Jerold S. Bell, DVM
Dept. of Clinical Sciences, Tufts Cummings School of Veterinary Medicine, N. Grafton, MA, USA
There is renewed interest in recommending breeding systems and new tools to address the health and vitality of dog and cat breeds. There are several reasons for this emphasis. The general public perceives pure-bred and pedigreed animals to be unhealthy. Their view has foundation based on the prevalence of hereditary disease in pet animals. We see increased genetic disease in pure-bred and cross-bred animals because of a lack of genetic testing and selection (health quality control) of breeding animals. However, the public perceives that breeds are unhealthy solely due to inbreeding.
The social stigma concerning inbreeding goes back to the bible. There is plenty of evidence that close breeding (first cousin matings in many human populations) results in the increased expression of genetic defects. How does this reality relate to the fact that pure breeds are mostly based on close breeding from limited numbers of founders? Is the entire system of pure breeding flawed by its own nature?
An ages old debate concerns the nature of inbreeding depression. One position is that homozygosity in and itself causes inbreeding depression. The opposite position is that inbreeding depression is solely caused by the homozygous pairing of deleterious recessive genes.
Answers come from experiments with laboratory animals and the creation of inbred strains. Repeated full-sib matings over generations causes many lines to die out due to infertility and genetic defects. However, other lines will thrive through inbreeding, even though they are homozygous at more than 99.9% of all loci. This has been shown in (among others) fruit flies (Drosophila), mice, and poultry (Festing 1979; Miller & Hedrick 1993; Lacy et al. 1996).
This does not mean we should desire that our cat and dog breeds become like inbred strains of laboratory animals. However, we must recognize the similarities of inbred stains to domestic breed creation. We repeatedly breed within families to produce a uniform phenotype that breeds true. This requires the homozygosity of genes that produce that phenotype. Like inbred strains, if the creation of a breed includes deleterious recessive genes (either through linkage to selected traits or genetic drift), then the breed will have issues with those genetic disorders.
The goal of breeding is not to create the most homozygosity in a breed, but to create and maintain healthy breeds that breed true. We cannot identify all deleterious recessive genes in populations. We can identify and select against those that cause observable genetic disease. It is also important to maintain genetic diversity in a breed to retain the ability to make selective breeding choices.
This then leads to the question of whether homozygosity in of itself causes disease. Specifically excluding deleterious recessive alleles, does homozygosity of normal genes confer diminished health? The only area of the genome where there is a suggestion that this can occur is in the major histocompatibility complex (MHC). In the dog, DLA haplotypes of the MHC have been associated with hereditary immune-mediated disease (Kennedy 2011). However, this association has more to do with the specific disease-related haplotype inherited from the parent, and not necessarily the homozygosity of any random haplotype. Some of these disease-associated haplotypes require homozygosity, and some require only one copy of the haplotype to confer disease risk (Barnes et al. 2009; Greer et al. 2010). So again, we are faced with selecting against specific disease-related genes or gene combinations for improved health, not necessarily a general reduction of homozygosity.
Some studies of dog and cat breeds focus on the inbreeding coefficients of individuals, and the effective population size of breeds as a measurement of their genetic vitality and ability to maintain themselves as pure breeds (Calboli et al. 2008). However, most breeds started from a limited number of founders, which necessitates high inbreeding coefficients and low effective population size for them to slowly grow and expand their population. As the population expands within a closed gene pool, expansion allows mating choices between individuals that are less closely related than the previous generation.
By studying the average 10 generation inbreeding coefficient of breeds over time, you find that it peaks, and then begins to diminish with population expansion (Bell 2011). This shows that populations are utilizing the breadth of their gene pools. If average 10 generation inbreeding coefficients again begin to rise, it is usually because breeders are concentrating on popular sires.
If breeds are lucky enough to avoid or expunge themselves of major deleterious recessive genes, then they can become vigorous, large population breeds. It is not the population size of a breed that determines its survivability, but its genetic vitality. James (2011), when studying gene loss in pedigree dogs found that there is very little influence of mean inbreeding levels and population size on gene survival. Shariflou et al. (2011) found that genetic diversity is not related to the size of the breed, but to breeding practices and the even contribution of founding lines.
