. From the 91 samples that were received, roughly 14% carried the gene. Of the samples received no English Shepherd sample was homozygous for the mutation.
The gene causes a defect in the blood brain barrier which protects mammals from toxic substances, allowing ivermectin -which causes paralysis in parasites- to enter the central nervous system. Affected collies were found to be homozygous for the mutation which they call MRD1-1 Delta. Being homozygous means that both parents carry the mutation.
A haplotype is a series of genes that lie close together on a chromosome. Because of their proximity, they are usually inherited as a group during crossing over and recombination of the chromosomes when the gametes are forming.
The study identified several different haplotypes that are associated with MDR1-1Delta.
They recorded which haplotype was present in each sample that had the gene.
Quoting from the article:
“History of mdr1-1. Dogs carrying mdr1-1 share a common ancestor that experienced remarkable evolutionary success, having contributed genetically to at least nine distinct breeds of dog. We propose that this animal lived in Great Britain in the 1800s, before the emergence of formal breeds. Before 1870, there were no established registries for sheepdogs, only regional varieties of working dogs that had been adapted to terrain, climate, breed of sheep, and working style. Industrialization in the 19th century brought changes in trade and transportation that may have facilitated admixture among these varieties. Socioeconomic changes almost certainly altered the role of working dogs because they were no longer needed to drive sheep over long distances to market.”
Although a few specialized strains rose in prominence, perhaps aided by success at field trial events (42), many strains such as the Galway Collie, the Dalesman, the Manx Sheepdog, and the Welsh Gray gradually began to disappear. The neglect of regional varieties may have contributed directly to the advent of dog shows, which aimed to preserve and restore strains by emphasizing form rather than function. The first bench show to admit herding dogs took place in Birmingham in 1860, with one class open to all ‘‘sheepdogs, colleys, yard, or keeper’s dogs (42).’’ This show marked the beginning of an important transition in the history of sheepdogs, from regional variety to registered breed, and from anonymous working dog to pedigreed purebred (reviewed in ref. 43).
The first formal breeds to emerge from working sheepdog populations were the Collie, Old English Sheepdog, and Shetland Sheepdog. Several influential founders of the Collie breed, such as Old Cockie and Trefoil, were born in the 1860s (42). Old Cockie and his grandson, Charlemagne
According to Baskerville, ‘‘Next to nothing was known of the pedigrees of the aforementioned dogs except that the majority of them came from a working strain of sheepdogs (37).’’ Working collies contributed genetically to the Shetland Sheepdog, which probably accounts for the presence of mdr1-1 in the latter breed. Thus, the allele may have already been prevalent among working collies by the 1890s.
The Old English Sheepdog was a founding member of the Kennel Club of England in 1873, and has probably been genetically isolated from other collie-related breeds since that time. Unlike the Shetland Sheepdog, the Old English Sheepdog is distinct from the Collie in size, shape, and behavior, so registered show Collies are unlikely to have been the source of mdr1-1. Rather, admixture among the working progenitors of these two breeds is the more likely explanation.
A collection of essays on pastoral life in 19th century Great Britain describes shepherds as using two complementary types of dog: the smaller collies that excelled at herding, and the larger, more versatile ‘‘old English type’’ that could drive, protect, and herd the flock (44). The use of both types by shepherds presumably afforded gene flow. Thus, the ancestral population that produced mdr1-1 was probably an admixed population of working sheepdogs. The ancestors of the Australian Shepherd, English Shepherd, and McNab also trace back to this ancestral population, roughly defined. Although these latter breeds were developed in North America in the 1900s, they were most likely derived from nondescript farm collies imported from Great Britain and Australia in the 1800s and early 1900s. Champion Christopher born 1887, imported by Mitchell Harrison in Philadelphia.
