Investigating Genetic Disease

From the October 2013 issue of The Stable Magazine – www.thestablemagazine.com/october 2013

HYPP, HERDA, SCID, OLWS...

What do these acronyms all have in common?

They are all genetic diseases found in horses. Various symptoms, management and prevention apply to each, although every one is inherited from a horse’s sire or dam - or an unlucky combination of genetic material. 

We take a look at genetic disease in general - and take a bit of a closer look at Overo Lethal White Syndrome (OLWS) - a paint breeder’s worst nightmare. OLWS is a devastating genetic disorder that results in the birth, and subsequent inevitable death, of a pure white foal. No treatment is available for these lethal white foals - however this condition can be avoided, using genetic testing and careful breeding methods. So why are lethal white foals still a frequent problem? How does it occur and which horses are affected?

Overo Lethal White Syndrome

Overo Lethal White Syndrome (OLWS) is caused by a recessive gene which causes affected foals to be born with an incomplete or underdeveloped gastrointestinal tract. These foals appear normal at birth, but after 24-48 hours develop colic as they are not able to pass the meconium, or any manure. The gene mutation that causes OLWS not only causes a failure of nerve endings to develop in the bowel, but is also responsible for the colour of affected foals - who are pure white with blue eyes, or almost entirely white with very few dark markings.

There is no treatment available for foals affected by overo lethal white syndrome, and although corrective surgery has been attempted, no foals have ever survived. It is a heartbreaking situation for both the owner and the mare. Once a foal has been confirmed as a lethal white foal, they are most often euthanised in order to spare them suffering a painful death from colic.

Overo Lethal White Syndrome has been researched in depth since the 1980’s, and has now been proven to be caused by a recessive gene found in many overo (particularly frame overo) horses. Many horses carry the lethal gene and are unaffected, however when two horses who are carriers of the gene are bred, there is a 25% chance that the resulting foal will be a lethal white foal - that in itself, being an inevitable death sentence.

The Overo Lethal White gene is associated with a single mutation of a base amino acid in the horse’s genetic code. This mutation continues to be passed on from horse to horse, meaning that lethal white foals are still a common occurrence amongst breeders using carriers.

Being a recessive gene, horses who carry the OLWS gene are not obvious carriers. In fact, horses of many breeds including paints, miniature horses, quarter horses, thoroughbreds, and part bred arabian horses have been known to carry the defective gene - and it appears even in horses of solid colours. There are also overo horses who do not carry the gene. This means that it is difficult to detect the defective gene in horses judging on a horse’s appearance alone - but there is a way to be certain - genetic testing.

All horses can easily be tested for the OLWS defective gene, which means that the occurrence of lethal white foals could be eradicated, simply by breeders choosing not to breed from horses who carry the gene. Of course, this would result in a loss of income for many breeders, and so, they would not sacrifice or compromise their income for the good of the breed. Testing for the defective gene typically costs between $60 and $80, and simply involves sending a sample of hair to a laboratory. Many breed societies and associations encourage members to have their horses tested for genetic defects, however in some cases are sadly unable to ban horses carrying certain defects from being registered.

Consequently, there are some horses who are still used in breeding programs although their owners are aware that their horse carries the lethal white gene. Admittedly, the breeding of these horses to horses who do not carry the gene will result in a normal foal, however failing to disclose this important genetic information to potential buyers of the offspring of a carrier can mean that these genes are further spread, even unintentionally.

Worse still, there are some breeders who are ignorant to the problem to which they are contributing, and other breeders who are deceiving potential buyers in order to maintain income from their breeding program. Stopping this process is possible, and it begins with education of breeders in all fields. With the introduction of paint horse crosses in breeds where colour wasn’t previously seen, there is a risk of carriers being bred. Some registries will not de-register horses who carry the gene, and cannot stop breeders from breeding carriers, but can force owners to have their breeding stock tested, include the results on registration papers, and force them to disclose this information to potential buyers of youngstock, or breeders who wish to breed to their stallions.

If this were to happen across all societies, buyers and mare owners could make informed choices regarding the breeding and purchase of horses who are carriers. Some may choose to breed carriers to non-carriers, and in this case, you cannot end up with a lethal white foal - but 50% of the offspring will carry the gene. The safest way to ensure you don’t end up with lethal white foals is to have your horses tested, and to be honest to other breeders and potential buyers.

NOT ALL WHITE PAINTS ARE LETHAL!

