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INHERITED: The genetics of Hidden Demons

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INHERITED: The genetics of Hidden Demons

Post by JSAN_911 on Mon May 28, 2012 10:02 am

INHERITED: The genetics of Hidden Demons

By Scot E. Dowd Ph.D.

2nd Draft

The magic of heredity - DNA, chromosomes, genes

This article picks up from previous chapters on genetics. If you have not digested the previous chapters, this chapter will likely not make too much sense to you. We will review previous information but not indepth. To fully grasp some concepts, it is important to read and then read again to develop better understanding. Learning is like building a pyramid. You start by putting the bottom together then work your way to the pinnacle. If you skip steps in your self education you will not have a structure of knowledge that will endure or withstand challenge of the elements.

The previous chapters included:
Beginning Genetics
Genetics 2
Genetics of Color
Breeding
Linebreeding
Outcrossing
Backcrossing
Scatterbreeding
And the prelude to this chapters,
Genetic Disorders


As we saw in previous chapters the way an APBT looks, acts, and the overall health of the pit bull depends on the quality and efficiency of the genes encoded in the dogs chromosomes. Gene are the words that make of the genetic book that defines the dog. These genes are carried on a series of chromosomes, which are the chapters of the book. Think of a chromosome as a long string of genes. Thousands of genes can be carried on a chromosome. It takes many chapters to make a good book (genome) and that good book tells all about the features, qualities, characteristics, diseases and behavior of your dog. Good genetics/good genes equals a good animal. Defective genes equals disease, bad temperament, Conformation faults etc.

The other important concept to fully remember from this point on, is that these Chromosomes occur in pairs in the cell nucleus (think of it as two differnt versions of the same chromosome). When an egg (mothers chromosomes) from the B@#$H is fertilized by the sperm (sires chromosomes) from the sire, the resulting puppy has one chromosome from each of the parents. This is the way in which one half of the genetic information comes from each parent.

There are 39 individual chromosomes and as noted in previous chapters each of these chromosomes has a paired or carbon copy derived from the other parent. The dam provides 39 and the sire provides the copies of these 39 chromosomes. There are tens of thousands of different genes all encoded on the chromosomes (remember your words/sentences of the chapter) these genes work together to define the phenotype of the dog. This is what traits that you see in the dog. Consider a litter of puppies from very tightly linebred parents that are themselves closely related. Each of the parents has many of the very same genes in the same order on the same chromosomes. Thus, when passing these chromosomes to the puppies most of the puppies will have very similar genes. This is how consistant phenotype is created. Unfortunately, the process is not as easy as it sounds. With any dog genome there are hidden genetic problems that can slowly and surely be narrowed and selected for and become consistant in a line just like working type and good structure. The color of the dog, the height, the size of the head and which diseases the dog carries are all encoded within its genes, chromosomes, and genome.


The above should be a refresher for previous chapters. Now we will delve right into how inheritance occurs and how genetic principles determine what traits are passed down. The easiest process we have already considered. This is the one gene one trait function. The example we looked at was nose color (red vs black).. We noted that black is a dominant gene and red is the recessive gene. Combine this with the 2 pairs of each gene concept (remember one from sire and one from dam). Lets revisit a few of the terms we have learned previously. So remember that each gene has a partner at the same position (or locus) on the matching chromosome. Each member of a gene pair is called an allele. If the 2 alleles are identical (BB or bb for example), the individual is homozygous at that locus; if the alleles are different (Bb), then heterozygous.


The inheritance of Disease

As noted in the previous chapter a breeder must be fully knowledgeable in the concepts of inheritance. Especially when tampering with Linebreeding and inbreeding. Some disease can be caused by the environment, toxins, injuries, poisons, pathogenic microorganisms or mutations, however, many many diseases are passed directly from sire and/or dam to the puppies. As a breeder you are responsible for what you put into a puppy. If you breed in blindness then you caused the blindness, if you breed in heart defects then you caused heart defects. This does not just include the direct puppies you produce but every single puppy from then on that has one of these puppies in the pedigree. As you will see knowingly breeding carrier dogs is beyond unethical it is downright F'ed up! Now obviously a breeder cannot know everything about the genetics of their lines but they should definitely know enough that those diseases of high prevalence do not become habitual problems within their line. If a breeder is producing an excessive number of diseased animals it is time to STOP breeding.

