The Relationship of Pigment to Health
by Geneva Coats, R.N.
Rare and exotic colors...one of the most attractive and exciting
features of our Pomeranians. Variety is the spice of life! Different styles
appeal to different breeders. However, there are some important pigment-related
health issues to consider.
BREED STANDARDS
Since the inception of purebred dog registries,
standards have been established for all breeds. The standard serves to protect a
breed from fashion whims. It strives to maintain a breed's traditional "look"
and purpose. The standard establishes desirable conformation goals, temperament
characteristics, and suitability for the original purpose of the breed. The
standard provides a goal for breeding practices. This is why standards are
written in the first place, to act as guides for breeders and judges. You don't
need to understand all the details and theories of genetics, but you do need to
abide by the standard when breeding and judging.
Our Pomeranian standard
was changed in 1997 to allow all colors, patterns, and variations thereof. This
may serve to promote some breeding practices which might ultimately be
detrimental to the health of the breed. We need to examine this issue carefully.
The direction we take in breeding is the path to our future. The desire for
health and concern for future generations must always take precedence over the
desire for aesthetics.
Why is a color or pattern so important to the
stewards of a breed? Breeders have always been keen scientific observers, even
before genetics became an established field. They have worked tirelessly toward
a goal of producing healthy dogs. Dog with health issues are in limited demand
as companions, and often unsuitable for work. Some breed standards disallow
excessive white, dilute colors or merle. Many breed standards specify that
parti-color dogs have a certain proportion of color to white, or that they must
have color extending over both eyes and ears. Most all standards call for full,
dark pigmentation of nose, lips, eye rims and pads. Albinism is generally
disallowed. These guidelines were not established for aesthetics' sake, but
because certain colors, patterns, and lack of pigmentation were known to be
associated with an increase in certain specific health problems. There is much
documentation and information related to the merle and white spotting patterns,
and they will be the focus of this article.
COAT COLOR DEVELOPMENT
The process of coloration and color patterns
in dogs starts with embryonic development. The cells which become melanocytes
(pigment producing cells) are derived entirely from the neural crest of the
embryo. Pigment cells develop from the same cells that give rise to the nervous
system. Defects in certain color genes can be associated with defects in the
nervous system, as evidenced by vision and hearing problems. Color provides a
logical genetic indicator, and explains why it is likely that certain patterned
dogs, such as extreme piebalds (>90% white) and merles may be at risk for
specific health problems. In studies to date, the coat patterns resulting from
genes producing white are significantly associated with deafness. In addition,
suppression by "white genes" of pigmentation in the iris of the eye is also
associated with deafness. On the other hand, the presence of pigmented, colored
patches in the coat is associated with reduced risk of deafness.
WHAT IS MERLE?
Merle is regarded as a coat pattern, not a color. The merle gene works like
other dilution genes, in that it lightens whatever color is already there.
Whatever the basic color of the dog-unless he is all white-the merle gene will
cause dilution and splotching imposed on the base coat color. The appearance is
a speckling or marbling, like when bleach is splashed on your clothes. The
pigment cells are affected individually in the fetus. Some are disabled
completely, leaving white areas. Some cells allow partial expression of pigment,
leaving merled or dappled areas. Some cells are unaffected, leaving the coat
color normal or non-merled. The amount of dappling or merling can vary. The dog
can have perhaps just a small dappled spot somewhere, or perhaps just a light
eye with a nondappled, normal coat. Or, it might display dappling throughout the
coat. The effect is most noticeable on a black coat; where the black is diluted
to grey, the color is called "blue merle".
Merle appears at first
glance to be dominant, because if a dog carries one gene for the merle factor,
he will be affected by it. However, merle is different, because it is
incompletely dominant. A single merle gene, inherited from one parent, produces
what is known as a "heterozygous" or "single" merle. This single copy of the
gene will usually cause the affected dog to display merling somewhere in the
coat. This can range from light dappling to extensive dappling. Sometimes the
effect on the coat is not evident, and there is no way to tell at maturity that
the dog carries the merle gene. Sometimes, blue flecks in the eyes are the the
only sign that a dog carries the merle gene.