Even if a foal is born all white, it may not be a lethal white. There are horses that appear all white and that are maximum overo, sabino or splashed white horses. Double dilutes such as cremellos and perlinos also have pink skin and blue eyes and are not lethal whites. Dilutes and double dilutes have nothing to do with lethal white horses.

A vet should always be called to check if an all white foal is a lethal white, and they should not be put down straight after birth. Colic is also not an uncommon condition in foals, and impactions can occur in otherwise healthy foals, so you should always seek the advice of your veterinarian if you suspect a lethal white foal, or experience anything abnormal with your mare or foal. If you have your mare tested, and she does not carry the gene, then there is no possibility of her giving birth to a lethal white foal.

Equine Genetics #101

When a foal is born, it inherits genetic information from both parents. The foal’s sire and the foal’s dam each pass on one copy of each chromosome to the foal - making up some 32 pairs of chromosomes - 64 in all, which contain the foals genetic information. GENES control where BASES are located during development. There are four base chemicals, which are formed in strands - and these strands are DNA - otherwise known as deoxyribonucleic acid.  Strands of DNA form the backbone of chromosomes - which are passed from parent to child - or from dam and sire to foal.

So all up, a foal inherits 64 chromosomes - 32 from each parent. 31 pairs of chromosomes are known as autosomes - which contain ALL of the genetic information used to ‘create’ the foal - like a set of instructions. The last chromosome pair is that which determines the sex of the foal.

All females have ‘XX’ sex chromosomes - while males have ‘XY’. The foal’s gender is determined by which chromosome the sire passes on to the foal.

DAM:               FOAL:               SIRE:

XX                       XX                   XY

ABOVE:

The foal of this breeding will be FEMALE, as it has inherited an ‘X’ chromosome from it’s dam, and an ‘X’ chromosome from it’s sire.

DAM:               FOAL:               SIRE:

XX                       XY                   XY

ABOVE:

The foal of this breeding will be MALE, as it has inherited an ‘X’ chromosome from it’s dam, and a ‘Y’ chromosome from it’s sire.

The same applies to all genetic factors - like coat colour. Each gene has a locus (or designated location) on each chromosome. What makes genetics so interesting is that there are many kinds of ALLELES - that is, one gene could be an allele for a black coat colour - and another gene could be an allele for a chestnut coat colour. This is when genetics and breeding get really interesting!

A foal receives two copies of each gene - one from the dam, and one from the sire. Some alleles are dominant, and some are recessive, which means some characteristics are always expressed over less dominant alleles.

The foal can either be:

HOMOZYGOUS -

which means that he has  copies of the same allele

or the foal can be

HETEROZYGOUS -

which means that he has copies of two different alleles.

HOMOZYGOUS:  LL LL   

HETEROZYGOUS:Ll Ll

A horse’s genetic makeup is expressed in his coat colour, among all other factors that make the horse what he looks like.  A horse’s genetic code is called his GENOTYPE. What the horse actually expresses - in his coat colour, for example, is called his PHENOTYPE. A horse might carry the gene for roan in his GENOTYPE,but it might be a recessive allele, and so the roan is not actually visible in his coat colour or PHENOTYPE.

For a little more detail on equine genetics, see the July 2013 issue of The Stable Magazine - http://www.thestablemagazine.com/july2013

The Overo Lethal White gene is recessive, which means that the genotypefor lethal white foals is ‘oo oo’. A horse that does NOT carry lethal white, nor is affected by lethal white would be dominant homozygous- ‘OO OO’.  Carriers of the recessive overo gene are HETEROZYGOUS‘Oo Oo’ and can pass on the recessive gene if bred to another carrier. Carriers appear as normal horses, and can be of any colour or appearance - even solid, and not overo..

Overo lethal white foals can only be born to a sire and dam who are BOTH carriers of the Overo Lethal White gene. A horse of any colour can carry the gene, although most often the Overo Lethal White defective gene is present in frame overo horses. The offspring of an overo carrier can still carry the gene, even if it is another kind of paint horse - such as tovero, sabino, splashed white - or even tobiano. It is possible for paint horses to carry genetic information for more than their expressed coat pattern.

The square on the LEFT shows the possible outcomes of breeding a CARRIER of the defective gene with another horse that is a CARRIER. The square on the right shows the possible outcomes of breeding a NON CARRIER with a CARRIER. As each resulting combination takes one chromosome from the sire and one from the dam, there are three possible outcomes.

Not Only Paints

Overo Lethal White syndrome can occur in any offspring where the sire or dam carry the defective frame overo gene - and this isn’t just paint horses. Miniature overo horses are quite popular - and some of these horses possibly carry the defective gene. Same goes for any other breed. In fact, the defective gene has been found in a range of breeds including half arabians, ‘crop out’ American Quarter Horses, and even in Thoroughbreds.