Many conditions that have a well-documented hereditary basis may also have other causes. For example, there are several forms of heart murmurs, but heart problems may also occur as a result of injury, toxins, or pathogenic microorganisms. In trying to determine whether a disorder is inherited, many factors, including the age of the animal when the disease becomes apparent, the health of the siblings, parents, and others closely related, and especially whether the disease is prevalent in the entire breed. It is very important that inherited disorders be identified so that information can be relayed back to the breeder, and on a larger scale, so that breeding programs can be designed to reduce or eliminate these debilitating conditions in dogs.


Autosomal Dominant Inheritance:
In spite of the fancy name this is the easiest of inheritance to understand. Dominant alleles like the work indicates overrule any other trait encoded at that locus. Autosomal means that the trait is determined primarily by a single gene.
If the gene encoded by one of the alleles Dominant (actually the term is autosomal dominant), then it rules out the second allele even if it is for a different gene. Thus a gene that is dominant requires only 1 copy is required to express the trait; if recessive (autosomal) then both copies of the gene have to be the same for the trait to be expressed. Remember that as a color Black (B) is dominant over red (b). Upper case letters are traditionally used to represent dominant traits, lower case letters for recessive traits. Thus for a dominant trait, such as black either BB (both alleles Black) or Bb (One allele Black the other red) will express that particular characteristic (in this case the dog will be black), while for a recessive trait only bb will express the characteristic. Thus, only if both alleles are brown will the dog be red. The heterozygote (Bb) will be a carrier -red and able to pass the red allele to the offspring. Autosomal dominant traits are very easy to remove from breeding lines and for this reason there are not many good examples.

You can continue to promote dominant disease conditions In many instances because there is a phenomenon known as incomplete dominance. Similar to the example below the trait may be dominant but may not affect each individual fully. Thus a breeder must look and test for some of these traits. What this means is that if either parent is affected, all puppies have a susceptibility to the disorder but not all will be affected equally. Another type of dominant inheritance is incomplete penetration. If penetration of a disease is 75% for example, only about 3 quarters of the pups who inherit the trait will express it. This means that the puppies that do not express the trait will still carry it and pass it to their offspring. Thus, even though dominant autosomal inheritance is quite easy to rid from a breeding program only the most astute breeders can OR WILL identify these traits and remove the individuals from the breeding program.

Lets consider a disease whose tendency is toward autosomal dominant inheritance.
Cataracts are an opacity of loss of transparency of the lens of the eye. This can be mild or can result in complete blindness. What this means is that if either parent have cataracts and the gene is passed to a puppy, then that puppy will have cataracts. Many environmental factors influence how bad cataracts can get including diet, stress, and exposure to toxins, however a puppy that gets this gene will have this disease.

Diseases that are Autosomal Dominant Include:
lymphedema?
aortic stenosis -variable expression?
spinal dysraphism? -co-dominant variable penetration
Ehlers-Danlos? syndrome?
familial canine dermatomyositis?
dermoid cyst -incomplete?
skin-fold pyoderma?
nodular dermatofibrosis?


Autosomal recessive Inheritance
Recessive disease that are depended upon both alleles being in the disease state is a very common mode of inheritance for genetic diseases in the pit bull. The biggest problem with understanding this method of transmission is that the disease can remain hidden within a bloodline. To show the disease the pit bull must have inherited a diseased gene from both of the parents. The sire and dam both have to be carriers or diseased. Thus, it takes 2 copies of the gene (genotype bb), 1 from each parent for the disease to be evident. It is very dangerous to have recessive diseases passed heavily into a bloodline. There are instances where very popular breeders have even bred dogs that had dual recessive disease states (obvious disease) and these dogs were used as foundations. This means that entire bloodlines are contaminated.


In autosomal recessive disease the normal dog has the genotype CC or Cc (carrier). Both the normal and the carrier are without sign or symptom of disease. However, the carrier will pass the affected gene to approximately half the offspring. Thus, even breeders that utilize animals that are carriers (Cc) and mated these to non-carrier dogs (CC) will ensure that the offspring will be unaffected but some will still remain carriers. If 2 carriers are mated, some of the offspring (approximately 25%) will be affected.
The table below gives the example of breeding normal to diseased (all the pups will be carriers), normal to a carrier (all the pups will be normal but many will then become carriers also), and breeding two carriers (Most the the pups will either be carriers or will be diseased). Remember that in this example the small “c� is the diseased allele.
example:

