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Bearded Collie Auto Immune Disease Genetics Co Efficients of Inbreeding Way Forward
 
 
Beardies Past, Present and Future
 
 
Co efficients of Inbreeding for Dummies
An explanation of what COIs are and what they mean
 
 
Gap Analysis Report
 
 
Basic Beardie Genetics
 
 
Effective Population Size
Bearded collie. dangers of low population size
 
 
Bottleneck Sires
 
 
Auto Immune Disease
 
 
Addison's Disease
 
 
Addison's Disease Update
 
 
Auto Immune Haemolytic Anaemia
 
 
Symetrical Lupoid Onchodystrophy (SLO)
 
 
Immune Mediated Hypothyroidism
 
 
Idiopathic Thrombocytopenia Purpura
 
 
LINKS
Useful links to other websites
 
 
The Cohort Study
This page describes the study that will collect comprehensive and valuable data on the health and welfare of the Bearded Collie.
 
 
Dilated Cardiomyopathy
questions the possibility of some instances of DCM being auto immune problem
 
 

Basic Beardie Genetics

For many people the word “genetics” incites a glazing of the eyes followed by a complete shutdown in brain function. Genetics has a series of technical words difficult to pronounce and to spell so the subject can be confusing, difficult, challenging to grasp and perhaps above all boring. When I have stood at a meeting and mentioned the dreaded word I’ve felt like I’ve condemned the audience to a lecture on quantum physics, such is the immediate lack of interest and enthusiasm.

However Like it or not, we need to have a grasp of basic genetics if we are to understand the science of breeding and above all the importance of maintaining and improving the health, welfare and future of the Bearded Collie. Try first of all to understand the language of genetics and you should be able to grasp the essentials of the subject with only minimal time and application.

Many billions of cells make up the Bearded Collie and every cell contains the blue print design for a dog in the form of CHROMOSOMES  and their associated GENES. The study of all the genes and chromosomes has allowed scientists to work out their full arrangement and this is known as the GENOME. Every dog has 39 pairs of chromosomes in every cell with the exception of the sex cells ova and sperm which have half that number. This compares to only 23 pairs of chromosomes in a human. The difference accounts for the widespread variation in shape and size of dogs compared to humans.

Each of these chromosomes are packed with genes, which control details of the form and appearance of the dog as well as susceptibility to abnormalities and disease. The traits or characteristics exhibited by a dog are passed from one generation to the next by the genes. Each dog has a pair of genes at the same point on the same chromosome , one coming from each parent. Some genes are described as DOMINANT , whereas others are RECESSIVE. If a dog has both a dominant and a recessive gene then the dominant gene “hides” the recessive. Some genes are neither dominant nor recessive and these are described as showing incomplete dominance.

The appearance of the dog is described as its PHENOTYPE and what the genetic make up is described as the GENOTYPE. This can be illustrated with one of the simpler traits to understand the colour of the dog.

Colour genetics is a subject most breeders will have grasped, perhaps because the results are easy to see, unlike some of those hidden traits that are controlled by the same principles but which are not immediately obvious in the new born puppy.

Remember genes can be dominant or recessive. Dominant genes mask the effect of recessive genes and the effect of recessive genes will only become apparent if the dog inherits two, one from each parent.

Every  dog has two colour genes, one from each parent. There are limited possibilities. It could have inherited a black gene from each parent This is traditionally written as BB giving it the geneotype Black Black (BB), it could have inherited a black gene from one parent and a brown gene from the other, giving the genotype Black Brown ((Bb) or it could have inherited a brown gene from each parent, giving it the genotype Brown Brown (bb). It is customary to use capital letters for the dominant gene and lower case for the recessive gene. Colour is further complicated by the existence of the dilute gene, which changes black to blue and brown to fawn.  Non dilute is dominant over dilute so if a puppy inherits one non dilute gene (D) from either parent it will be black or brown. Black is dominant over brown so any puppy carrying the black gene will be born black or, if it has two dilute genes, blue. A puppy carrying two brown genes will be brown unless it has also inherited two dilute genes, in which case it will be fawn.

