Burmese? What are they and why us.

(return to index page)

All modern day Burmese can trace their ancestry to a small brown cat named Wong Mau, who came to the USA from Burma in 1930, with a Dr. Thompson. Thompson, a retired Ship's doctor and practising Psychiatrist, who also bred cats. Realizing that Wong Mau was different from his Siamese cats, Dr. Thompson persuaded three breeder/geneticist friends to investigate Wong Mau's genetic make-up. This investigation showed that Wong Mau was in fact a hybrid of Siamese with a new dark-coated breed of cat which became known as Burmese.

The Burmese breed was first recognized by the American Cat Fanciers' Association, (CFA), in 1936. By 1946 some Burmese were achieving major success at shows. By 1949, Burmese were imported into Britain.
 

Ch Casa Gatos Darkee (Dar-kee), (above), ( See historical pedigrees ) was one of the original six cats imported into Britain from the USA in the early 50's. Darkee is said to have had the most impact on the development of the breed and made possible the blue diluted form. In the late 60's another line on Burmese where imported into England by Dr Allen from Ontario, Canada .That cat was GC Halton Ridge Alfie of Silkwood whose pedigree is posted herein.

We particularly like this above picture  as our very favorite cat Quinton ( seen below) is a dead ringer of this beautiful boy.

Quinton -fall 1998
 

Black and white pictures 1 and 3 above and information are from " The Burmese Cat " edited by Robine M. Pocock and printed by Unwin Brothers Ltd. for the Burmese Cat Club Benevolent Fund 1994 in England.

This text contains the most complete history of the Breed that we are aware of.A revised edition of this book is still available.  It can be obtained from the Burmese Cat Club in the U.K.  Details (says Debbie Howard)are on their website in the Merchandise section: http://www.burmesecatclub.com

All early Burmese were a deep rich brown colour called Sable in North America and brown in England. Breedings of Burmese on both sides of the Atlantic were similar and cats have moved in both directions into the 80's.

Two Events then took place which brought this to an end.

First

"The semi-foreign type of the Burmese of the 1950s remained until the early 1960s when breeders started changing the type to the shorter, cobby (read square ed. note) Burmese seen today." Quoted from Gloria Stephens book the 'Legacy of the Cat' in her discussion of the North American Burmese.

Second

While this was happening genetically recessive Cocolates/Champagne and Blues were beginning to appear on both sides of the Atlantic in the early 70's. This caused some upset which continues to this day in the US based Cat Fanciers Association (CFA) wherin the Chocolate/Champagne is considered a Dilute (having the Malteseing Gene as in Blue and Platinum/Lilac cats) which it is not (see GS book). Recognition, classification, and Standards of the North American and British Burmese started to diverge.

At the same time in England two Breeders had introduced the red gene by two separate Burmese breedings, one with a red pointed Siamese male Southview Havoc, and the other with an unregistered shorthair red tabby male.This sex linked gene changes the way colour for the hair shaft is manufactured. The more normal Eumelanin which appears as a black or dark brown is manufactured as Phaeomelanin giving the redish colour (again see Gloria Stephens book).

The Burmese Cat Club (UK) approached their Governing Council of the Cat Fancy (GCCF) for recognition in 1973 and full recognition was granted in 1977. Burmese colours now allowable under their jurisdicition were the Red, Cream (dilute of red) in both males and females, and the Tortie of the now recognized original four colors, in females. A Burmese could then be Sable (Brown in England), or its dilute Blue; Champagne (Chocolate), recessive to Sable, or its dilute Paltinum (Lilac); the tortie of each ie. BlueCream (Tortie), Sable Tortie, Platinum Tortie, or Champagne Tortie ; Red or its dilute Cream.

Well that was just too much for the CFA. This largest Cat registry in world is extremely conservative in nature and formal structure. They saw red. They were only just recognizing the Champagnes, Platinums and Blues. By the 1990s Burmese from England could not be recognized, though a few trickled in in the late 80s. Additionally, due to the changing shape (see reason #1) of the Burmese in North America, the English Burmese(and by now Australian, South African, New Zealand, and continental European, who follow GCCF rules) were not seen as desirable, at least in the show ring. Thus came the formal block to the westward transatlantic travel of Burmese.

Back to The First

That changing shape in North American Burmese over the 70s and 80s became ever more extreme, most particularly with regard to the head. This look is called Contempory. The cat was chosen for the shorter skull, flatter look, the "good nose break" ( this is the desirable 90 deg angle at the top of the nose), and the larger eyes.

The only text we have that deals with the look technically is Dr. Bruce Fogle's 'The Encyclopedia of the Cat' p 57.

Unfortunately this look, which is highly prized in the show ring, is recessive, requires considerable inbreeding, and is genetically associated with a fatal head defect in Burmese. For the pet owner these cats have "a shortened brachycephalic skull, small rounded sinuses, and crowded teeth.".

As a result a minority of American Burmese breeders and most Canadian breeders abandoned their Burmese of Contempory lines and only breed Burmese unassociated with this head defect. They call themselves Traditional Burmese Breeders. This was done with considerable pain and difficulty for some and is very controversial. There is no formal division of the two lines other than the avoidance care taken by the Traditional breeders in choosing who they breed with. Contempory cats continue to win in CFA show rings. A number of influential CFA judges breed this cat. We are not aware of these cats being shown in Canadian Cat Association (CCA) shows.

The GCCF in England banned the importation of all Burmese from North America in the early 90's for fear of importing this head defect. Various other jurisdictions have followed suit. Thus came the formal block to the eastward transatlantic travel of Burmese.

Definitions
Thus there are 4 types of Burmese in the world today. Contempory, Traditional, Foreign and European.

If you are from other than North America then chances are to you a Burmese is plain and simply "a Burmese".

Horizons and Strathkirk do not deal with Contempory Burmese. Although we do not concentrate on breeding of Traditional Burmese we do select and keep some specific blood lines of particular quality to enhance our gene pool. We are particulary concerned about the problems associated with inbreeding. These lines provide certain characteristics such as intelligence, interactive personality, and overall health within our Burmese and Burmilla Programs.

There are two types of non North American Burmese within our catteries. Those who have exclusively English (now called European by the CFA) pedigrees; and those that are not exclusively European and are of mixed pedigrees. By mixed, we mean having both English/European and Traditional Burmese parents or grandparents. (Please note this discussion is not intended to exclude our friend's Burm's from Europe, South Africa, Australia and NZ etc., who are categorized in North America as European).

The Canadian Cat Association, (CCA), has classified Burmese from England/Europe, and those cats who have the orange gene, (i.e. Red, Cream, and Tortie coloured cats), in their background, as "Foreign Burmese". That is to say that within the Foreign Burmese Breed Standard the section that deals with acceptable out-crosses allows "Breeding with Traditional Burmese".

The Cat Fanciers Association, (CFA), to which we also belong, will now only accept Burmese cats to be "European Burmese" if they are exclusively of European pedigrees for 5 generations. That is to say that no North American Burmese show in their pedigrees for the 5 generations. No acceptable out-crosses are allowed. (This has been now changed to 8 generations. see comments below)

In order to clarify for our American customers we are changing our nomenclature with regards to the Burmese that is used on the attached pages. Those cats that either have a European pedigree or meet the standard of European as defined by CFA (5 generations without a Traditional [North American] cat in the line) will be called such. The Foreign cats on these pages will be classified with an F number ie. an F1 would have a Traditional parent, an F2 a traditional grandparent.
We remind you that all CCA cats of these lines are classified as Foreign., there is no European designation in CCA.

There are a number of good links to the various cat associations that describe the fine points of the differences of Foreign/European and Traditional Burmese.

For the pet owner, the Foreign cat exibits all the advantages of outbreading in a purebred line. It is larger and most often more robust than the pure North American Cat. The face/head is "natural". This longer head and reduced nose break provides a higher ridge to the nose. In our experience in the rough and tumble of a cattery there are far less problems with eye and sinus infections.The body is deeper over the hind quarters, (ie less tube like) and often kittens have more energy reserves. These cats are larger boned, have larger teeth, and their claws are often twice as thick and seldom damaged. The cat comes in all the same colours as the Traditional: Sable/Brown, Blue, Champagne/Chocolate, and Platinum/Lilac with the addition of Red, Cream, and the various Torties. Our above mentioned "mixed" breed cats are Foreign/European in appearance and show considerable hybred vigour, as mentioned, with few birthing and developmental difficulties.They are well balanced and make the best of pets.

Over the last 3 years we have developed a very clear understanding, and an eye for the advantages, of outcrossing through the Burmilla program. It was of some surprise when we saw the magnitude of this "hybred"effect when we began breeding recently imported French/Swiss and South African Burmese with our English and Foreign Burmese. The kittens produced have (and will continue to) confused the local judging process and give a very clear view of the level of inbreeding within much of the existing North American Burmese population.

If the reader should have any questions as to this approach we suggest you read "Feline Husbandry" by Neils C Pedersen DVM PhD. This book is Library of Congress Cat. card # 90-081326. He has a section in Chapter 2 page 122 titled Breeding Programs - Creating a Breed. This is a 6 page chapter has sections titled Breeding Practices, Loss of Vigour, and Genetic Anomalies.  This text defines the standard to which we apply ourselves. We particularly like his concluding paragraph which says;
"Do not breed for extremes in show standards. Fixing of extreme traits requires a great deal of inbreeding. Phenotypic selection of this magnitude can seldom be achieved without inbreeding at other genetic loci."