A
B
C

Sire
?
Dam
Sire
?
Dam
Sire
?
Dam

CC
X
cc
CC
X
Cc
Cc
X
Cc

normal
?
diseased
Normal
?
Carrier
Carrier
?
Carrier

Cc
CC and Cc
CC and Cc and cc

All are carriers
Normal and carriers
Normal and carriers and diseased



Additional dangers with autosomal recessive diseases is that the apparent disease can remain hidden (as carriers) within the lines and only an occasional individual will show the disease. This is easy for breeders to ignore. Then by chance two carriers from the line are mated and the number of carriers is not only intensified but the disease becomes apparent in some of the puppies. In any case the frequency of carriage in the bloodline may become unusually high due to breeding of close family members, or because of the "popular sire" effect , where a sire with a harmful recessive gene is mated frequently because of desirable traits.

Because the carrier animals appear normal and become Grand Champions, it is very difficult to eradicate these traits. Good breeders can reduced carriage and even eliminate recessive diseases through test matings (often involving inbreeding) or through various genetic tests that have been developed. The use of this information in breeding programs is still only up to the breeders ethics. Another primary method to uncover the problems with bloodlines is to share information between individuals that are working with the lines. By speaking out about the issues breeders can uncover the “genetic trail� of autosomal recessive diseases.

There are many diseases that are inherited through an autosomal recessive pattern.

These include:
thrombopathia?
coagulation disorders? e.g. von Willebrand's disease, hemophilia
canine cyclic hematopoiesis?
phosphofructokinase- PFK- deficiency?
pyruvate kinase? PK deficiency
thrombasthenic thrombopathia?
Tetralogy of Fallot? -variable expression
ventricular septal defect? -VSD- variable expression
diabetes mellitus?
juvenile hyperparathyroidism?
hypopituitarism?
hyposomatotropism?
choroidal hypoplasia?
glaucoma?
((ocular dysgenesis syndrome ))
retinal dysplasia?
cherry eye, eversion or inversion of third eyelid cartilage
chronic hepatitis?
cleft lip? cleft palate
chronic liver disease?
exocrine pancreatic insufficiency?
wheat-sensitive enteropathy?
megaesophagus?
protein-losing enteropathy?
pyoderma?
Wobbler syndrome, cervical spondylomyelopathy?
lion's jaw?
hemivertebra?
hereditary myopathy?
Legg-Perthes? disease? -incomplete penetrance
myotonia?
osteochondrodysplasia?
cerebellar hypoplasia?
congenital deafness? and vestibular disease?
deafness?
Krabbe's disease?
hypo-dysmyelination?
Scotty cramp?
laryngeal paralysis?
leukodystrophies?
tracheal collapse?
lysosomal storage diseases?
myasthenia gravis?
neuroaxonal dystrophy?
acanthosis nigricans?
acral lick dermatitis?
acral mutilation syndrome?
brachycephalic syndrome?
epidermal dysplasia?
epidermolysis bullosa?
follicular dysplasia?
lethal acrodermatitis?
pinnal alopecia?, saddle alopecia
seborrhea?
urolithiasis?

Sex-linked traits
As the name implies this form of inheritance is based upon transmission from mother to son. Remember that female dogs have two female chrmosomes known as the X chromosomes (XX). Male dogs have one X and one Y chromosome (XY). What this means is that if there is a diseased gene located on the X chromosome (For instance) then all males of the line will have the disease. This is because they do not have the second X chromosome with the paired Good version of the gene. Remember males only have 1 X and its pair is actually a different (MALE) chromosome (the Y chromosome). Thus 1 dose of a recessive X-linked trait (x) will cause the expression of that disease in a male, while a female with only 1 dose (Xx) will only be a carrier . An example of this type of disease is the bleeding disorder hemophilia. So if a mother who is a carrier for a harmful recessive gene (Xx) passes the recessive gene (x) to her daughter, the daughter will be an unaffected carrier, but her sons who receive that gene will be affected.


Similarly if there is a diseased gene on the Y chromosome then the males of the litter will always inherit this disease. Often sex linked diseases are autosomal recessive as with hemophilia. However, sex-linked genes can also incorporate themselves into polygenic inheritance schemes (discussed below)

The following are examples of sex linked diseases
Hemophilia?
severe combined immunodeficiency? SCID
x-linked muscular dystrophy?
x-linked cerebellar ataxia?
congenital hypotrichosis?
cryptorchidism?
disorders of sexual development?