Some breed organizations and agencies have embraced the belief that close breeding is the cause of impaired breed health, and have adopted protocols and programs that restrict close breeding. The Kennel Club in the UK recently adopted a "Mate Select" program that lists health test results, but also seeks to find a mate that is the least related through pedigree analysis; i.e., outbreeding to produce the lowest inbreeding coefficient and the most heterozygosity. This process is akin to a Species Survival Plan (SSP) that is utilized when attempting to "rescue" an endangered species. It is using the tool of the inbreeding coefficient as the goal of breeding.
The vast majority of dog and cat breeds do not show evidence of genetic depletion as seen in endangered species, such as low reproductive success, and increased stillborn and neonatal mortality. Leroy (2011) found that dog breeds have on average, comparable levels of genetic diversity to those of other domestic species (cattle, sheep, and pigs). He also found that as only a limited number of individuals reproduce, optimizing the contribution of parents and avoiding the popular sire effect is the best method for maintaining genetic diversity.
Recommendations to outbreed (only breed to those least related) homogenize breeds and erase the genetic difference between individuals. It is a self-limiting process. It requires that matings be done between individuals who are different from each other. However, eventually there will be no more "lines" with differences. Everyone will be in the center, and no one at the periphery. If a genetic disease or deleterious trait comes up, there will be no "other line" to breed and get away from it. Breed gene pool diversity requires distinct lines in order to create selective pressure.
Prudent breeding practices allow some linebreeding, some outbreeding, and even occasional inbreeding, with different breeders maintaining breeding lines or crossing lines as they see fit. It is the different opinion and breeding actions of breeders that maintain breed diversity. This is not something that can be legislated or regulated.
When breeds have issues with genetic diseases, the only way to improve their gene pool is through selection against the specific diseases and their associated liability genes. The types of matings (linebreeding or outbreeding) have no bearing on controlling deleterious genes, or the genetic health of breeds. Pure and pedigreed breeds are only endangered if breeders ignore selection for healthy breeding stock.
1. Barnes A, O'Neill T, Kennedy LJ, Short AD, Catchpole B, et al. Association of canine anal furunculosis with TNFA is secondary to linkage disequilibrium with DLA-DRB1*. Tissue Antigens 2009;73:218–224.
2. Bell JS. Population dynamics of dog and cat breeds and breed-related defective genes. Proceedings of the 5th Tufts Canine and Feline Breeding & Genetics Conference 2011.
3. Calboli FCF, Sampson J, Fretwell N, Balding DJ. Population structure and inbreeding from pedigree analysis of purebred dogs. Genetics 2008;179:593–601.
4. Festing MFW. Inbred Strains in Biomedical Research. Oxford University Press. 1979
5. Greer KA, Wong AK, Liu H, Famula TR, Pedersen NC, et al. Necrotizing meningoencephalitis of Pug dogs associates with dog leukocyte antigen class II and resembles acute variant forms of multiple sclerosis. Tissue Antigens 2010;76:110–118.
6. James JW. 2011. Is gene loss in pedigree dogs surprisingly rapid? Vet J 2011;189:211–213.
7. Kennedy L. Identifying genetic markers for auto-immune diseases in the dog. Proceedings of the 5th Tufts Canine and Feline Breeding & Genetics Conference 2011.
8. Lacy RC, Alaks G, Walsh A. Hierarchical analysis of inbreeding depression in Peromyscus polionotus. Evolution 1996;50(6):2187–2200.
9. Leroy G. Genetic diversity, inbreeding and breeding practices in dogs: Results from pedigree analyses. Vet J 2011;189:177–182.
10. Miller PS, Hedrick PW. Inbreeding and fitness in captive populations: Lessons from Drosophila. Zoo Biology 1993;12:333–351.
11. Shariflou MR, James JW, Nicholas FW, Wade CM. A genealogical survey of Australian registered dog breeds. Vet J 2011;189:203–210.