As of the fall of 2001 two additional Burmese had been imported from England. They are both from the very well known Rumba cattery. There are presently breedings in progress that will give us access to German, and Australian blood lines. We expect another round of English/Irish lines, and an arrival of an exceptional American blood line, in the spring of 2002 if all goes well.  All imports have outstanding pedigrees but HEALTH is our number one criteria. It is the first standard we look to when choosing the future breeding cats in a litter. As health is so clearly related to outcrossing, and a diverse gene pool, we will continue to subordinate show ring ribbons and "type" to strong and vigorous cats. Our cattery remains 'open' not 'closed' and we are happy to work with and assist any like minded cattery.

Update 2008
The reader will note from our index page that since 2001 a number of cats have been imported. We also have found a rather interesting publication that details the efforts of a Mr. E McCabe in 1997 concerning Foreign Burmese and the certification of the European Burmese in CFA. We hold it for historical reasons.  The reader is free to draw any conclusions they wish from it. Our only comment is that we do not agree as is noted, Mr McCabe is somewhat free with his dates as suits his purpose, the reader should bear in mind that at the time there was no CFA on the internet, and we are currently members of the CFA's European Burmese Breed Club , founded by Mr. McCabe at his invitation.




Genetics and the head defect -  5 Generations vs 8 Generations

We will put forward our position based on the facts as we understand them.
 The appendix that follows lists our references and copies them for the reader.The highlighting in those texts is ours. We hold them here without premission  in order to hyperlink the reader to our point reference. We hope the authors will excuse us and understand; they are clearly identified.

The 5 generation issue of the "European Burmese has plagued us for a number of years. It has recently reoccurred within the proposed standards of the Burmilla.. The historical background is detailed on these pages and is discussed again in the documents in the appendix.
Fundamentally there is no "Legal"  way within a Burmese pedigree document of differentiating between a Contempory and Traditional Burmese,that have "two separate Burmese Breed pools."

These concerns with the head defect became widespread and resulted in the establishment of the "European Burmese" classification in CFA.
Burmese were then imported back into the CFA registry from England and countries outside the USA / Canada (from where they originally came) under this new title and using the breed standard applied in England/GCCF that detailed the longer face ( the original standard).
Initially the standard required a 5 generation pedigree with no North American Burmese in the background. That was recently amended to an 8 generation requirement.

The supposition was 1) that the original Burmese cats exported to England (and thence around the world), were free of the head defect, and 2) that 5 come 8 generations separated from "American" Burmese would guarantee defect free pedigrees.

These 2 supposition have no basis in fact, in our opinion.

First of all we need to establish some basic understanding of fact
We refer the reader to  the response to the NABB request for proposal  of Dr. L Lyons request for funding. the first 3 paragraphs.
(For those interested we understand  Good Fortune Fortunatus  as the boy who is the tracable original cat to have delivered this defect.)

1) We shall use the term mc as suggested by Dr. R Robinson to represent the syndrome.

2) There is significant breeding data to indicate the inheritance is autosomal recessive.  It is Dr. Lyons view , is attested to by breeders and is I am told also the outcome of a study by Dr. Susan Little for NABB.    
 
Thus a cat that dies of the condition would have to be mc/mc. The mc gene would have to come from both parents - both parents would have been heterozygous.    (MC/mc)   - -  Poor Fortunatus  - - 'e done got all de blame.
Inheritance of offspring would be 25% MC/MC,  50% MC/mc,  and 25 % mc/mc and die; and is in fact thus.[ See Karen Thomas(03/04/05) and Donna of BrentwoodBurms (03/03/05)].

3) The syndrome is polygenic. Yes Jenelle it can be both. A genetic characteristic can be both polygenetic, and exhibit a simple dominant or recessive mode of inheritance.

First let me demonstrate how this happens.

The MC   gene may be epistatic.  (first question to LLyons it is epistatic)
Epistasis is "an important phenomenon of gene behaviour also known as masking" Robinson's P 40.
An example of this would be the question as to if your Sable Burmese is an Abby tabby or a Mackerel tabby, golden or silver , spotted or not.
All cats are Agouti or not.
Not is called Self (genetics is hard 'cause not everyone uses the same words).
Agouti is dominant self is recessive, so an Agouti cat would be A/- a self cat would be a/a.
An A/a cat would look the same as an A/A cat so an Agouti cat is genetically written as A/-.
All cats are Abby tabby or not. Tb/- or tb/tb
All cats are Mackerel Mc/- or classic mc/mc
All cats are Spotted Sp/- or not  spsp
All cats are silvered I/- or golden i/i
Problem is if a cat is aa you don't know what pattern it is - unless of course you breed red
Then you can see it
If it is Tb/-. You don't know what Mc pattern it has and if it is spotted  or golden based but regardless of what you see those characteristics are there. They exist in all cats and they are not mutations when they occur.

All cats have all genes,    not all have the recessive form. this must be clearly understood

Given this information, if we look at the head defect situation as we would a "combination lock" ---
To arrive at a silver spotted Ocicat cat  --- he must be in sequence  A/-, tb/tb, Mc/-,I/- Sp/-.
That is Agouti, Abby tabby not, Macherel, Silver and Spotted.
If the same cat was changed to golden and classic he would be a Bengal
We thus have a 5 sequence "combination lock" for a Bengal like cat.
Chances for a Bengal (sic) out of a Burmese  2x2x2x2x2 = 32.
Is that combination there in the Burmese? --- Yes it is and we have seen it. ;-)) Surprise!

SO if one was working with a pure bred populaton that had refined all genes "in front of the MC gene pair" then in that population the offspring would exibit the simple dominant or recessive mode of inheritance.  If the sequence to unlock the situation was for example 5 genes then any one gene pair out of sequence would disrupt the occurance. ie If the deadly combination was  a/a, b/b ,c/c,d/d, mc/mc (and I am by no means suggesting that all would be recessive) then an A/a would destroy the sequence, the cat would be A/a, b/b ,c/c,d/d, mc/mc and live and be a "super carrier". So too would a cat who is a/a, B/b ,c/c,d/d, mc/mc. Thus you would have two populations that if mixed would not show a simple dominant or recessive mode of inheritance but would individually.  Thus two completely separate breeders could spend 10 years sorting out their cats to be A/A, b/b ,c/c,d/d, mc/mc, and a/a,B/B ,c/c,d/d, mc/mc respectivly, mix their lines to get A/a, B/b ,c/c,d/d, mc/mc cats , then breed those cats  to their originals or each other  and get a head defect kitten.

They would of course blame each other, never talk to each other again, and would  both be great people. ;-)).

(second question to Dr. Lyons what number of genes is suspected)

Dr Lyons does say not clearly say "the charactistic is polygenetic" (third question for Dr Lyons)I understand the questions are out of sequence.
That is certainly implied within the text. There are some who believe that the MC gene is 'power ball' ie one that triggers the other genes see BrentwoodBurms (03/03/05). - maybe but unlikely (Corollory question to Dr Lyons  - -( do all cats with mc/mc die) and if we are correct so far rhe answer would have to be "no".

re polygenetic

A) It kind of is beyond comprehension that anything so complex as a head is not polgenetic.
B) the study  of the Burmese Co-operative Research Project would have resolved the issue if was, - - it is an easy solution.
C) Burmese history  tells us that the offspring of Wong Mau were inbred to purify the line. If it was simple  simple dominant or recessive mode of inheritance. the head defect would have shown up then.
D) If it was imported into the breed pool and it was simple  simple dominant or recessive mode of inheritance. it had to come with in 1 to 2 generations proir to Good Fortune Fortunatus and any such cat would have left many many very obvious markers both geneotypic and phenotypic. That did not happen.
E) Mathematics should be able to estimate the depth of the gene I.e its polygenicity by looking at the number of generations from the time of institution of "alternate style of Burmese" until  defects started to occur.

Lets step asside here and talk genetics and populations in general

I would like to clarify one comment re "mutation".
The following is from a CFA statement on  their web site  page Rules governing acceptance and advancment of new breeds,  where in they say:

New breeds of cats occur either as spontaneous mutations or result from the hybridization of two previously known breeds. When two cats come together and produce offspring unlike either parent, a mutation is strongly suspected. It does happen that a diff erent offspring may occur as a result of different breeds or colors in the ancestry of the parents. Such a kitten is not a mutation, but rather a reflection of its ancestry.

Mutations take the form of skeletal changes (Manx, Scottish Folds), new coat forms (Cornish Rex, Devon Rex, American Wirehair), and new colors (Red Abyssinian). Examples of hybrid breeds are the Himalayan-Persian, the Exotic and the Oriental.

I believe the above statement to be fundamentally incorrect,  essentially egocentric,  can be misleading with regard to timing,   . . . and would not have the support of the scientific community. (Question to Dr . Lyons what is you view of the above noted statement.)

I do not understand the process of "spontaneous mutation" that CFA has advanced here.   Mutating a gene or developing a new gene within a species  is, I think, still theory but "The Seven Daughters of Eve": The Science That Reveals Our Genetic Ancestry: a Book by Bryan Sykes is a good place to start for the layman and is available from amazon.com. I believe "spontaneous mutation" to be ranked with Imaculate Conception in its reality and it's mathematical possibilities. We are open for any input on this issue.
For more on Mutation go http://www.biology-online.org/2/8_mutations.htm
or
http://anthro.palomar.edu/synthetic/synth_4.htm
but I will give you two quotes.