A registered American Quarter Horse Mare has been reported as having given birth to an Overo Lethal White foal. Quarter Horses are not accepted into the AQHA if the amount of white on their bodies falls outside the accepted areas of face and leg markings. The mare’s sire was later found to be a chestnut overo - however the mare was a solid chestnut with no ‘illegal’ white markings. Tobiano horses have also been known to carry the defective gene. The moral? Looking at the horse’s coat colour is not a good indicator of whether the horse does or does not carry the defective gene for Overo Lethal White Syndrome.

Why White Foals?

What makes Overo Lethal White Syndrome fatal is the incomplete digestive tract of the newborn foal with the condition. It is a ‘failure of embryonic cells that form nerves in the gastrointestinal system’, says the American Association of Equine Practitioners. Strangely, these defective cells also seem to have a role in determining skin colour - so all afflicted foals are white. Some have been reported to have black tails, but all are said to appear like perfect little white, blue-eyed foals.

Genetic Mutations and Inherited Disease

Genetic mutation is a difficult thing to control once established in a population of horses. It begins with just one gene being formed incorrectly in one single location amongst the thousands of genes in one cell of an embryo at conception. That one cell containing the genetic information is replicated throughout the body cells of the animal.

This genetic mutation may not be life threatening. In fact, this one mutated gene may not even appear obvious, and the foal may prove healthy, and may live out his life naturally. However, if the horse carrying this mutated gene is bred, and passes on this gene to his foals, and they in turn are bred, sometime down the track in generations to come, many horses may carry this defective gene. If it is recessive then no apparent problems may present in any of the horse’s offspring who are carriers of this gene.

In the case of Overo Lethal White foals, the gene is expressed when two carriers are bred, and when the foal is homozygous for the recessive gene. The resulting homozygous recessive foal is lethal white. Unfortunately, there are many other examples of genetic disease and other hereditary syndromes... Examples of inherited mutations and diseases can also be seen in the form of:

HYPP (Hyperkalemic Periodic Paralysis) - This genetic condition is commonly found in Quarter Horses, Paints and Appaloosas. It is essentially a muscular disorder where too much sodium enters the muscle cells, causing the horse to twitch, sweat, suffer respiratory difficulties and weakness.

This disease is thought to have originated from ONE stallion ‘Impressive’ - a champion in halter in the USA - although this has not been officially confirmed. There are now tests available in order to detect HYPP in these breeds of horses.  Some horses with HYPP have not exhibited symptoms, and these horses often make wonderful riding horses when HYPP is managed carefully and successfully.

SCID (Severe Combined Immunodeficiency Disease) - This genetic disease affects Arabian horses and is caused by an autosomal recessive gene. Basically, foals are unable to respond to being immunised, and have a very low number of lymphocytes in their bloodstream. They are not able to produce immunoglobulins, which means that they are unable to fight off infection effectively. Most foals that are born with this disorder die of infection, and no foal with this condition has lived for more than five months.

EPITHELIOGENESIS IMPREFECTA  Another syndrome caused by recessive genes, this particular condition means that affected foals are born missing hair, parts of skin, oral membranes, and sometimes even hooves. In less severe cases, the horse may just be missing patches of hair, and in these patches the skin is leathery. Most foals with this condition die within days of birth.

HERDA(Hereditary Equine Regional Dermal Asthenia) - A relatively recent discovery, HERDA is a condition where the skin of affected horses is weak. There are three layers of skin - the outer epidermis, the dermis, and the sub cuti. When a horse suffers from HERDA, these three skin layers do not bind together correctly.

Consequently, when these horses suffer wounds, or when the skin is damaged, it doesn’t heal correctly, and leaves the area open to infection. The affected areas cannot be stitched due to the weakness of the skin - and often riding these horses makes injuries worse. HERDA is again a recessive disorder, and horses who suffer with the condition are sometimes euthanised, depending on the severity of their affliction.

There are other genetically inherited conditions, including dwarfism, cryptorchidism (retained testes), haemophilia (impaired blood clotting, which is rare), and various other conditions resulting in lack of co-ordination and muscular problems. The severity and implications of genetic disease vary greatly, with some conditions able to be managed, and others that prove fatal in all instances.

This article was originally published in the October 2013 issue of The Stable Magazine – Australia’s FREE Online Horse Magazine.

Read more great articles online at www.thestablemagazine.com