Several lines of evidence suggest that the mdr1-1 mutation event predated the formal establishment of British herding breeds, beginning in 1873. The high frequency of mdr1-1 in both subpopulations of Collies, the broad distribution of haplotypes I and II among multiple breeds, and the distinct haplotypes of the Old English Sheepdog together suggest that mdr1-1 was widely dispersed by the time breeds were being registered.Although based on several assumptions, the allele age estimates suggested that mdr1-1 was not an ancient allele (e.g., one introduced into the British Isles by Roman or Viking dogs; Fig. 1). Thus, the allele may not be broadly distributed beyond the collie lineage, except as a consequence of focused introgression.
The presence of the mutation in sighthounds may provide a more recent historical perspective on mdr1-1. Reports of ivermectin sensitivity in these dogs were initially explained as having resulted from well known crosses between Queen Victoria’s Collies and Borzois given to her by Czar Nicholas II (I. Combe, personal communication). However, the strong LD and the limited number of mutant haplotypes in sighthounds were consistent with a more recent event. The Longhaired Whippet is described as an ancient variety that was apparently restored in the 1950s by a single breeder who also bred Shetland Sheepdogs. It is interesting to speculate that mdr1-1 accompanied an allele for long hair during focused introgression, through either linkage or drift. Both the Longhaired Whippet and Shetland Sheepdog favor haplotype II (Table 3), which is consistent with this interpretation. The Silken Windhound was developed even more recently (in the 1980s) by crossing multiple sighthound breeds, including the Borzoi, Whippet, and Longhaired Whippet; the latter is the probable source of mdr1-1 (Fig. 4). This explanation is also consistent with a preference for haplotype II in both breeds (Table 3).
The Importance of Genetic Drift. Within each breed, the genotype frequencies were consistent with Hardy–Weinberg equilibrium. Thus, there was no evidence of selection or nonrandom mating with respect to mdr1-1. Therefore, the allele frequency differences observed among breeds (4–50%) may be attributable to genetic drift, perhaps aided by the rapid expansion of formal breed populations since the late 1800s. The high frequency of mdr1-1 in the Longhaired Whippet (42%) is also likely to be a consequence of drift. This frequency is five-fold greater than that of the Shetland Sheepdog (8%), the suspected source of the allele. These results support the view that genetic drift, in addition to artificial selection, has played an important role in defining the genetic composition of breeds.
Collies had become quite the rage with the very wealthy subsequent to Queen Victoria taking a liking to them. The Collie Club of America Inc. was organized in 1886, two years after the establishment of the American Kennel Club (AKC), and was the second breed parent club to join the AKC. The collie club came up with the Challenge Trophy and Sam Untermeyer and J. Pierpont Morgan competed for the best blood from Great Britain. This marks the initial divergence between working dogs and show dogs, although the show collies were still being used on farms in this country well into the early decades of the twentieth century. The first registration of English Shepherds we are aware of is 1934 with the United Kennel club. Unfortunately most of our early records were lost in a fire.
Sefton Hero, purchased for the sum of $5000, and imported by J.P. Morgan was born in 1891.
J.P . Morgan also imported and Ch. Wishaw Clinker (who was born in 1898 after the 1893 influx of Borzoi blood in the queen’s kennels) at $10,000, quite a hefty sum in those days!
Here is a relative :
An interesting observation in table 3 is that the most prevalent haplotype in our breed is only found in common with the collies from Great Britain. Most of the ancestors of our breed had been in this country since the mid seventeen hundreds; records show that Plymouth had Milking Devon cattle and Wiltshire Horn sheep as early as 1624, and it would be unlikely that they brought sheep with no dogs to help herd and protect them. Leicester Longwool sheep are documented from the mid-Atlantic north from the mid 1700s and Tunis sheep from the late 1700s, so they are accurate for Colonial Williamburg. Poultry was also imported extensively.
I speculate that perhaps one of the late 1800s collie imports during the establishment of modern purebred breeding systems and registries was found to be useful to the farm people and had more genetic success contributing to our breed. Before the influx of Borzoi blood people did not recognize the British type of show collie and the American collie as distinct breeds. They crossed the imports with local collie females.
The Dog Book, by James Watson, published in 1906 pictures this dog and identifies her as a collie of American breeding, and her female line was American, although she was by Ch. Scotilla, one of Morgan’s earlier imports:
So perhaps there was some dog that carried that variant of mdr1-1delta that entered our population among the imported dogs in the late eighteen hundreds. It is fun to speculate.