"Barring all external factors, mutations occur very rarely, and are rarely expressed because many forms of mutation are expressed by a recessive allele."
and another

In order for a mutation to be subject to natural selection, it must be expressed in the phenotype of an individual.  Selection favors mutations that result in adaptive phenotypes and eliminates nonadaptive ones.  Even when mutations produce recessive alleles that are seldom expressed in phenotypes, they become part of a vast reservoir of hidden variability that can show up in future generations.  Such potentially harmful recessive alleles add to the genetic load of a population.


 
I repeat  All cats have all genes,    not all have the recessive form. this must be clearly understood.


The so called "mutation" term as it is being used by many,   must in fact refer to the expression of a gene/gene pair that exists is all cats. In fact, the gene may be very old and exist in many species that predate the evolution of the cat such as the gene for agouti (A/). Many commentators use this mutation term simply because they view it as abnormal i.e. not usual. Such genes are most often certainly recessive, and most often benign, and clearly not unique. Please note we do not call white skinned people "mutants".

I hate to blow anybody's bubble here but headlines re  "New mutation" just doesn't wash., not in our lifetimes. What is more correct is "Recessive Gene Exposed".

Thus  my view is this MC gene exists in all cats. It may well exist in all mammals and in Humans. What is questionable is where it exists in the mc form.
The opposing view based on this "spontaneous mutation" hypothesis suggests that only Fortunatus offspring can have this gene. (Please see Austriana email in apendix3 highlighted section) This can not be the case as the gene is recessive and  only mc/mc cats produce the defect.  Thus Fortunatus must have been paired with a cat that also carried the defect. This being the case then we must understand when and where the defect occured. There is no rational reason to conclude it is unique to the Burmese and to Fortunatus lines BUT that is somerthing Dr. Lyons could readly tell us from her swabs. ( although I doubt the cat fancy would appreciate the truth [as I suspect it] as it is most convenient to believe the problem is confined to the contempory Burmese.  

Given the situation above there is every rational reason to suppose that this gene is  randomly distributed it the general cat population.

Now this statement blows the top of a lot of breeders. Particularly those rambunctious Aussies. Therefore before anyone vents steam you need to think about what I have said  - -find the hole in the argument. It has no validity to say "I have never had a head defect".  for if you do not breed to the extreme  i.e.  you have not refined the head genetics to the flat face, you will never get it, for it appears that flat face requires a number of genes and a lot of refining to get there. see history

There are those who say the head defect is not related to the flat face ..... (Clearly that is not what Dr Lyons is saying). We suggest that depending on what gene in the series that creates the head defect you may be playing with (i.e. some have more effect that others(?)) this may appear to be true.

There are those who say the Persian (with the very flat face ) does not have the head defect. That has been disputed. BUT the existing American Persian breed pool may well have started from an MC/MC cat. Lucky them.
Head defects are occurring in other breeds. Dr Lyons refers to the American shorthair in the letterbelow. (This defect  is called the brachycephalic skull - see Dr Bruce Fogle's book the Encyclopedia of the cat.) If my conjecture is correct this defect  will continue to increase within the breeds that select for this look.

So where does this all go

The head defect (mc) gene exists in most cat gene pools.
You will only see it if you select your cats to the extreme and the population is excessively homozygous recessive  as in  - showing inbreeding depression.
The breeding population of the European Burmese comes from the same place as does Fortunatus and those cats before him who transmitted the head defect. Thus we know for certain it is in some Burmese.
There is no rational reason to believe that E. Burms.  do not have this mc gene. randomly distributed in the population  - - in fact we know it is.
Head defects will unlikely (say not?) occur in a heterozygous population selected for a moderate face.
Gene Pools selected for a short face that do not exhibit the head defect may well be MC/MC, and could clearly be said to have a reduced possibility of the mc gene occurrence in the population over populations that do not select for short face.
The North American Traditional Burmese is probably a " safer cat " than the European Burmese for outcrossing     
    IF    short face is to be a selection criteria in the resulting breed.
    IF NOT then  any concerns are largely frivolous as significant outcrossing will occur.
The move of the E Burm standard from 5 generations to 8 generations has no validity in science and is political.
Dr Lyons research has not found a marker for the mc gene.



Definitions
I did not know what 'autosomal recessive' was  and looked it up. Robinsons refers only once to "autosomes" and is not clear. Stedmans medical dictionary says "any chromosome other than a sex chromosome; a's normally occur in pairs in somatic cells and singly in gametes"

Thus an autosome is the chromosone pair that we refer to when we discuss for example A/a which would be a heterozigous autosome for agouti. An autosomal recessive of that would be (a/a) non agouti as in a Burmese, if I understand correctly.

Appendex a


a1  Proposal is in response to the NABB  by  Leslie A. Lyons, PhD
a2 Progress report by  Leslie A. Lyons, PhD on the above
a3  1997 Email from Erika  Graf-Webster AUSTRIANA Cattery. Erica was the one who iniated the Winn study of Dr Lyons above. She details early breeding issues and the history of the head defect.

a4 Comments from K Rutledge (breed council chair) re issues within the breed council


This document is by
Leslie A. Lyons, PhD
Assistant Professor, VM:PHR
Staff Scientist, CRPRC
and is available on the web site shown at the end


Proposal is in response to the NABB request for proposal: A Study of Craniofacial Malformations Occurring in Burmese Cats.

Introduction

The Burmese became an established breed of pedigreed domestic cat in the late 1930's. The foundation of this breed in the United States originated with an importation of a single female, "Wong Mau", from the capital of Rangoon. Wong Mau was phenotypically distinct from the Siamese cats of her homeland in that she had a distinctively more cobby body frame with a walnut-brown coat color, exhibiting darker brown points. A breeding program was established initially between Wong Mau and Siamese cats, then with successive backcrosses and brother-sister matings (1). Over several generations, it was established that Siamese, intermediate, and Burmese type cats could be produced. The Siamese cats express coloration most markedly at their points; the intermediates, like Wong Mau, (now know as Tonkinese) express coloration throughout their coat with darkening at the points; and the Burmese express a deeper, richer, coat color with less point demarcation. These cats are now known to possess different alleles at the albino locus, C, for coat color (2,3). The Siamese carrying cscs, the Burmese carrying cbcb, and Tonkinese expresses the incomplete dominance of the alleles, carrying cscb. Each genotype expresses less than full production of pigment in the coat color. Along with the cobbier body frame, the cats with the cbcb genotype established the Burmese breed, and were accepted for stud book registration by the Cat Fancy Association (CFA) in 1936. The present CFA standard for the Burmese breed reflects a cat of medium size with substantial bone structure, good muscular development and a surprising weight for its size. The head should be pleasingly rounded without flat planes. The face is full with considerable breadth between the eyes and blends gently onto a broad, well developed short muzzle. A visible nose break is present, the eyes are large, set far apart, with rounded aperture (4).

During the 1970's, a alternative style Burmese cat was established. Phenotypically still within the CFA standard, this strain of Burmese expresses a more rounded head with a higher frontal prominence, a shorter, broader muzzle, seeming larger and more prominent eyes, and generally a more demarcated nose break. This shorter, broader muzzle form has been referred to as the "Eastern", "new look", "Contemporary", or "more extreme". The longer, narrower muzzle form is referred to as "Traditional" or "less extreme". The "more extreme" strain of the Burmese quickly became popular in the show ring and intensive breeding programs ensued. Shortly after the widespread establishment of the "more extreme" strain, an increasing proportion of litters involving the "more extreme" cats were producing kittens with a severe congenital craniofacial deformity. An investigation of the defect by Zook et. al (5), provided a detailed clinical description of the defect as well as a suggestion that the deformity may elicit an autosomal recessive mode of inheritance. By 1983, over 90 purebred Burmese from a disperse group of catteries had been afflicted with the deformity. No obvious infections, toxic agents or environmental conditions could be correlated with the deformity. The common genealogy of the cats producing the deformity in their litters revealed cats of common ancestry that had been extremely proliferative, including a line of show-winning cats that had been extensively bred. This suggests that the Burmese have experienced inbreeding depression within a sub-population of the breed and the "more extreme" cats were producing deleterious homozygous recessive offspring as a consequence of inbreeding.