Polygenic inheritance
The above-mentioned traits are basically inherited in a straightforward manner. A breeder who really wants to identify and eliminate them can if they have enough knowledge of genetic principles and enough desire to do so. Similar to obtaining good pigment or breeding red nose to red nose. A good breeder can choose healthy stock and eliminate those individuals that carry defects that result in disease or disease carriage.

The hard part is that many disease conditions that are inherited do not rely on autosomal inheritance. IN otherwords it is not one gene that causes the disease. Most Conformation traits that pit bull people, either in the show or the working world are trying to select for are based on the combined interaction of many genes. Modifying one gene in a cluster that causes a polysomal disease influences how the others in the cluster are expressed. It becomes very complex to begin to describe or understand some of the intricacies of polygenic inheritance so we will maintain a glossary overview. Epistaxis occurs when alleles at one locus mask the action of another pair of alleles.

Polygenic traits clusters (a group of genes that determine a given train) can contain two, three or even dozens of different genes. these groups of genes can in turn be controlled by a single gene or by multiple genes. Throw in the influence of the environment on polygenic expression. Yep, the traits that adjust Conformation are not only controlled by many many genes but they are also influenced by factors including gender, nutrition, breed, rate of growth, and amount of exercise. These traits are quantitative traits - that is, there is a wide range within the population. Such traits include height, weight, character, working abilities, and the major topic of discussion (DISEASE).

Because it is virtually impossible to determine the exact genotype for such traits, it is difficult to control defects with a polygenic mode of inheritance. There are many examples of controlling polygenic traits or "leading them in the right direction". On of the best examples is the grading scheme for identification of dysplasia. By using breeder policy, recording and databasing health scores for dysplasia a breed community can slowly resolve these traits and the population as a whole can improve. This does not take rocket science or intensive knowledge of genetic principles LUCKILY! I guarantee the biggest overbreeders will not take the time to learn genetics. Canine hip dysplasia is as noted a polygenic trait that remains a problem in most large breeds of dog,


Polygenic disease are incredibly hard to rid from a breeding program
Examples of polygenic diseases include:

Histiocytosis?
atrial septal defect? ASD
patent ductus arteriosus?
vascular ring anomaly?
((pulmonic stenosis (threshold)))
tricuspid dysplasia?
hyperadrenocorticism?
Addison's disease?
corneal dystrophy?
dermoids?
entropion?
exposure keratopathy syndrome?
eyelash abnormalities?
pancreatitis?
perianal fistula?
portosystemic shunt?
osteochondrosis of humeral condyle?
peripheral neuropathies?
colour dilution alopecia?
familial kidney disease?
Fanconi syndrome?

Unknown inheritance

Yes, as if polygenic inheritance is not hard enough to understand and interpret. There are groups of disease that are obviously inherited and genetic but for which the specific pattern of inheritance has not been established. IN Addition there are diseases for which the pit bull is predisposed and for which there is no known inheritance.
The following diseases have no known causes

Unknown Pattern of inheritance
immune-mediated thrombocytopenia?
histiocytomas?
shaker dog syndrome?
histiocytomas?
mitral valve disease?
portosystemic shunt?
sick sinus syndrome?
acquired growth hormone deficiency?, adrenal sex-hormone dermatosis
dermoids?
imperforate lacrimal punctum?
keratoconjunctivitis sicca? KCS dry eye
lens luxation?
micropapilla?
spinal muscular atrophy?
vertebral stenosis?
chronic superficial keratitis?
persistent pupillary membranes?
histiocytic ulcerative colitis?
hyperlipoproteinemia?
spina bifida?
inflammatory bowel disease?
intestinal lymphangiectasia?
pyloric stenosis?
small intestinal bacterial overgrowth?
atopy?
autoimmune hemolytic anemia?
bullous pemphigoid?
immune-mediated thrombocytopenia?
systemic lupus erythematosus?
pemphigus?
hypoplastic trachea?
selective IgA deficiency?
intervertebral disk disease?
eosinophilic myositis?
odontoid process dysplasia?
panosteitis?
degenerative myelopathy?
hydrocephalus?
idiopathic epilepsy?
meningitis?
lissencephaly?
cutaneous mucinosis?
urate urolithiasis?
ectodermal defect?
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