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THE MYTH OF INBREEDING AS A MEANS TO PURGE MUTATED GENES.
By
Bernd Fritzsch, Ph. D.

     As a trained biologist, I have often wondered where the persistent myth that inbreeding is good for domestic breeds has come from.  This is particularly troublesome in light of the many examples found in the wild suggesting that in nature inbreeding leads to inbreeding depression, and ultimately to extinction (Frankham and Ralls, 1998).  Therefore, inbreeding is a serious threat for conservation biology and a real problem where culture meets and splits natural breeding grounds into smaller and smaller parcels.  Consequently, zoos that engage in captive breeding programs monitor very closely the degree of inbreeding.  In addition, nature has invented schemes to avoid inbreeding via many different mechanisms.  One is known as optimal discrepancy, where most mating happens between distantly related animals.  Flowering plans have evolved molecular mechanisms to avoid self-fertilization (Stone et al., 1999).  Even the best known case of high levels of naturally occurring inbreeding, the blind mole rat, has genetic exchange between the different underground colonies, thus keeping a degree of genetic diversity not unlike humans and domestic cats (Page and Holmes, 1998).
     So, why do we think that breeding dogs or other domestic animals is any different?  While I can not completely resolve this problem, I found a few reasons that make it likely why this myth came into existence.  One of these reasons relates to the apparent achievement of fixing a specific type that is so easily achievable by inbreeding.  Any natural breeding will result in some variation around a given type.  In contrast, even inbreeding over only a few generations will result in reduced variability, thus making the offspring look more alike because of loss of genes responsible for the increased variation.  We accept the price tag that comes with this in our food plants and have to defend them against invasion by pathogens which would wrack havoc in these diversity depleted populations if left alone (Stachowicz et al., 1999).  Similarly, many dog breeds will not survive in the wild as we have selected for specific features and not necessary for their ability to survive. 
     Thus, while inbreeding is a powerful tool to minimize variation in a desired type, a breeder needs to be aware of the unwanted effects of inbreeding that will ultimately result in the extinction of this extremely homogenous line so carefully generated by inbreeding.  This are at least the lessons taught to us by nature.  So, with this knowledge in hand one wonders what other arguments are there in favor of inbreeding, other then the desire to generate over the short run dogs that closely fit the standard of the breed.  One argument I frequently hear is that inbreeding is actually beneficial for a breed as it will unmask deleterious genes and can help eliminate those carriers.  I will show below that this is hardly a reasonable argument.  However, as with many bad science examples, once invented they can hardly be eliminated because somebody will find the original paper and simply be ignorant about all the contrary data and re-emphasize the original idea.  After all, we lived for several hundreds of years with the flat earth myth.
      As a biologist I am afraid to admit that apparently the idea of inbreeding as being beneficial for reproduction apparently goes back to C. Darwin.  Darwin noted, as have others before him that inbreeding does not appear to be a major mode of reproduction in wild populations.  However, he also noted that inbreeding in domestic and wild populations causes inbreeding depression.  Astonishingly, one of his lines of morning glory flowers he studied for this inbreeding depression phenomenon appeared to come out of this inbreeding depression during Darwin's life time and appeared more healthy than lines of limited outcrosses.  Darwin named this line Hero, for obvious reasons.  From this example, Darwin and others concluded that somehow the accumulation of bad inherited material can be purged and after an inbreeding depression of variable length the population may emerge healthy again or even healthier than the original population. 
      While apparently such purging and exit from inbreeding depression can occur, Darwin had no idea how frequently that is or whether it will regularly occur.  Over the last 150 years we have learned that the successful exit out of an inbreeding depression is in fact very rare.  Out of 52 published studies conducted, only two have clearly shown that this can occur (Pennisi, 1999).  All other cases showed a lasting inbreeding depression with no apparent signs of recovery or even extinction of populations.  Moreover, recent attempts to restore fertility in severely inbred populations by introducing new individuals showed dramatic restoration of fertility and recovery of local populations from the brink of extinction.