A research cooperative was established to investigate causation and the mode of inheritance of the craniofacial deformity (6). The cooperative was known as The Burmese Cooperative Research Project, and a cattery, Searchcore, was established to oversee the test breedings for the project. Under the assumption of a recessive mode of inheritance, Searchcore established matings between known carriers (all "more extreme") and non-carriers and/or cats of unknown status (both of the "less extreme" phenotype). The kittens of the resulting litters were then bred to known carrier cats, which all were of the "more extreme" phenotype. The 33 second generation matings produced 151 kittens of which 20 expressed the craniofacial deformity. The interpretation of the test matings and data collected from 46 questionnaires to breeders is convoluted and unclear. Frances O. Smith, D.V.M., of the University of Minnesota, was enlisted by the Searchcore to interpret the pedigree analysis. Dr. Smith suggested an incomplete dominant mode of inheritance and that the deformity was a result of the "more extreme" phenotype (6). Deformed kittens being homozygous and the heterozygous form to be expressed as the "more extreme" phenotypic cats. Searchcore also established a collaboration with Cornell University to investigate the developmental mechanism of the deformity (7). Over 40 of the deformed kittens were examined. The defect was originally described as either maxillonasal hypoplasia (5) or incomplete diprosopus (8). The Cornell study initially suggested a mechanism of transformation of the medial nasal part of the frontonasal process, naming the defect: telencephalic meningohydroencephalocele. This defect was also referred to as: Incomplete conjoined twinning, by the Cornell group. This group restated Dr. Smith's interpretation that the "more extreme" phenotype is a less severe expression of the deformity, and some homozygotes cross a threshold which results in the lethal malformation. This may be tested by examining facial and cranial measurements in an attempt to qualitate the structure variations. The inheritance pattern was informally addressed by Sponenberg and Graf-Webster in 1986 (9). Of 22 litters born to matings between Burmese parents which previously had produced the craniofacial defect, 19 of 88 kittens expressed the deformity. The 69:19 ratio did not deviate significantly from an autosomal recessive mode of inheritance (X2 = 0.545) at the 95% confidence interval. The gene symbol, mc, was suggested by Dr. Roy Robinson to represent the meningoencephalocele syndrome (9). The association of the craniofacial deformity with the "more extreme" phenotype of the Burmese has raised a severe dichotomy amongst the Burmese breeders and a rift within fancy cat breeding societies. Conflicting results of the initial investigations, concerns of accuracy, confidentiality, and inaccurate interpretations has posed the question as to whether the "more extreme" phenotype should be propagated, and to whether "more extreme" phenotypes can be maintained without the deformity. As a result, the National Alliance of Burmese Breeders (NABB), a solely "more extreme" Burmese breeding group, has initiated a request for proposals for the Study of Craniofacial Malformations Occurring in Burmese Cats.

This proposal is in response to the request of the NABB. We propose a combination of a prospective and retrospective study to investigate the genetics of the craniofacial deformity expressed in a portion of Burmese cats. We have reviewed the previous studies and the limited available data, and have determined that a single gene is highly likely to be responsible for the defect, thus a beneficial study can be initiated. The project has four goals: 1) formally verify the mode of inheritance of the craniofacial defect and formally address the mode of inheritance of the Burmese facial morphology, 2) establish genetic linkage or non-linkage between the craniofacial defect and facial morphology in formal pedigree analysis of existing and proposed pedigrees, 3) test a panel of high resolution polymorphic genomic markers, feline microsatellite loci, for linkage to the craniofacial deformity and Burmese facial morphology, 4) provide suggestions for the eradication of the deformity from the Burmese breed.

Identification of Genetic Markers for an Inherited Craniofacial Deformity Syndrome in Burmese Cats.

L.A. Lyons, M. Menotti-Raymond, S.J. O'Brien.

Inbreeding depression, as a result of population bottlenecks and founder effects, has been shown to cause severe health and reproduction problems in cats (10,11). Bottlenecks can be a result of natural phenomenon or man-made crisises. A portion of the Burmese cats has apparently experienced a man-made bottleneck and founder effect situation. This is inherent in most all domesticated breeding programs, due to the artificial selection of particular desired phenotypes and the culling of undesired phenotypes. Unfortunately, an unforeseeable, undesirable trait has reached a critical level in portions of the Burmese breed, threatening this sub-population with extinction.

Study Design

This study will be divided into three parts in order to address: 1) the Burmese associated craniofacial deformity mode of inheritance, 2) the mode of inheritance of the dichotomized facial structure of the Burmese, 3) determine if the deformity can be separated from the "more extreme" Burmese phenotype, 4) develop genetic markers for the possible identification of deformity carriers and, 5) provide suggestions for the eradication of the deformity. The collection of the data and the analyses of the modes of inheritance, and baseline breed data should be obtainable within 12-18 months. Identification of a marker associated with the deformity/head structure can proceed once a database is established, but is not predictable. We are currently proceeding with a 5-10 year plan for a marker saturation of the feline genome.

Part 1: Pedigree Ascertainment

With the cooperation of NABB and other Burmese breeders, Burmese pedigrees will be collected to further investigate the modes of inheritance of both the craniofacial deformity and the "more extreme"/"less extreme" phenotypes. These same pedigrees will be used for the marker identification. Pedigree collection will include: blood samples (20ml or appropriate to cats weight), a tissue biopsy, phenotypic data, and breeding records. Ascertainment will be through the identification of a single deformed kitten. Retrospectively, if all parental and grandparental cats of a litter, which has previously included at least one deformed kitten, are available, then these pedigrees will be selected for the study. Kittens from litters of the exact parentage, even though a deformity may or may not have occurred in that particular litter, will be of interest. Prospectively, once a current or future breeding produces a deformity, we will collect that pedigree and any previous or future exact parentage litters, regardless of deformity presence or absence. We will request that immediately post-mortem, deformed kittens be kept frozen until shipment to our research facility. If known outcrossed breedings, implying either "less extreme" to "more extreme" or "more extreme" to a different fancy cat breed can be identified, these pedigrees would also be collected. Pedigrees of lines never associated with the deformity but exhibit a range of phenotypic expression will also be collected. Deformed kittens will be grossly examined for conformation to the defect and karyotypes will be performed on a two male and two female kittens. A formal segregation analysis using the pedigree analysis program, Pointer, will be used to evaluate the data (12) to determine modes of inheritance.

Part 2: Breed Sample Collection

In order to establish a baseline of the gene pool and to determine the inbreeding depression for the Burmese cats, we will require the collection of 10-20 blood samples (20ml each) of various fancy cat breeds. This will include non-pedigreed domestic shorthairs; and breeds associated with the Burmese, including; Siamese, Tonkinese, Dilute Burmese (Malayans), Persians, Tiffanys, Bombays, and Foreign Burmese. The genetic background of these cats will be important for future breeding recommendations, should the deformity not be separable from the "more extreme" phenotype, and to determine the "genetic" health, or inbreeding depression, of the breed. Until the genetic background of the breeds can be established with the genetic markers, test crosses will not be suggested for the study. Outbred cats should show a higher level of heterozygosity than line bred cats. The reduced heterozygosity is a measure of inbreeding depression.

Part 3: Genetic Marker Isolation and Characterization

Initially, deformed kittens will be examined for correlations with similar syndromes in humans (13). Should strong similarities be identified, then candidate genes for the defect may be suggested. If a candidate gene is suggested, this gene would be then mapped in the cat using feline interspecific backcrosses (14), thus potentially narrowing the area of the genome to scan for associated genetic markers. Micro-satellite genetic markers will be isolated and examined for polymorphism in the Burmese pedigree parents (15,16). Polymorphic markers will be typed in the pedigrees to establish the linkage of a marker with the deformity and/or head structure phenotype. Several linkage analysis programs are available, including LIPED, LINKAGE, MAPMAKER, and CRI-MAP(17-20). These programs will determine marker association with the deformity and/or head structure phenotypes and provide an estimate of distance which would be used for the accuracy of carrier detection and future breeding recommendations. Marker typing will proceed immediately in the parents, grandparents, and the associated breeds. Pedigree typing will proceed once the database is significant.

Logistics

Prior to sample collection, all Burmese breeders and breeders of the associated breeds (as listed above) will need to be informed of the study and of the required pedigree ascertainment. This will be initiated in appropriate newsletters and coordinated with the assistance of concerned volunteers. Once appropriate pedigrees and breeders are confirmed, sample collection coordination will begin. Sample collection may be most efficient and accurate at various CFA cat shows. Veterinarians will be required to assist in the sample collection, which will require anesthesia administration, blood sample collection and tissue biopsies. CFA judges will be required for phenotypic evaluation of the parental, grandparental cats, and mature offspring. Photographs, frontal and profile, will be taken of the cats for permanent record. To maintain consistency, we will minimize the number of CFA judges. CFA judges which breed Burmese cats will not be employed to avoid any possible phenotypic biasing. The phenotypic data may be quantatized be making various head measurements during the phenotypic evaluations. The measurements would at least include: muzzle breadth, distance between ears, distance between eyes, head size, as well as others. A significant database must be established prior to pedigree analyses. If pedigrees were known to be matings of two parents heterozygous for the defect (both carriers) and the genetic markers are also heterozygous, then approximately 60 offspring could detect markers of a minimum of 5cM, implying a test approximately 90% accurate for the determination of carrier status. More accuracy requires an exponential increase in offspring of the compound heterozygous matings and in marker typing. Cats which "breed true" implies homozygosity of the genes causing the selected phenotype. Markers close to the selected genes will also be homozygous and make mapping difficult at closer distances. Less informative matings, marker homozygosity, will increase the required offspring. Over 300 markers, spaced at 10cM intervals, will be required to saturate the genome, which will be selected from over 1,000 random markers.

References

1. Thompson J et al: Genetics of the Burmese cat. Heredity 34, 1943

2. Robinson R: Genetics for Cat Breeders. 3rd Ed. Pergamon Press, Oxford, 1991.

3. O'Brien SJ et al: Chromosome mapping of beta-globin and albino loci in the domestic cat reveals mammalian chromosome group. J Hered 77:374-378,1986.

4. Show Standards: The Cat Fanciers' Association, Inc. May 1,1993-April 30, 1994.

5. Zook BC et al:Encephalocele and other congenital craniofacial anomalies in Burmese cats. Vet Med/Small Anim Clin 78:695-701, 1983.

6. Searchcore: Report of the Burmese Research Group. June 14, 1984.

7. Noden DM and Evans HE: Inherited homeotic midfacial malformations in Burmese cats. J Craniofacial Genet Devel Bio (Suppl) 2:249-266, 1986.