If two heterozygous merles are bred together, statistically 25% of the
offspring will inherit two merle factor genes, one from each parent. When this
happens, we produce what is known as a "Double (homozygous) merle". The effect
of the gene is then doubly intense. There is so much color dilution that the dog
is usually predominantly white, and almost always has impaired hearing or
vision-or both.
In Great Danes, merle interacts with another gene called harlequin, which
bleaches the gray areas of the coat to white. In the pure homozygous form,
harlequin is lethal. In Danes and Aussies, the tweed pattern is a variation on
merle which adds a third, intermediate shade to the coat.
Many double merle dogs are so defective that they do not survive to birth.
(estimates are as high as 50% mortality in utero). Those that survive are the
ones with "just minor" defects...minor enough to handicap rather than kill. A
gene that destroys half of those carrying it in a double dose in utero cannot be
dismissed or ignored.
In French, the word "merle" means "blackbird", and "le merle blanc" ("The
white blackbird") is an expression, meaning something that is impossible
or something that cannot exist. This is an admirable goal for the white merle
dog!
HOW MERLE WORKS
Merle is a gene that is inherently unstable. It is a "transposon", or
transposable element; a mobile parasite segment of DNA in the chromosome.
Transposons usually originate from viruses. A virus is a particle containing DNA
which inserts itself into the host cell, thereby infecting it. If the virus does
not kill the host cell, it can leave behind a piece of its genetic material in
the DNA of the host cell. When this happens in the sex or germinal cells, the
particle can become a part of the genetic makeup of some of the offspring. This
is a way that mutation occurs.
Transposons have also been called "junk DNA or "selfish DNA", as they
rarely provide any benefit to the host cell. Transposons are also often referred
to as "jumping genes." The transposon can move to different positions in the
cell in a "cut and paste" process. In so doing, it may cause mutations, or alter
the amount of DNA in the genome. The merle transposon segment may lose some of
its DNA particles during cellular replication during early embryonic
development. Coat color in that area will then be less affected by the gene, or
even unaffected, and the underlying true coat color will be expressed. This
explains why there are some areas of the coat which are NOT dappled, and other
areas which ARE.
The decorative variegated Indian corn is produced by transposon elements in
the corn gene. Many viruses, such as those responsible for AIDS and feline
leukemia, function as transposons. In humans, hereditary diseases such as
hemophilia A and B, predisposition to colon polyps and cancer, and Duchenne
muscular dystrophy, are all related to inherited mutations produced through the
transposon process. Genetic engineers sometimes use transposons to try to
intentionally introduce certain genes into an organism.
There are also documented cases of homozygous merles producing non-merle
offspring ("germinal reversion"). This is further evidence of the instability of
the gene. Not only can you sometimes get non-merle pups (which should not happen
according to the rules of Mendelian genetics), but worse things can happen. The
"cleft palate syndrome" is a rare and isolated Aussie defect that has been the
subject of numerous scientific journal articles and symposia presentations. It
is a sex-linked (on the X chromosome) defect, in which females have minor
abnormalities, like extra toes, while males die of massive skeletal
abnormalities and a cleft palate. This disease started with a homozygous merle
bitch that was kept for coat color research.
PIGMENT PLAYS A ROLE IN
HEALTH
Many breeds have the white spotting and merle factors in their gene pools.
These genes are not colors per se, but do affect the expression of coat color.
In breeds which have traditionally included the merle color pattern, the
predominantly white (double-factored) merle has been disallowed in the show
ring, as well as selected against in the whelping box. And with very good
reason. The gene which produces the merle pattern is associated with some very
serious health defects. Both the white spotting gene and the merle gene are
known to sometimes affect hearing. The merle gene, however, is unique in that
it interacts in an as-yet undetermined manner with genes for eye features.