 So, what can we learn from these examples for dog breeding?  Apparently, firstly we have to look at fertility rates of more inbred as compared to outcrossed dog populations of various breeds.  If statistics were to be trusted and claims of fathers confirmed one would likely see that multi generation of inbreeding will result in statistically significantly lowered numbers of viable offspring.  The recent public exhibit of the cross of two mutts resulting in 17 puppies certainly supports the notion of hybrid vigor at the offspring level.  In humans, inbreeding depression causes a 40% lethality or severe disabilities of offspring produced from brother/sister mating (Page and Holmes, 1998) and it is a reasonable assumption that this will be comparable in dog brother/sister mating. 
      The next question is, of course, what is the scientific basis for inbreeding depression and the occasional success of purging the genes responsible for this depression as well as exiting the inbreeding depression as an apparently purified population.  To be honest, nobody knows for sure. This simply relates to the large number of still unknown genes even in the human genome and the even less known interindividual genetic variability.  Thus it can well be that the two cases known in which purging seems to have worked, may have started with less genetic defects than those in which inbreeding led to extinction.  Can we know beforehand whether the population we want to breed falls into one or the other category?  Unfortunately not!  If we would know that, we could redesign our breeding efforts of endangered species.  As far as rare breeds of dogs are concerned, it is apparently bad advice to bet on the occasional self-healing capacity of inbreeding.  More likely is that the dog breed in question will fall into the category of disastrous outcome of inbreeding. This conclusion is supported by a number of clinically relevant findings in inbred dogs that would have been impossible to achieve in the less inbred human population. 
      One outcome of inbreeding is that genes, which we inherit from both father and mother as two slightly different variations, will be more uniform.  Less genetic variation makes animals look more alike (and thus make them conform better to a given standard) but also makes them more sensitive to spread of infections (more difficult in a more heterogeneous population of hosts for a disease; Stachowicz et al., 1999).  The good part is, if one of these genes is defective and causes a lethal mutation, the carrier will disappear in the next generation.  Thus, some people actuall think they are able to purify through this approach their line.  However, there are a number of issues this assumption has not resolved.  First, given that any breeder will no be able to breed more than about 25 litters of multi generations of inbreeding of sister/brother mating (assuming a mean breeding age of two years for the dogs and a breedering program of 50 years) any breeder will hardly be able to see the outcome of his effort (either positive or negative).  If we look for longer breeding programs there is a population of lions in India which have gone through almost 100 years (or about 50 generations) of inbreeding.  This population now has the lowest known genetic variation of all wild animals tested to date (Page and Homes, 1998).  While still healthy, it is possible that any infection entering this population will spread rapidly and erase the entire population. In contrast to these lions, dogs have been domesticated for thousands of years and have been selected  to a reasonable extent to serve the whims of their breeders, which are not necessarily compatible with a dogs ability to sustain its life, a simple fact that rules the survival of the lions mentioned above. 
     Another issue relates to the fact that the differences between the fatherís and the motherís genetic material tends to be increased by mutations every generation.  This counteracts to some extent the uniformity generated by inbreeding.  In dog breeds which started with small foundation populations and have been enlarged to several thousand individuals in part by excessive inbreeding to fix the type, this issue becomes a big problem simply because the selection pressure applied (conformation to a specific type) does not take all genes that are necessary to develop an animal into account.  Thus, while focusing on the perhaps 1000 genes relevant for the desired traits, those breeders (and others before and after them) have ignored the remaining 139,000 genes necessary for a fully functional dog.
      One of these dog breeds that was recently generated from a small foundation population is the Doberman Pinscher.  These dogs have recently featured in a significant scientific discovery because of their highly inbred background. The discovery is that a single gene causes, if mutated, a condition called narcolepsy (Lin et al., 1999).  This condition is typically elicited by strong positive emotions.  The dog will jump up, all excited and suddenly collapse and fall asleep. Because of the highly inbred strains of both Doberman Pinscher and Labrador retrievers available, geneticists could isolate the gene involved in this disease, and could characterize how this gene causes this disease (Lin et al., 1999).  However, while this is scientifically useful, it does not help the breed.  Clearly, in the wild an animal that will fall asleep when it sees a mate or prey will not survive as an individual nor propagate into the next generation.  Nevertheless, purging by inbreeding would likely not help as the carriers are normal and show no symptoms.  This is in contrast to other inherited diseases such as human sickle cell anemia.  While individuals carrying two mutated genes are not viable, the carrier of a single mutated gene is only impaired in his oxygen transport, but otherwise healthy.  Clearly, if a gene does not cause any recognizable phenotype in the heterozygotic state it can not be selected against, and the lethal homozygotic state will appear only in highly inbred population in a few individuals (about 25% of each litter).