8. Sekeles, E: Craniofacial and skeletal malformaitons in a cat. Feline Prac 11:28-31, 1981.

9. Sponenberg DP and Graf-Webster E: Heredity meningoencephalocele in Burmese cats. J Hered 77:60, 1986.

10. O'Brien SJ et al: East African cheetahs: Evidence for two population bottlenecks? Proc Natl Acad Sci USA 84:508-511, 1987.

11. Roelke ME et al: The consequences of demographic reduction and genetic depletion in the endangered Florida panther. Curr Biol 3:340-350, 1993.

12. Lalouel J-M and Morton NE: Complex segragation analysis with pointers. Hum Hered 31:312-321,1981.

13. McKusick VA: Mendelian Inheritance in Man. Johns Hopkins University Press, Baltimore, 1991.

14. Copeland NG and Jenkins NA: Developoment and apllications of a molecular genetic linkage map of the mouse genome. Trends Genet 7:113, 1991.

15. Weber JL and May PE: Abundant class of human DNA polymorphisms which can be typed using the polymerase chain reaction. Am J Hum Genet 44:388-396, 1989.

16. Stallings RL et al: Evolution and distribution of (GT)n repetitive sequences in mammalian genomes. Genomics 10:807-815, 1991.

17. Ott J: A computer program for linkage analysis of general human pedigrees. Am J Hum Genet 28:528-529, 1983.

18. Linkage Analysis Package: Linkage Version 4.8, January 1989.

19. Lincoln S and Lander ES: Constructing Genetic Linkage Maps with MAPMAKER. 1987.

20. Lander E and Green P: Construction of multilocus genetic linkage maps in humans. Proc Natl Acad Sci 84:2363-2367, 1987.

Budget

Principle Investigator support: 3,000.00 (Travel to CFA shows, catteries, coordination efforts)

Transport of samples: 1,000.00

Veterinary Fees: 1,000.00

Technical Support: (Salary for 20 hrs/wk) 10,000.00

Total: 15,000.00

This genetic marker identification is a direct function of man-power and will be facilitated by this project and other projects contributing to the feline genome project. The technical support will cover sample processing and support, DNA isolation, and marker typing of the collected samples, specific to this study. Currently, nearly 100 micro-satellite markers are available for testing. An estimate of at least 12 samples will be collected for each ascertained deformity, including 4 grandparents, 2 parents, and 6 offspring of the same or other exact parentage matings. Heterozygous mating types would require at least 10 such pedigrees, minimum 120 samples, implying over 12,000 typings. Materials for processing and marker isolation and typing will be covered by the NCI. Below are estimates of actual costs: 1) Materials for collecting and processing 120 samples: 6,000.00 (vacutainers, needles, saline, lysing solutions, tissue culture media, DNA isolation buffers...) 2) Isotopes for DNA test 6,000.00 3) Equipment for microsatellite assay 15,000.00 4) Storage of sample at -70 C. 2,000.00 5) Computer software 2,000.00

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10 April 2002
Winn Feline Health Foundation
1805 Atlantic Avenue
PO Box 1005
Manasquan, NJ 08736-0805

Dear Hilary and Tom,

This is a progress report on the project entitled "Identification of Genetic Markers for an Inherited Craniofacial Deformity Syndrome in Burmese Cats". No previous report has been made on this project as funding for the project was not received until February, 2002, at UCDavis. The Center for Companion Animal Health, CCAH, has provided matching funds of $10,000.00 per year for this two-year project. In general, funding for this project supports 50% of the salary for Dr. Heather Roberts, a post-doctoral fellow in the laboratory who also works on PKD. Recently, the Burmese head defect has been appearing in American Shorthair breedings, thus a new enthusiasm has been gained by the breeders. We have received several stillborn kittens with the defect from both Burmese and ASH breedings this past week. We plan to provide a detailed report to the breeders at the CFA annual this June. ASH breeders are experiencing several of the other anomalies that are seen in Burmese, such as "Cherry eye", which may be a result of the gene or that the shortened facial structure is becoming too extreme. My interpretation is that the facial structure is becoming too extreme. These issues will be clarified and discussed in June. The recently obtained defects are consistent with what has been observed with our previous collections. With over 30 deformed kittens, we find the condition to be a very consistent presentation, thus we need to be careful with the new observations by the ASH breeders. We also have now identified a strong candidate gene for the condition. Many genes are known to control facial and body patterning, these are termed HOX genes. HOX genes come in clusters of 13 genes and are located in at least four groups in the genome of the cat, hence a potential 52 genes are strong candidates. But, one gene that is not part of the HOX cluster family, is called Sonic Hedgehog (yes, like the Nintendo game). This gene is expressed specifically in the region of the upper jaw (the maxillary region), hence is currently our focus for the head defect in the Burmese. HOX genes are still strong candidates, but Sonic Hedgehog will be analyzed first. We are now designing genetic assays to isolate this gene in the cat. To compliment this approach, we will also continue to collect the kittens and the close relatives to perform an association study. This association study should suggest whether the candidate gene is correct and hence that we should continue to analyze and sequence that particular gene for a causative mutation. This preliminary data has been used for a grant submission to the NIH, National Institute for Dental and Craniofacial Research (NIDCR), April, 2002. The attached NIH proposal is confidential. This proposal is for two years and requests funding for $50,000.00 per year as a model for mammalian facial development.

Best regards,

Leslie A. Lyons, PhD
Assistant Professor, VM:PHR
Staff Scientist, CRPRC

Proposal to: Winn Feline Foundation
Attention: Mr. Thomas H. Dent
P.O. Box 1005 Manasquan, NJ 08736-0805

Submitting Organization: The Regents of the University California
1 Shields Avenue
Davis, CA 95616

Title of Proposed Research: Identification of genetic markers for an inherited craniofacial deformity syndrome in Burmese cats

Total Amount Requested: $30,000
Proposed Duration: 2 years
Desired Starting Date: 03/01/01 - 02/28/03
Principal Investigator: Leslie A. Lyons
Department: VM: Population Health & Reproduction
Phone Number: 530-754-5546

Matching Funds/Operating costs: UCDavis - Center for Companion Animal Health: $10,000.00 per year
UCDavis laboratory of Dr. Leslie A. Lyons: ~$10,000.00 per year

Scientific Abstract

The Burmese cat is a moderate size short-hair domesticated breed that is common to the world-wide cat fancy. The breed is distinguished by body conformation and are homozygote for the "Burmese" allele, cb, at the tyrosine locus. The contemporary line of Burmese cats carries an autosomal recessive cranial-facial defect. This defect produces a duplication of the upper maxillary region and is non-compatible with life. The presentation is congenital, non-pleiotrophic, fully penetrant and has clear and distinct features. The most extreme facial conformationsof the contemporary lines of Burmese cats have the highest likelihood of carrying the defect, but the exact demarcation as to facial conformation and carrier status is difficult to determine. Outcrossing of the contemporary lines of the Burmese cats to other breeds and Burmese populations naive to the defect have proven the mode of inheritance. Thirty deformed kittens, their first-degree relatives and controls from various lines of Burmese, other breeds, and random bred cats have been ascertained for the study. Feline-derived microsatellite are polymorphic in the Burmese breed, but do not have sufficient density for a genome-wide linkage analysis for the defect. We will attempted a focused approach to develop genetic markers near candidate genes using the feline BAC library. Known developmental genes, such as HOX 1-4@, will be isolated from the BAC library and positive clones will be screened with oligo probes of common dinucleotide repeats for the development of markers. Linkage between the markers and the defect will be determined by standard linkage analyses and homozygosity mapping.

Layman Abstract

The new feline genetics laboratory of Dr. Leslie Lyons at the UCDavis School of Veterinary Medicine is continuing the investigation of the Burmese head defect. The initial goals of the project when it was initiated in the summer of 1995 were: 1) determine the mode of inheritance of the Burmese craniofacial deformity, 2) determine the mode of inheritance of the dichotomized facial structure for the Burmese, 3) determine if the deformity can be separated from the "more extreme" Burmese phenotype, 4) develop genetic markers for the possible identification of deformity carriers, and 5) provide suggestions for the eradication of the deformity. The craniofacial defect that presents is very unique and distinct, no easily mistaken. The defect has an autosomal recessive inheritance pattern, implying two copies of the defect are required. The "more extreme" type is controlled by many genes that affect facial development, as for any cat. The defect does travel with the "more extreme" type from contemporary lines, but since the face type is a complex interaction with genes, determining the exact cut-off for extreme face type that may carry the defect is difficult. Hence, some moderate to slightly extreme cats, from contemporary lines, may not carry the defect, the correlation is difficult. Breeders should also realize that non-contemporary lines have also been selected for a "more extreme" type, but these lines are not at risk for carrying the defect. Genetic markers should help demarcate which cats carry the genetic defect. The genetic markers had never been tested in a domestic cat breed, only random bred cats, and we found that they will be affective for analysis. But, the present markers are not sufficient. Effectiveness of a marker search is determined by the amount of variation of the markers, how close the marker is to the defect and the sample size. A marker can be more distant with a larger sample size and if it has high variation. The smaller the sample size, the closer the marker needs to be. Breeders have been supportive of the project but hundreds of samples are not feasible. Over 250 samples from Burmese, Foreign Burmese, Egyptian Mau, American Shorthairs, Scottish Folds, and random bred cats have been collected for the study. But only thirty deformed kittens have been acquired, including deformed kittens from Belgium. Thus, with this sample size, markers had to be developed near candidates for continuation of the study. With the development of a large DNA (BAC) library in the fall of 1999, a focused approach to develop more effective markers for this study could now be accomplished. Many genes are strong candidates for facial development, including the HOX genes. But these genes are abundant and come in several large clusters. With the library, we can isolate specific genes of interest and develop markers near these genes. These markers can then be tested in our Burmese sample set. Thus, we have initiated a focused attempt to develop markers around candidate genes in order to include or exclude them as the gene causing the defect. Detection of a marker for the deformity will be performed by standard linkage analyses and homozygosity mapping. Until a marker is developed, breeders are cautioned as to using "extreme" cats from contemporary lines, either within their program or as outcrosses. The defect does manifest in Bombays and breeds that have used contemporary Burmese. Since this defect is autosomal recessive, it will be difficult to eradicate without a genetic test.