MERLE AND EYESIGHT
There is a complex of eye defects associated with the merle gene. These
defects can be superficial in nature, such as a difference in color between the
iris of one eye and the other. The example of this is a dog with one brown eye
and one blue eye. (Note that this trait is not necessarily indicative of
possession of the merle gene, because it can also be found in dogs with extreme
white spotting). In addition to superficial indicators there are also major
effects, such as absence of the reflective substance which lines the back of the
eye, resulting in reduced ability to see in low light. There can be lack of
retinal pigment, which directly reduces vision. Small or absent eyeballs,
irregular or starburst pupils, and clefts in the iris can occur, as well as
persistent pupillary membrane, strabismus (cross-eyed), lens luxation , and
juvenile cataracts.
THE MERLE LINK TO MICROPHTHALMIA
The term "microphthalmia" means a smaller than normal, tiny eyeball due to
a defect in early development. Microphthalmia is a defect very commonly
associated with merle; particularly homozygous "double" merle, it even rarely
occurs in heterozygous or "single" merles. Complete absence of the eyeball in
the eye socket sometimes occurs. This is known as anophthalmia.
MITF, or "Microphthalmia Transcription Factor", was discovered in 2007 to
be the location of the gene that affects pigmentation, causing white spotting
(otherwise known as the particolor or piebald pattern).
The merle gene is believed to affect eye development through some sort of
interaction with MITF. Now, why would microphthalmia occur in association with
merle and not just with white coat color in particolor dogs? I've asked several
canine geneticists, but have received no answer! This relationship is still a
mystery. The exact mechanism by which merle interacts with the white spotting
gene and produces the defect of microphthalmia is still waiting to be
discovered!
MERLE AND HEARING
Hearing impairment can occur in merles due to a
lack of melanin or pigment in the inner ear. Not all merles will develop
problems with hearing, it all depends on whether or not the inner ear is
pigmented. If the inner ear isn't pigmented, the nerve cells responsible for
hearing can't develop as they should. Then, the nerve endings atrophy and die
off in the first few weeks of the puppy's life, resulting in partial or total
deafness. The deafness is neither dominant nor recessive, but is linked to the
merle gene which disrupts pigmentation and secondarily produces deaf dogs.
White outer ear color is often associated with lack of inner ear pigment
and deafness. However, sometimes deafness occurs even with patches of color on
the ears. Mild to moderate hearing impairment may never be noticed, and is
rarely tested for.
ONE COPY OF THE GENE HARMLESS?
The popular belief is that
heterozygous merles are completely normal, and that only homozygous merles have
health defects. Heterozygous merles can have expression of lesser defects of the
eye such as clefts in the iris, and a thinning of the retina (similar to what is
found with Collie eye anomaly). There are also rare cases of microphthalmia in
"single" merles. Deafness can also sometimes occur, if the merle gene prevents
pigment deposition in the nerve cells of the inner ear during embryonic
development.
Heterozygous "single" merles often have reduced eye pigment which produces
the characteristic blue eyes. Interestingly, the amount of white even in
homozygous merles does not correlate to severity of eye defects. In a study of
the embryonic origin of merle eye defects, Dr. Cynthia Cook, of the University
of California, San Francisco, observed that the severity of eye defect and
amount of pigment were not related. This is in contrast to hearing impairment
in merles; the likelihood of deafness increases with increasing amounts of white
in the hair coat.
The Hannover Veterinary School in Germany conducted studies on Dapple
(merle) Dachshunds. Their studies demonstrated eye problems, sperm
imperfections, and hearing impairment. These problems were found in homozygous
merles, and also heterozygous merles. Hearing faults, ranging from slight
hardness of hearing to complete deafness, occurred in 54.6% of homozygous merles
and 36.8% of heterozygous merles. As a result of these studies, in 1986 it was
suggested that FCI restrict the breeding of merles on welfare grounds. These
studies, however, are now generally considered outdated. Future testing of
vision and hearing in merle dogs will hopefully paint a clearer picture for us.