My Ch Diotima Sea Wolf at Ramsgrove has only ever thrown black puppies and I am confident his genotype is BBDD, that is he carries two black genes and two non dilute genes. His sire, Ch Gillaber Drummond, sired puppies in all four colours so must have the genotype BbDd, he had one black gene, one brown gene, one dilute and one non dilute. Sea Wolf’s son Ch Ramsgrove Rumba had a brown dam so inherited one brown gene from her. Rumba sired black and brown puppies but no dilutes, so his genotype was BbDD, meaning he carried the genes for black, brown and non dilute. Rumba’s brother Ragthyme sired pups in all four colours so must have inherited both the brown gene and dilute gene from his dam. His genotype was BbDd, black, brown, non dilute and dilute.

My own dog, CH Diotima Sea Wolf at Ramsgrove , is dominant black and does not carry the dilute factor. This means that ALL of the puppies he has ever produced have been born black. His puppies inherit one black gene and one non dilute gene from him and as these are dominant they will mask any brown or dilute genes inherited from the dam. Study the pedigree below :

 

 

 

Jack, BLACK DOG

 

Patrick, Black Dog

Diotima Sea Wolf at Ramsgrove (Black)

Brown Bitch

 

Bella, Brown Bitch

Brown Dog

Fawn Bitch

 

 

Deidre, BLACK BITCH

 

Daniel, Black Dog

Diotima Sea Wolf at Ramsgrove (Black)

Fawn Bitch

 

Sassy, Fawn Bitch

Brown Dog

Fawn Bitch

 

Patrick and Daniel have inherited their black gene from Sea Wolf. They may also have inherited a brown gene from their dam, and Daniel may have inherited a dilute gene from his dam, but both dogs will be black as they will have inherited one black gene and one non dilute gene from Sea Wolf. These dominant genes will over ride the effect of any other colour genes. Jack and Deidre both carry the black gene from Sea Wolf, it would have been impossible for them to have inherited them from any other dog as none of their other ancestors carried the black gene. Both Jack and Deidre will carry brown genes and may even carry one non dilute gene, inherited from their grand and great grand parents, but that black gene that has determined their colour has been inherited from Sea Wolf and no other dog.

Jack and Deidre could produce a litter containing all four colours as they will both definitely carry brown. Deidre will definitely carry the dilute, inherited from her dam and Jack may carry the dilute, inherited from his great grandmother. Any black puppies in this litter would have inherited at least one black gene from Sea Wolf and it is possible they will have inherited two black genes from Sea Wolf. These puppies would have inherited their two colour genes from the same dog, Sea Wolf.

Where a single pair of genes are involved from the same position on a pair chromosomes they are known as ALLELES. And the pair of chromosomes are described as HOMOLOGOUS. Where single pairs of genes are involved in the inheritance of a trait it is known as simple Mendelian Inheritance. Gregor Mendel was the father of Genetics. Many inheritable conditions such as length of back, setting of tail, nature of the coat and many others have many pairs of genes involved. The inheritance is then much more complex and is known as polygenic inheritance.

 The sex determinant chromosomes are designated X and Y. Some genetic diseases are only carried on the X chromosome. They are usually recessive. A bitch will always have two X chromosomes XX  and a dog will have one X and one Y and so is genotypically XY and phenotypically a male with penis and testicles. In diseases like haemophilia the male dog will be affected if the single X chromosome he has is carrying the abnormal gene. However a bitch who has one affected chromosome and one unaffected will be a carrier. She should not be bread from, as half her male children will be affected with the disease

A PUNNETT square is a useful way of predicting the outcome of a particular mating. The two genes of the male are written across the top of the square and the two genes of the female down the side

As an example two phenotypically black beardies but both carrying brown (so genotypically Bb) are mated together so the following genotypical possibilities arise   

             

 

     Dog                             B             b

     Bitch            B            BB           Bb

                          b            Bb           bb

So in a litter of puppies one in 4 would be brown , two in 4 would carry brown but be black and one in 4 would be homozygous black.  Remember however that puppies do not understand statistics and chance. Just as it is possible to toss a penny six times and get all heads, so it could be possible to have six brown puppies from two black dogs. I have now introduced another term HOMOZGOUS which means both genes are the same. If they are different they are described as HETEROZYGOUS

 