Progress Report

The Burmese head deformity project was initiated by Dr. Leslie Lyons, while at the Laboratory of Genomic Diversity (LGD) of the National Cancer Institute during the summer of 1995. This project was in response to a request by the National Alliance of Burmese Breeders (NABB) to the Winn Foundation. The Winn Foundation responded with a request for proposals specific to this project. Two years of breed-specific funding, totaling $30,000.00 was awarded for this research, summer 1995, 1997. The project was initially divided into three parts that would address five questions; 1) determine the mode of inheritance of the Burmese cranial-facial deformity, 2) determine the mode of inheritance of the dichotomized facial structure for the Burmese, 3) determine if the deformity can be separated from the "more extreme" Burmese phenotype, 4) develop genetic markers for the possible identification of deformity carriers, and 5) provide suggestions for the eradication of the deformity. It was anticipated that the collection of the data and the analyses of the modes of inheritance, and baseline breed should be completed in 12-18 months, but identification of markers for the deformity or head structure would be unpredictable and would become a long-term project for the laboratory. The three parts to the project included, 1) pedigree ascertainment, 2) breed sample collection, and, 3) genetic marker characterization and isolation. The mode of inheritance for the Burmese head deformity has been confirmed to be autosomal recessive. The previous studies and literature had suggested this mode of inheritance, but confusions in nomenclature had occurred, giving the impression that different patterns had been suggested. The deformed kittens only occur when two copies of the defective gene have been inherited, one from each parent. Several catteries provided their breeding records that confirmed the autosomal recessive inheritance pattern. The most compelling data was obtained from France and Belgium. With the importation of one "more extreme" Burmese, deformed kittens were produced when the imported cat was found in both the maternal and paternal lineage. Data from outcrosses to American Shorthairs, Scottish Folds, and Bombays have supported this evidence. A detailed formal analysis using segregation analysis programs was not necessary for this aspect of the project due to this straight-forward and compelling data. The mode of inheritance of the head structure, "more extreme" or "less extreme", has been evaluated but not formally addressed. The development of measurements of the skull and facial structure were determined to be beyond the scope of project funding and would be difficult to obtain. Developmental experts at Johns Hopkins in Baltimore, MD were consulted for this aspect of the project. The coordination of specific individuals to evaluate head types and to get all the cats available at specific ages would be necessary and logistically difficult. Regardless of a formal evaluation, the correlation with the "more extreme" head type and cats that have kittens with the deformity is extremely strong. We have obtained no evidence that a "more extreme" cat has proven to be clear of producing the deformity. At this time, no conclusions can be made as to whether the gene(s) involved with the head structure is/are the exact same gene(s) producing the deformity. Normally, many genes are involved with determining the structure of the head. The deformity is caused by a single gene, acting autosomal recessively. We suggest that the gene for the deformity is physically near the genes involved with the "more extreme" head type, if not one of the genes involved with the structure of the head. If so, the use of genetic markers could identify cats that have most of the genes causing the "more extreme" head type, but have lost the gene causing the deformity. This can occur by the natural process of recombination. The frequency of the occurrence is determined by the distance between the genes involved. Since many cats have not been found to be clear of the defect but of the "more extreme" head type, the physical location of the genes involved must be extremely close. Thus, we can not determine if the deformity can be separated from the "more extreme" Burmese head type until a cat is test mated to be proven clear of carrying the deformity, or until genetic markers are found for the deformity. Over 250 samples have been collected for the study and are detailed in Table 1. Thirty deformed kittens have been collected from ten different litters, including deformities collected in Belgium. Bombays samples were received this fall at UCDavis for the study. The preliminary baseline data required 25-30 samples from cats that represent the gene pool of each breed involved in the study. The collection of samples from breeds other than Burmese and Foreign Burmese was hampered by the impression of finding Burmese genes in cats that are not Burmese. The investigators have worked hard to dismiss this misconception and have emphasized that the data is confidential. Breeders who have participated from the other breeds have had a general interest in genetics and the health of cats in the cat fancy. Many of the samples from the other breeds are from only a few catteries, thus we must be sure to not use closely related cats in the analysis, and attempt to obtain cats that represent the gene pools of each breed. A general request for samples has been published and we intend to focus heavily on Tonkinese and Bombay breeders. Buccal swabs can now be used to obtain these comparison samples, but blood samples are still required for relatives of the defective kittens. Sample collection for a related breed project has improved the sample collection and adequate samples are now available at UCDavis for the related breeds. Preliminary data has shown that the microsatellites will be powerful markers for the study and are capable of identifying a marker for the deformity. Most of the microsatellites tested in the Burmese have been heterozygous and should be informative for the study. No candidates genes for the deformity have been identified in the literature or from discussions with cranial-facial specialists at Johns Hopkins University, thus a genome wide search with all the available 300 microsatellites was considered. The samples acquired from the outcrosses to other breeds and samples collected from Europe will be particularly valuable in the search for a marker. But a small sample size and inadequate marker coverage did not suggest a high probability of detecting linkage, thus work on the project has not progressed due to the focus in the development of more sophisticated feline resources. The Burmese deformity has spread to other fancy cat breeds and to the Burmese in Europe. Personal communications with researchers at the veterinary college in Bristol have indicated that the defect has been seen in the UK but is not a present concern. We recommend that "more extreme" cats are not used in other breeding programs nor used as exports. The use of "more extreme" Burmese should be confined to "more extreme" Burmese breeding programs only.

UCDavis Burmese Project

As a new faculty member at the UCDavis School of Veterinary Medicine, Dr. Lyons' new lab will focus on feline genetics and inherited diseases, thus will reinstate the research on the Burmese. This reinstatement is possible due to the recent development of a large and robust DNA library of the cat. This library, the Feline BAC library, was coordinated by Dr. Lyons and was a collaborative effort between Dr. Lyons and Dr. Pieter DeJong at the Roswell Park Cancer Research Center in Buffalo, New York. This library became commercially available in fall, 1999, and is available at UCDavis. Burmese breeders have expressed an interest in the continuation of the project and Dr. Lyons' has a focused commitment to the project. Matching funds from the UCDavis Center for Companion Animal Health and Dr. Lyons' lab can guarantee focused attention to the research. Approximately 50% of the Burmese samples collected while at the NCI are currently at UCDavis and requests have been made for the remaining samples. Once funding has been obtained, formal requests by the Winn Foundation to the NCI will formalize the transfer of the remaining samples to UCDavis. Work can progress on the research prior to the acquisition of the outstanding samples but will be eventually required. A new call for samples will be initiated. Deformed kittens should continually be collected. Adult siblings and outstanding parental samples must be acquired. Specific breeders will be contacted for these samples. Genotyping of the cats involved with litters that have produced a deformity will recommence. We will attempt a focused approach to develop genetic markers near candidate genes using the feline BAC library. Known developmental genes, such as HOX 1-4@, will be isolated from the BAC library. The candidate genes selected will have sequence available from the mouse and humans. This sequence will allow the development of short sigments of DNA, termed primers, which can be used to amplify the feline counterpart of the gene from cat DNA. This feline specific amplified fragment of the gene will then be used to probe the cat BAC library. The library holds very large inserts and hence, a full copy of the gene can be held in one clone. These clones can then be cultured to produce many copies of the gene of interest. We will not initially analyze the gene, but the BAC library inserts are so large, DNA surrounding the genes is generally also present. This surrounding DNA will likely hold a very polymorphic marker, a microsatellite. To isolate a microsatellite from the gene of interest, short DNA segments that are composed of the microsatellite repeat sequences are used to probe the gene clones. Positive clones will be sub-cloned and sequenced to get the complete DNA sequence of the microsatellite. From this DNA sequence, short segments of DNA can be synthetically produced, termed primers. These primers are then used to amplify the microsatellite marker in the Burmese samples. Linkage between the markers and the defect will be determined by standard linkage analyses and homozygosity mapping.

Background (Original 1994 - 1995 Proposal)

UCDavis Project Budget:

Dr. Roberts will be hired as a post-graduate researcher V, which is appropriate for her degree and experience. All post-doctoral fellows have a three-year commitment upon entering the lab. This commitment includes the time to learn new laboratory techniques, collect data, analyze data, and formulation of data for publication.

Personnel PGRV - NS, Heather Roberts, PhD, 50% effort $ 18,504.00 Benefits, 18.5% of salary 3,423.00 -------------- Total salary: $ 21,927.00

Supplies Reagents: $1,000/month x 12 months $ 12,000.00
Travel Presentation of work at one scientific meeting and one breed associated meeting $ 1,500.00 ---------------
Total yearly budget: $ 35,427.00 CCAH matching funds (see attached letter): -$ 10,000.00
UCD Lyons' laboratory operating expense: -$ 10,427.00 -------------- Requested funding: $ 15,000.00

Back to Head Defect Page

Identification of Genetic Markers for an Inherited Craniofacial Deformity Syndrome in Burmese Cats.