GENETIC LINKAGE CAN CAUSE SPREAD OF DEFECTS
Genes on the same chromosome are usually inherited together. However,
during cellular division and replication, sometimes chromosomes will randomly
break and recombine. Genes that were formerly associated with each other can
then become separated and inherited independently. This process is known as
genetic linkage. We have already mentioned the Aussie cleft palate
syndrome which originated with a merle bitch. Iris coloboma, or missing part of
the iris, is being reported in non-merle Aussies. Coloboma appears as a notch at
the edge of the pupil, giving the pupil an irregular shape. This sight-altering
defect is believed to have been brought into the breed through linkage with the
merle factor. This trait is now inherited independently from merle.
It is likely more than coincidence that breeds in which merle is most
common are also breeds which are heavily plagued with a variety of eye defects.
Yearly CERF testing by a veterinary ophthalmologist can help screen out
heritable abnormalities. Further studies in merle dogs are needed to observe the
frequency and exact methods by which eye defects are produced. It is theorized
that some mutations are produced by damage done to portions of the chromosome
located near to the erratic merle transposon.
BREEDING RECOMMENDATIONS FOR MERLE
Sometimes a dog is genetically carrying the merle factor gene, but there
are no outward signs (cryptic or phantom merle). This dog could easily be
inadvertently bred to another merle and result in the production of homozygous
double merles, so for this reaon it is usually recommended to avoid breeding
merle to brindles or any purely phaeomelanin (orange-red-gold-yellow) coat
colors.
It is almost universally recommended to NEVER breed two merles together, to
avoid producing defective double merles. But, unfortunately, some breeders
will intentionally breed merle to merle, hoping to produce a higher percentage
of merle offspring. This is sadly a misinformed idea. Others may breed merle to
merle in an attempt to produce a double merle sire to use for future breeding.
Such a double merle dog (even if vision or hearing impaired) will produce 100%
merle offspring. There is a demand for the unusual merle color. Although this
method of breeding may be considered unethical, it does happen in many breeds,
by uneducated or uncaring breeders.
A merle dog should be bred to a dark colored mate, preferably black or
black and tan. A dominant black dog will only produce black offspring half the
time, unless he carries two copies of the dominant gene for black. Couple a
black with a merle parent, who will produce merle offspring 50% of the time, and
the odds just dropped to 25% for producing a blue merle from a black to merle
mating...the same odds of producing a sable merle or hidden merle from such a
breeding.
Black and tanpoint pattern is recessive and would breed true. If one parent
is also merle, you have a 50/50 chance for producing blue merle offspring, and
50/50 tanpoint who are not merle. Recessive black would also breed true, just as
black and tan does, but recessive black seems to occur only very rarely in our
breed. Also, In our breed, there is a widely carried recessive gene "e" which
suppresses all black pigment in the coat. This gene can double up in the
offspring to hide the visual appearance of merle.
Here is part of a statement by canine geneticist Sheila Schmutz, written
for the Pomeranian standard revision committee in April 2006:
"Yet another gene in the "blue" family that can cause health issues is
merle. Merle can not be seen in dogs with an e/e genotype. This e/e genotype
occurs commonly in Pomeranians since orange, red and white probably account for
the majority of Poms. The problem is that M/M (homozygous merle) dogs are always
deaf based on our studies. We recently genotyped 24 mostly white Australian
Shepherds and all tested M/M (based on the Clark et al. 2006 PNAS published
test) and all were deaf. A proportion of these dogs were also blind in one or
both eyes since microphthalmia is another common side effect in M/M dogs.
Although in many breeds it is possible to educate breeders to never breed two
merle dogs together this advice is not possible to follow in Pomeranians since
e/e dogs would not show the merle pattern. It would therefore be necessary
instead to advise all persons who breed a merle dog to use only a black or sable
mate or to have DNA testing done on their red, orange or white mate prior to
breeding to be sure it did not carry merle."
Further complicating the picture is the case of breeding a merle to any
dog with excessive white in the coat. Breeding merle to parti-color dogs with
more than 50% white coat is advised against; especially if the merle parent also
carries genes for particolor or "white spotting". It would be difficult to
determine if the resulting puppies were merle or extreme piebald white-or
both-without DNA testing! In either case, hearing can be affected.