More information about the history of show collies and farm collies in this country can be found at Gina Bisco’s website, Collies Back to the Future. Of particular interest are the articles in the Country Life in America magazine from the early twentieth century.
Another possible explanation as to why our breed has the haplotype in common with the British Collies could be that it existed in the Mohns’ line that was imported in the 1930s. June Mohns told me that her late husband Harold’s father was importing Percheron horses from England and they would let him have one dog with every pair of horses that he bought.
However, determining the source of the mutation is not as important as answering the question- “where do we go from here?”
The article states:
Applications of mdr1-1_ Genetics. An understanding of the genetic basis of differential drug response can be used to identify individuals that might be predisposed to adverse drug effects. Veterinarians can use DNA testing of mdr1-1_ to screen animals before administering certain therapeutic drugs. Denying entire breeds an effective treatment, which is currently done with ivermectin and herding breeds, is now unnecessary; clinicians can treat animals based on genotype rather than breed affiliation. The pharmacogenetics approach can be extended to treatment with all drugs that are P-glycoprotein substrates. More than 20 drugs are known substrates (Table 4); each could exhibit a unique dose–toxicity curve among MDR1 genotypes. Genetic background differences among breeds may further modify mdr1-1_-based responses. Many potential drug–genotype interactions must therefore be examined to fully explore the phenotypic spectrum of mdr1-1_. Although pharmacogenetics affords a near-term solution to mdr1-1_, genotype-based selection could ultimately eliminate the mutation from breed gene pools. The allele and genotype frequency data reported here will aid in the design of breeding strategies. For the Shetland Sheepdog, where the allele frequency is low and the number of dogs is large, mdr1-1_ could be removed in a few generations. For the Longhaired Whippet, the allele frequency is high and the number of dogs is small, hence a more gradual approach could be applied.
In other words there are so many Shelties, breeders won’t lose any other important genes or cause other possibly worse mutations that may exist to become more frequent in the gene pool if they test and eliminate all carriers of this gene immediately.
In Longhaired Whippets, because the population is smaller, and the gene more widespread, elimination of all carriers of a certain gene would cause monumental changes in the balance of the gene pool and would very likey cause the increase of a hidden deleterious recessive or the accidental increase of the frequency of the genes that in certain combinations cause case other detrimental conditions. It is likely that one or more of these genes will be more serious- painful debilitating and lifeshortening than mdr1-1delta. In our gene pool CHD would be an example of a polygenic detrimental condition. Other possible polygenic traits that would be apt to accompany a loss of diversity are immune deficiency, and certain heart problems.
So with our 7% frequency for this allele what does this mean to us?
The English Shepherd gene pool is more diverse and has a lower frequency of the mutation, than that of the Longhaired Whippet, but the population is also very small. The affliction is not that serious- consequences can be avoided by avoiding certain medications, therefore I think a cautious approach to eliminating the mutation in the gene pool is in order.
In a specific case:
If we have a pup born that receives a copy of MDR1-1Delta from each parent we say that he is homozygous for that gene. Such a pup will be more susceptible to Ivermectin and other such drugs causing complications because it can cross the blood brain barrier and enter the central nervous system.
If anyone has the genetic testing done before he treats his dog with Ivermectin, it is important that he share the findings with everyone else so that we can have a better idea about whether close relatives should be tested. This mutation is not a serious problem so long as we know where it exists.
It is the fashion in the dog world (as well as in the livestock world) to try to locate and eliminate anyhing that may be considered a “genetic defect” — presumably to create a picture-perfect animal or breed. And, it is the common practice in all dog breeding circles to routinely outcross between relatively unrelated bloodlines — again to avoid anything that might make animals less than perfect. I think this is a mistake because it can distribute undesirable mutations throughout the gene pool. There are many ways that diversity appears and is passed along through breeds and breed groups. Let’s continue to learn more about our breed, its health status, and its unique genetic combinations and remember the old adage that the first rule of successful tinkering is to save all of the parts.