Leslie A. Lyons, Ph.D., Marilyn Menotti-Raymond, Ph.D., and Stephen J. O'Brien, Ph.D.

Laboratory of Viral Carcinogenesis, Frederick Cancer Research and Development Center, National Cancer Institute, Building 560, Room 21-105, Frederick, MD 21702-1201

Requested Funding: $15,000.00

Ed note:  For those interested the pedigrees discussed below can be followed and reviewed at on line at the Burmese Prdigree data base

Austriana@aol.com, 8/3/97, Burmese Head Deformity



Hi List!

Sorry it took me longer than promised to get back to you on this. Here it goes:

Since the beginning of the Breeders and the Burmese lists, numerous postings have discussed the head deformity. There has been the usual acrimony about it, and ethical issues have been raised, sometimes with religious fervor. Those of us who have dealt with the deformity for many years do indeed get tired of responding to, what often seems to us, very uninformed and sometimes vicious comments. A few days ago, l promised to post what I knew about the deformity, so here it is. I ask that you read what I say with an open mind. I will discuss what I KNOW from personal experience, as well some things that I suspect, and some things that truly puzzle me about the deformity.

Just to give you a feel for the level of experience that I bring to this I purchased my first Burmese in 1972, and it turned out that she produced the head deformity!  So my history with this defect goes back well over 20 years. When it became clear to me in the late '70s that this was indeed a genetic factor that was popping up repeatedly in my line, l tried to obtain professional help. I was put in touch with Dr. Bernard  Zook, who, at the time, was doing research at George Washington University  on genetically inherited heart disease in Burmese. Dr. Zook studied the physiologic and pathologic nature of the deformity, and published the results in an article "Encephalocele and Other Congenital Craniofacial  Anomalies in Burmese Cats" in the Journal of Veterinary Medicine/Small Animal Clinician, in May 1983 (to which I contributed as a co-author). Interestingly, Dr. Zook hypothesized (this is not in the article) that the source of the defect was probably a mutation due to exposure to a toxic chemical by some cat in the ancestry of the current breeding stock. He said that he had seen similarly  dramatic defects, though in other parts of the body, due to toxic chemical exposure.

I also contacted a geneticist, Dr. Philip  Sponenberg, at the Veterinary School at Virginia Tech University. I had kept very careful records of the incidence of the defect in my litters. Dr. Sponenberg analyzed these data as well as data from other breeders, and arrived  at the conclusion that the defect was due to an autosomal recessive gene (the same conclusion reached by Dr. Leslie Lyons in her recent studies). Dr. Sponenberg published his findings in an article in the Journal of Heredity, in 1986 (I think). I was not entirely convinced by Dr. Sponenberg's conclusion, because the defect did not seem to me to always behave as a single gene would (more about this below). I also had contact with Cornell during the Searchcore Study, and contributed a sample deformed fetus. I thoroughly disagreed with the findings of the Searchcore Study in two areas: (1) that the defect was due to a dominant gene with variable penetrance (this is  diametrically  opposite to the findings of Dr. Sponenberg and Dr. Lyons), and (2) that the defect was intrinsically tied to the more rounded head conformation, commonly known as the "contemporary" style cat I had personal experience that this was simply not true as a categorical statement.

There was continued dissatisfaction on the state of our knowledge about the deformity, and in 1994 the National Alliance of Burmese Breeders (NABB) decided to try to get some kind of a gene study to be initiated to address the many unknowns. The club had built up a considerable treasury, and felt that the time had come to spend the money needed to get some definitive answers. We contacted the Winn Foundation for help in addressing the request to the research community. The Winn Foundation recommended that we develop a formal "Request for Proposal", outlining  exactly what it was that we were after. I developed this Request for Proposal, which identified two major objectives of the study: (1) To develop a technique for identifying carriers of the defect, and (2) to determine the mode of inheritance of the defect. The Request for Proposal was sent to Universities and other research facilities that seemed to have the appropriate technology to tackle the problem. While a number of institutions expressed some interest, three formal responses were received (one of which was from my old friend, Dr. Sponenberg). Of these, Dr. Lyons' proposal from the National Cancer Institute was judged to have the best chance of success, since she had already started the Feline Genome project. Dr. Lyons was awarded the grant, and has been busily at work on the study for about a year and a half. (Part 2 follows)

So, I've had a long association with the defect and with attempts to try to resolve it. Here is a summary of some of the things I've learned:
It is amazing how many misconceptions exist about this deformity, and how many things we still don't know about it, even though we've had to deal with it for a number of years.

Let's first address some of the common misconceptions:

Misconception (a)The head deformity started with the contemporary head-type cats of the mid70s. GrCh Day Ho Hobo of Sangazure, DM, and his     son, GrCh Good Fortune Fortunatas, DM, are commonly cited as the source.   

NOT TRUE. From personal experience, I know that the deformity predates both those cats. My first Burmese, GrCh Karrob's Mystique of Austriana, who is a couple of years older than Hobo, turned out to be a carrier. Certainly there had been rumors in various parts of the country about cats who produced kittens with deformed heads prior to this time. The one cat to which all     known carriers can be traced back is Chirn  Sa-Hai Soo Watt, born sometime     before 1958. Her son, Chirn  Sa-Hai Kil-O-Watt (born in October 1958), was apparently  a frequently used stud. We don't know how many generations before Soo Watt might include carrier cats, nor do we know whether other cats unrelated to Soo Watt might also have been carriers. One good breeder friend of mine was warned in the late '50s, when she was first starting out, to    "stay away from Casa Gatos lines, because they carry  a head deformity".    . Soo-Watt's pedigree does go back to some Casa Gatos stock, as do just about     all our cats, whether traditional or contemporary, since Casa Gatos was one of the first  and very successful Burmese catteries. However, many pedigrees that go back to Casa Gatos do not carry the deformity, and only those that contain the cited Chirn  Sa-Hai  cats can be shown for sure to produce carriers.

Another conclusive case for Hobo/Fortunatas not being the source of the     deformity is that the Chinquapin line generally does not contain Hobo (with the exception of Baubles, Bangles and Beads), but did produce the deformity, in some cases in cats years older than Hobo. The Chinquapin line does, however, go back to those same Chirn  Sa-Hai  cats.

If the head deformity was in the gene pool of the breed going back over many     years, why was it not recognized as a severe problem early on? I claim that     this was because the cats who were the carriers at that time were not the big show winners. Therefore, they were not used extensively in breeding programs, especially not for line breedings. This kept the deformity from spreading noticeably. The occasional incidence of a kitten with a deformed head may have been put down to a developmental problem during gestation, instead of a genetic problem. It wasn't until the deformity associated     itself with the winning  cats of the mid '70s, who were used so extensively for breeding, that the deformity became common and noticed.

Misconception (b)  Traditional lines do not carry the deformity.

NOT TRUE. Though they are rare, a few carriers have been identified from  lines which we typically call "traditional". Again, my own cat Mystique is     an example -- her sire is a Glen Crest male, while her dam is from Havasu Cattery. Both Glen Crest and Havasu are thought of as typical lines; however, Chim Sa-Hai Soo Watt is in the Glen Crest line. There are a few other examples of traditionals producing the deformity that people have mentioned to me over the years. This is why I have chosen not to define "traditional" as based on specific lines or on not being carriers of the deformity. I urge you all to use the term "non-carrier" if that is what you mean, rather than "traditional". The two are simply not synonymous.

Misconception (c) - All offspring of contemporary cats are carriers.

NOT TRUE. Again, though they are rare, a few cats have been identified as being non-carriers  even though one of their parents was a known carrier. An example again from personal experience is GrCh  Austriana Kirah of WindflowerKirah is the daughter of GrCh Austriana Carina, a Fortunatas daughter and known carrier. However, Kirah produced well over 30 kittens out of known carrier males and never produced a head deformity. She was bred a few times to traditional males, whom we presume to have been non-carriers. All of her offspring  out of those breedings were also shown to be non-carriers,  down through what is now the fourth generation. Other breeders have cited additional examples. So it is possible to produce non-carrier cats out of the contemporary lines, but they do seem to be quite rare. There was a flurry of postings a few months ago that Alapose cattery in Alaska had used contemporary cats, but was able to breed out the carrier state after some generations. I have also been told that a Cattery in New Hampshire, using primarily  contemporary stock, has not had a deformity in 3 years. In addition, the incidence of the deformity has dropped off dramatically in  several catteries, mine included.

Misconception (d)  -  All cats with extreme head type produce the deformity. Cats with a moderate or elongated head do not produce the deformity.
NOT TRUE. If the defect were tied intrinsically to the extreme round head-type, why don't Persians carry it? From personal experience, some of my most extreme cats produce the defect very rarely. One of my extreme cats produced one defective kitten out of 28, while another (my most extreme cat at this time), has yet to produce any  - - she has had 17 kittens to-date.
Furthermore, I have test-mated cats whose head-type can be termed moderate, and one whose head-type actually looked like a long modified wedge, and they DID produce the defect. REGARDLESS OF ITS HEAD-TYPE, IF THE CAT IS FROM A LINE THAT CARRIES THE DEFECT, IT CAN PRODUCE A DEFORMED KITTEN!