      I often hear the argument that one should keep a genetically affected animal for test breeding with presumed carriers.  The logic is compelling, so it seems.  Once a carrier has been identified, it will not be used for breeding. Good.  But how about the siblings of the carrier? Do we cull them all?? And how many test breeding do we need before we can go ahead and breed that dog?  About 25 to make sure that the dog does not carry the most frequent genetic diseases?  And how about the less-frequent ones, and those that are not yet characterized as being inherited?  25 times 4 puppies would mean 100 puppies have been produced (and killed) just to make sure that the dog in question does not carry any of the 25 mutated genes involved in the arbitrarily defined 25 investigated genetic diseases.  This does not appear to be a humane and efficient way of approaching the problem.
      Last, but not least, in order to do the test breeding you have to have a dog that has the mutated genes.  So, in order to test for the 25 genetic diseases, you have to have the 25 sick dogs you need for test breeding.  Imagine anyone visiting a kennel to choose a puppy and the breeder shows off with all the sick dogs they have to do the numerous test breeding to generate a genetically healthy (for the tested genes at least) dog.  Again, the problems with the test breeding and culling scenario are obvious.http://www.sighthoundmagazine.com
      In summary, in most dog breeds, and in particular in rare breeds, inbreeding is not a solution but a problem.  In fact, the very reason given, unmasking mutations otherwise unrecognizable, is not a good reason for inbreeding.  If a genetic disease is uncovered by inbreeding, the breeder would need to eliminate both lines used for this breeding because the heterozygotic animals can not be detected on phenotype alone.  The argument of testbreeding to a known carrier sounds good on paper but would require excessive culling of puppies and, minimally, sterilization of the tested lines which are also needed to generate affected dogs for the next generation of test matings. It seems, the very genetic techniques that will eventually allow us to correct these mutations will also allow us to screen for mutations without going through the peril of inbreeding with its highly unlikely cure of purging all deleterious genes.  Thus, in the next millennium we will probably be able to debunk the inbreeding myth simply by showing that its single alleged application, testbreeding and purging, is not a rational way to handle genetic problems in a breed.  After all, wolves are conforming to their type based on a high genetic variation (Vila et al., 1997).  The challenge will be to generate type in combination with genetic variation rather than depleting this by excessive inbreeding.

Literature:
Lin, L., Faraco, J., Li, R., Kadotani, H., Rogers, W., Lin, X, Qiu, X., de Jong, P.J., Nishino, S., and Mignot, E., (1999) The sleep disorder canine narcolepsy is caused by a mutation in the Hyporetin (Orexin) receptor 2 gene.  Cell 98: 365-376.
Page, R.D.M. and Holmes, E.C. (1998) Molecular Evolution: a phylogenetic approach.  Blackwell Science, pp. 346
Pennisi, E. (1999) The perils of genetic purging. Science 285: 193.
Frankham, R. and Ralls, K. (1998) Inbreeding leads to extinction. Nature 392: 441-441.
Stachowicz, J.J., Whitlach, R.B., and Osman, R.W. (1999) Species diversity and invasion resistance in a marine ecosystem. Science 286: 1577-1579.
Stone, S.L., Arnoldo, M.A., and Goring, D.R. (1999) A breakdown of Brassica self-incompatibility in ARC1 antisense transgenic plants. Science 286: 1729-1731.
Vila, C., Savolainen, P., Maldonado, J.E., Arnorim, I.R., Rice, J.E., Honeycutt, R.L., Crandall, K.A., Lundeberg, J., and Wayne, R.K. (1997) Multiple and ancient origins of the domestic dog.  Science 276: 1687-1689.

 


 
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