A Closer look at Genes

We have already established that the blue print for the dog is stored in the nucleus of every cell, with the 39 pairs of chromosomes. Under the electron microscope the nucleus of a cell can be examined and the chromosomes identified and paired up. One Chromosome of each pair is known as a CHROMATID. The individual units on each chromosome are the genes. There are very many genes on every chromosome. The genetic material is made up from long strands of DNA. (Deoxyribose nucleic acid)which is tightly packed into the chromosome. Scientists describe as in the form of a double spiral helix. It looks rather like a twisted ladder. It is a chemical made from three different building blocks called NUCLEOTIDES. There is a phosphate group a sugar group and a nitrogen base. There are four different nitrogen bases known as ADENINE (A), THYMINE (T) , GUANINE (G) and CYTOSINE (C). A gene is a sequence of these bases on the chromosome. Genes can vary greatly in size but will have between a thousand and a million nitrogen bases. Now the genome is fully worked out we can understand the base sequences. These are usually written as a string of letters such as ATCGTTAGC, each letter representing the nitrogen base described above. These nitrogen bases are always paired so adenine is paired with thiamine and guanine with cytosine. It is important to understand this as when errors occur in the sequence it can be responsible for a MUTATION which is passed to the next generation. In the twisted ladder described earlier the rungs are made up of the pairs of nitrogen bases linked and bonded by hydrogen bonds. There are three ways a mutation  can occur; the addition of an extra base, the loss of a base, or the substitution of one base with another. The effects of a mutation will vary from extremely serious and perhaps lethal, to beneficial depending on its nature. This is the way in which inherited disease can suddenly appear when has not been apparent in ancestors

When considering the history of the Beardie it is important to realise that DNA was not understood  until 1953, well after Mrs Willison had started her breeding programme to establish the Kennel Club Registered Bearded Collie. She and the other early breeders would have none of the available knowledge of today. Watson , Crick et al. who published the research have enabled the breeders of today to have a clear understanding of the basics of inherited disease and to recognise the dangers of inbreeding which increases the risks of potentially dangerous recessive genes being brought together.

 

Haplotypes and SNPs

In the last decade since the Genome has been worked out , geneticists have made much progress in understanding the structure of the genes. A Haplotype is defined as a combination of DNA sequences on a chromosome at the same location and adjacent locations that are always transmitted together. SNPs are normally pronounced “snips” and is short for Single Nucleotide Polymorphisms. Each SNP represents a difference or change in a single DNA building block. For example instead of adenine (A) there is the nucleotide guanine (G). There may be as many as 10 million SNPS in the canine genome. The vast majority have no effect on health and development. However recent and ongoing research is showing that some SNPs may help predict an individual’s response to certain drugs, toxins or other environmental factors and assist in assessing the risk of developing particular diseases. The presence of some SNPs may increase the risk of a disease whereas others my offer more protection. They can be used to track the inheritance of disease within pedigrees

Research continues with more evidence becoming available every month. The genetic basis of disease will be discussed more fully later

It is important to be able to locate a specific gene on a specific chromosome. It is like giving it an address. Through the electron microscope it can be seen that each chromosome is divided into two sections based on the location of the narrowing or constriction called the CENTROMERE. These sections are known as arms. By convention the shorter arm is called “p” and the longer arm is called “q”. The first part of an “address” is therefore say 14 q. The exact position being further defined by two digits and sometimes a decimal point and two more digits. So 14q21 is position 21 on the longer arm of the chromosome 14.

 

Focus on Chromosome 12

 

The Major Histocompatibility Complex usually called the MHC is present in all mammals and is located on Chromosome 12 a consists of over 100 genes. These in turn are divided into three classes ( I-III) according to their function and location Research in the last few years has revealed just how important this is in the development of immunity in Beardies and to the susceptibility of various auto immune diseases. The genes in the MHC play an important part in the recognition of the animals own tissue as well as the recognition and destruction of foreign elements like bacteria, viruses and other pathogens.   The canine MHC is often known as the DOG LEUCOCYTE ANTIGEN or DLA as it is usually called. Within the DLA class II genes are three very variable or polymorphic genes usually known as DLA-DRB1, DQ1 and DQB1. . These three genes are inherited as a set from each parent. These three genes have many variants which are called alleles. There are already over 250 DLA-DRB1 alleles, 45 DQ1 alleles and 120 DQb1 alleles. New ones are being discovered all the time.  The sets or combinations are known as HAPLOTYPES. Over 300 haplotypes have been found in canines, but when you look at each breed separately you will generally find relatively small numbers with a couple much more prevalent than the others. So far the Bearded Collie has been shown to have 7 haplotypes.