DNA TEST FOR MERLE
We now have a DNA test for merle! This is a wonderful tool for breeders who
choose to avail themselves of the technology. A cheek swab from the dog is sent
to the lab, and they can tell you if your dog is merle or not. This test can
also tell you if your dog carries one copy or two copies of the gene.
Unfortunately, the US company offering this test closed its doors in March 2009.
However, another company (Idexx) is poised to take over this service.
Here is the link to the Idexx website:
Unfortunately, the merle test costs close to $100, so some breeders will
not o use the test, even when available. These breeders continue to try to guess
the merle status of their dogs solely by appearance, noting the amount of
dappling and/or white coat color.
AKC registration for Pomeranians now allows for designation of color as
merle. However, this will remain an inaccurate system unless breeders DNA test
all questionable offspring from their merle parents. Currently, merle is
uncommon in the Pomeranian breed. However, as the pattern becomes more popular
and widespread, it will more likely show up when least expected in a breeding
program.
WHITE SPOTTING AND HEARING
Another pattern gene strongly associated with deafness in dogs is
the "S" series-commonly known as white spotting, Irish spotting, or piebalding.
Breed examples are the Bull Terrier, Samoyed, Greyhound, Great Pyrenees,
Sealyham Terrier, Beagle, Bulldog, Dalmation, English Setter, Papillon and Fox
Terrier.
The recessive "S" gene covers the coat color with white, and when weakly
expressed allows patches of color. This process is believed to be related to the
path of migration taken by the pigment cells in the embryo. During fetal
development, the melanocytes (cells that produce pigment) are concentrated in
the neural crest. The neural crest is the area which eventually becomes the
brain and spinal cord. From the neural crest, the pigment cells migrate to the
peripheral areas of the body, such as the head, legs and tail. However,
sometimes the melanocytes don't travel completely over the body. Any areas where
the pigment cells fail to migrate will remain white. This is why sometimes
dogs will have a white spot on the end of the tail, the tips of the toes, or on
the chest. If pigment-producing melanocytes fail to reach the inner ear,
deafness will result.
White color on the head is often, but not always, associated with lack of
inner ear pigment. Patched-colored dogs with dark eyes have been selected for in
many breeds. These dogs have reduced incidence of hearing impairment when
compared to dogs which are almost totally white.
Not all breeds with the "S" -extreme piebald pattern have been reported to
be affected with deafness, and there is also inherited deafness in several
breeds which is totally unrelated to coat color.
HEARING TEST
The only way to know for sure if your dog is hearing impaired is
through a Brainstem Auditory Evoked Response Test, or BAER test. This testing is
only available at select facilities and can be expensive. It need only be
performed once in a dog's lifetime (preferably at a young age) to rule out
hereditary hearing impairment. A complete list of BAER testing facilities can
befound on Dr. George Strain's website:
www.lsu.edu/deafness/deaf.htm. Selective breeding for
hearing dogs, as evidenced by normal BAER testing, can reduce the incidence of
deafness in dogs, including those with high risk factors.
OTHER PROBLEMS
Other health concerns associated with lack of pigmentation are skin
allergies, skin cancer and sunburn, demodicosis (immune-mediated hair follicle
mange), follicular dysplasia (coat which is dull and breaks), reduced fertility
and sterility, and photo-induced epilepsy.
CONCERNS RELATED TO THE PRODUCTION OF HANDICAPPED DOGS
Some animal
welfare specialists endorse humane euthanasia for all dogs deaf in both ears
(bilaterally deaf). Hearing can not be accurately assessed before 5 weeks of
age. At this age, euthanasia can be an agonizing decision for any caring,
ethical breeder.
Deaf or blind dogs require special placement arrangements. A breeder
is morally and ethically responsible for care and placement of handicapped dogs.
We may see in the future an increase in handicapped Pomeranians turned over to
rescue or to shelters. As there are always so many healthy dogs in shelters and
rescue who cannot find homes, the odds of finding homes for handicapped dogs are
even greater. Support for rescue from our parent and regional clubs will likely
need to increase.
WHERE DO WE GO FROM HERE?
Many people have voiced concern that the merle pattern has only
recently been introduced to our breed, through crossbreeding with merle dogs of
other breeds. However, all breeds have been created through such methods at some
point in their history. The concern is not so much HOW the pattern appeared in
our breed, but rather WHERE it will take us in the future.
APC is the parent club for the Pomeranian, and as such, should serve the
breed with the commitment and resonsibility that the word "parent" implies. It
is a responsibility of a parent club to discourage breeding that is known to
increase the probability of dogs with health problems. This can be attempted
through education of breeders and the public. Such education can be provided on
the club website or through the person designated as health and genetic liaison.
Education should include factors to consider in selecting a canine companion, as
well as methods of developing a breeding program with an emphasis on producing
healthy offspring. Public awareness of health issues may eventually create an
increased demand for dogs bred as much for good health as for physical
beauty.
Many breed clubs promote responsible breeding through the breed
standard Itself. (For instance, our Pomeranian standard stipulates that eyes
must be dark).
Guidelines can also be provided through a breed club's code of ethics. The
guidelines might contain recommendations such as:
1. Yearly CERF
testing for all breeding stock, particularly merles. (Clinics should be made
available at national and regional specialties).
2. BAER testing should
be performed once in a dog's lifetime prior to breeding. This is especially
important in merle and extreme piebald patterns.
3. All dogs from
merle litters be sold only to knowledgeable breeders or transferred to new
owners after being spayed or neutered. This will help prevent uneducated
breeding and the production of handicapped dogs.
4.Vision and hearing
health should be guaranteed in all puppy contracts, Dogs so affected should be
readily taken back by their breeder at any point in their lifetime.
5.
Any puppies from a litter with a merle parent who do not appear to be merle
should be DNA tested to determine merle status, (unless of course they are going
to be sterilized, in which case DNA merle testing would not be necessary).
As breeders, we need to avoid the ostrich syndrome. Let's not
stick our heads in the sand and hope problems will go away....they might get
worse if we do!
STUDY!! We should learn all we can about genetics and heredity-of
all breeds, not just our own. The other guy's problem today may well be ours
tomorrow.
SUMMARY
Our breed already has some health concerns. It would seem unwise
to encourage an increase in defects purely for the sake of novel color patterns.
Through education and personal responsibilty, risky breeding practices can be
minimized. We should strive to produce puppies blessed with the gifts of normal
vision and hearing. If this article serves to prevent the birth of just one
handicapped dog through heightened breeder awareness, it will have been
worthwhile.
PIGMENT-RELATED DISORDERS IN HUMANS
One in 17,000 persons in the USA has
some type of albinism, as indicated by little or no pigment in their eyes, skin,
or hair. People with albinism always have problems with vision. This results
from abnormal development of the retina and abnormal patterns of nerve
connections between the eye and brain. It is the presence of these eye problems
which defines the diagnosis of albinism. Albinism may be limited to the eyes or
involve hair and skin to varying degrees.
Waardenburg syndrome is an
inherited disorder in humans characterized by varying degrees of hearing loss
and changes in skin and hair pigmentation. This syndrome was named for the Dutch
ophthalmologist who noticed that people with pigmentation abnormalities of the
hair, eyes and skin, often had hearing impairment.Those with Waaardenburg
syndrome may have two differently colored eyes, one brown and one blue.
Sometimes, one eye has two different colors. Others may have unusually brilliant
blue eyes. People with Waardenburg syndrome also have distinctive hair coloring,
such as a patch of white hair near the forehead, or they might have white
patches of skin. Waardenburg's is associated with other birth defects such as
spinal or intestinal disorders or cleft palate.
After doing this research, I
finally realized why I reach for sunglasses each and every time I go outdoors on
a sunny day! I have blue eyes, and cannot tolerate the bright light. My eyes
lack sufficient light-blocking pigment!