The higher the number of alleles or haplotypes, the better the diversity within the breed and higher likelihood for the proper function of the DLA class II immune system

Some very recent research based in the UK and in Finland has studied over 250 Beardies. Research geneticists  have identified 3 different DLA-DRB1 alleles, 2 different DLA-DQA1 alleles and 4 different DLA –DQB1 which combine to form 5 different haplotypes . In the studied population about 42% have haplotype 1, 30% have haplotype 2, 10% have haplotype 3, 6%have haplotype 4, 5% type 5 and very small percentages for 6 and 7..  There were a few other single occurrences of other haplotypes within the breed in one or two individuals. These single haplotypes are probably present because the dog concerned is not truly purebred, or descended from one that was not.

The number of haplotypes present in the breed represent genetic diversity. Much is still to be learnt and research contines to understand the significance of the different haplotypes. The common ones may be common for a good reason and the rarer ones rare for a good reason. There is already evidence that some haplotypes may give protection against some diseases whereas other are associated with an increased predisposition to auto immune disease. It is probable that the commonest Haplotype 1  is so common because it promotes health. Alternatively the use of popular sires and bottle necks in breeding may have lead to it being so common. There is good evidence now to suggest that having two haplotypes the same, that is homozygous, results in a Beardie that is less able to withstand challenges to the immune system compared to one who is heterozygous, that is with two different haplotypes.  Very occasionally being homozygous may prove to be an advantage but heterozygosity is much to be preferred. In humans there is a disease known as Sickle cell anaemia. Having a single abnormal gene for sickle cell disease means the individual is to all intents and purposes normal but as a bonus has a built in resistance to malaria compared to the normal. The homozygous individual with two abnormal genes for sickle cell disease will be seriously affected with a poor prognosis. As a general rule heterozygosity is always preferable to homozygosity.

The standard poodle is another breed to have been investigated with 9 haplotypes being identified. There is some geographical variation in the prevalence of different haplotypes . Haplotype 1 is present in 42% in both the USA and the UK whereas haplotype 4 is more common in the UK compared with the USA. Miniature poodles have 14 different haplotypes and toy poodles have 15. In the miniature poodle 5 are shared with the standard poodle and in the toy poodle 3 are shared.

Considerable research in other animal species particularly in endangered species can be seen as pointers as to what may be happening  to the Bearded Collie. As an example a population of arctic foxes living on a remote eastern Russian island. The population was decimated by a mange outbreak in 1918 and has still not been able to recover despite protection from hunting and other conservation measures. It has been shown that all the foxes were homozygous for the same haplotype in the MHC, whereas another population on a nearby island was thriving and those foxes were shown to have several different haplotypes

In another Finnish study of 77 Beardies, 39% were homozygous with the same haplotype in both chromosomes. Amongst these homozygous dogs, 97% consisted of either haplotype 1 or haplotype 2 .

There is no doubt that homozygosity increases the risk of auto immune disease such as addisons disease, diabetes, underactive thyroid, and the distressing nail disease SLO ( symmetrical lupoid onchodystrophy). To complicate matters still further research now suggests that Haplotype 1 (present in 40% of beardies) is a risk factor for the nail disease SLO but protective against Addisons disease.. Haplotype 3 appears to carry a greater risk for the development of Addisons disease and Haplotype 4 is, in many breeds, associated with the development of auto immune haemolytic anaemia.

Sadly all this information does not mean we can go and test our dogs for their haplotype status, breed accordingly and live happily ever after. The haplotypes do not work on their ownbut are affected by about 40 other genes and by the all important environmental factors such as viruses. If a Beardie has all the genetic markers to predispose it to a particular auto immune disease but is lucky enough never to encounter the trigger virus he or she will remain healthy. And then a dog with a haplotype that predisposes it to a particular disease, but without the other multiple genes involved will also remain unaffected even if it encounters the virus.

These diseases with MHC associations are all “complex”. They are caused by the interaction of many different genes. Each of these other genes will have a different level of influence on the risk of developing the disease. Human studies show that the MNC confers about half the genetic risk for disease. Data for beardies is not available but it is a fair assumption that all mammals react similarly so the genetic risk in Beardies is also about 50%. Although the environmental factors are usually exposure to one or more virus we do not yet know which virus are involved. Stress may well also play apart from breaking a leg , coming into season or whelping and rearing a litter of puppies.

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