OTHER OBSERVATIONS OF INTEREST
The inheritance of the defect sometimes behaves very strangely (which is whyI had some difficulty for a while in accepting that it was a single gene factor or that it was a recessive). The normal incidence of the defect, based on it being a single recessive gene, is 1 deformed kinen out of 4 born. Over all my litters, up to about 5 years ago, this was probably true. However, I have had two cats who consistently produced it approximately 50% of the time. One of these was a female who produced ten small litters of 21 total kittens, of whom 10 were deformed. This was very disheartening, but the quality of her kittens was so exceptional, that I did continue to breed her. One of her offspring, however, was the cat who only produced one deformed kitten out of 28 and whose succeeding generations produced the defect very rarely. The remainder of the original female's offspring produced the deformity with the normal 1 in 4 frequency, or somewhat less than that. So,just because a cat seems to produce the defect prolifically, it doesn't mean that its descendants will do the same.
Another cat of mine, a grand-daughter of the one mentioned above, has been a prolific breeder, producing numerous large litters. She has been bred to four different males,, but most of her litters were out of one male (GrCh  Austriana  Atlantis). This particular breeding has produced about 24 kittens    I (including 5  Grands), but has never produced a deformity. However, bred to other males, she produced two deformed kittens out of 15.
Finally, for unknown reasons or sheer good luck, the incidence of the    I deformity in my cattery has been dropping to such an extent in recent years that I see maybe one a year now. Clearly, there are no guarantees that this will continue, ;but I  seem to be doing something right. And, yes, I am using    .ONLY contemporary style cats. This reduced incidence rate of the deformity is a very hopeful sign, and seems to jibe with Dr. Lyons'proposition that the defect is Not the e same gene that produces the contemporary head-type, though it may be carried  at or near the area of the chromosome that also carries  the genes that define the more rounded head. This means that it should be possible to have contemporary style cats who do not carry the defect. I have a suspicion that some of us may already have such cats, but without a definitive test for the carrier state, we don't know who they are.

To sum up my stand on the defect: Noneof us, certainly not 1, wish to breed Burmese with this defect just to get winning cats. We ail made our decisions to continue with these lines because they offer so many good qualities  - -great temperament, robust health and consistent type that fits the standard - - so that we deemed it worth propagating these cats, and fighting the     deformity without loosing these lines wholesale. We are funding the research that may offer us.the success we looked for in maintaining these lines while eventually eradicating the defect. We are not villains; we just love our cats and are doing our best to save them.
Best regards,

Erika  Graf-Webster
AUSTRIANA Cattery.






ed note:  
the highlighting is mine - one personal comment was removed, the document was reformated to fit this screen,  otherwise all is the same

Date: Fri, 4 Mar 2005 08:03:37 -0500


Kathy,
You are a wonder.  I hope everyone on the list and all those breeding Burmese in CFA can recognize the hard work you have put into your position.
Thanks to you, Pam, Erika and Ivan for putting this discussion on a more objective plane.  
'Unless someone sees a reason NOT to look for the gene I suggest that all of us do what we can to help the research along.  Today I sent samples and pedigrees from the cats of mine I had not already submitted.  Dr. Lyons group will send buccal swabs (a small sterile brush to swab the inside of the mouth for DNA) to anyone interested in submitting samples.  It's fast, easy (but not necessarily fun. I urge everyone on this list to send samples.

Karen Thomas

-----Original Message-----
From: Kathy Rutledge
Sent: Monday, February 28, 2005 8:37 PM
To: burmese_breeders@yahoogroups.com
Subject: [burmese_breeders] Recent discussions about Burmese cats


Hi, everyone....---
---
I'd like to weigh in again as the CFA Burmese Breed Council Secretary and make some observations.

I thought long and hard about whether I wanted to run for a second term as Burmese Breed Council Secretary, and central to my concerns was the difficulty of trying to represent a breed which is so divided and whose members do not seem to be able to rise above the issues that divide us.  While I was elected to a second term, I still have real concerns about whether I (or anyone) can help to lead the Burmese community in a positive direction.  

Thanks to Pam Morrison for establishing the list we are working on and for reminding us of the basic rules of civility.  We tried to have a CFA Burmese Breed Council list, but it died from lack of interest, so this list and the NABB list are our only established forums for online
discussions about the Burmese breed.  While some may think we are leaning to CFA, we have been talking about outcrossing, and we must focus on CFA if we are to talk about the CFA registry and its rules for outcrossing.  It is important to remember to focus on the requirements of this particular registry if we are trying to make changes in the registry. My postings as CFA Breed Council Secretary can
only speak to CFA issues.

I appreciate the factual information Jennifer has brought to the discussion, and the reinforcement of that information by Erika, based on her years of experience in working with both gene pools.  The terms "traditional" and "contemporary" are simply labels that we have invented to describe the two gene pools we are working with.  Traditional cats by definition come from the gene pool where the cranio-facial defect associated with the Burmese cat has not been expressed, and Contemporary cats come from the gene pool where the head defect exists.  These are just labels.  They don't exist within the CFA Burmese standard, which describes a cat whose essential feature is ROUNDness.  And regardless of what you might want to think, the standard has not been rewritten to favor the cats from the contemporary gene pool.  It's the same standard we've had for many years.  The labels have usefulness if we want to describe the two gene pools.  We should not be ascribing a moral or ethical value to the labels.

There is far too much misinformation being spread between the Traditional and Contemporary breeders, and this misinformation only hurts the breed.  Leslie Lyons has told us several times that while our genetic diversity is not yet endangered, we can ill afford to consider eliminating either gene pool.  She has also cautioned us against identifying the breed solely by the genetic defect part of the gene pool carries.  I am appalled to see the things being said about cats from the gene pool I work with that I know are not true, and I'm sure that breeders from the other gene pool feel the same way when they hear inaccuracies being spread about their cats.  We must avoid speaking with authority about things of which we have no personal knowledge.  If you don't know what the cranio-facial defect looks like, don't try to describe it.  If you haven't experienced breeding cats in the gene pool that carries that defect, don't spread misinformation about those cats.  And if you have only bred cats from the contemporary gene pool, don't talk about the problems you have heard of from cats in the other gene pool.

I discussed the Burmese cranio-facial defect at the meeting with the Breed Council Secretaries and the CFA Board of Directors at the June 2004 Annual meeting, and I was amazed at how little accurate information the other breeds have about the defect.  There are so many tales and rumors and horror stories, and so little factual information.  I referred people to Dr. Lyons' website.  I am highly suspect of any occurrence of the Burmese cranio-facial defect in breeds other than those where it is known to occur:  the Burmese, the Bombay and the American Shorthair (where it was introduced through the improper use of a Burmese cat in a breeding program). Because the American Shorthair is still accepted as an outcross for the Devon Rex breed, I did caution the Devon Rex Breed Council to be aware of the possible introduction of the Burmese defect into Devon Rex lines. And I encouraged the Breed Council Secretaries to be open about defects they experience in their breeds.  While Persians and other cats with similar head structures may have genetic problems relating to their cats' skulls, these are not the defect experience by the Burmese, and we must avoid the temptation to speculate on the genetic problems of other breeds if we have not worked with them.  I would be very skeptical of any report from a veterinarian about the cranio-facial defect seen in the Burmese unless that veterinarian had actually seen a cat known to carry that specific defect.

All pedigreed cats have genetic problems, and unless we work with a particular breed, we do not have knowledge of the choices breeders make when they choose to work with a breed.  We must not condemn other breeders and we must not condemn each other for those choices.  Some years ago, I tried to have a frank discussion with Lynette about the reasons I have for working with the cats I breed, and I
thought that while we agreed to disagree, she at least had a sense of my thinking.  I'm not so sure that is true now.

For those of you who are not up to date on Leslie Lyons' research, she has not found a marker for the gene which carries the head defect, and we are thus not able to identify the cats who carry or produce the defect, nor are we able to develop a plan for reducing or eliminating the defect.  If we are lucky enough to have such a marker identified, we can look to our own breed for a big boost of genetic diversity.  Even if we do find a means of identifying carriers, we are not going to be able to find a quick fix.  Ultimately, we might find a way for breeders in both gene pools to work together, and the location of a marker would be a major boost to both camps if we could come up with an action plan.  

We may be a few years from finding a marker, or we may never find one.  The discussions on outcrossing that have taken place among Breed Council members really should be seen as very long term thoughts about actions which might be necessary if we don't find a way to eliminate the cranio-facial defect.  

Meanwhile, there are other issues facing the breed, if we could only look past the great breach which divides us.  --(comment removed ed)---  I am trying to get people to focus on positive things that we can do for the breed.  When I made the Burmese breed presentation at the 2003 CFA judges workshop, I told the judges and the Breed Council members present that I was not going to use the "T" and "C" words.  I wanted to focus on the standard and on ways that we can celebrate the Burmese cat.  Unfortunately, I have not been able to bring people over the divide.

We do need to be concerned about the reduced number of breeders and the lack of Burmese being exhibited at many shows, but these are issues facing all breeders of pedigreed cats.  We are certainly not going to attract new breeders or to keep the newer generation of breeders committed to the breed with the kinds of exchanges that have been occurring.  I'd like to see CFA Burmese Breed Council members come up with some ideas to advance the breed in the circumstances in which we find ourselves today, as well as to introduce ideas for long-term solutions to keep the breed alive and healthy. We should not define our breed by its genetic defects. We should demystify the defect by keeping our discussions factual, based on actual knowledge, and then we should move on.  We should accept that we have two gene pools and resist all temptation to damn the gene pool in which we do not work.  These are the facts of the situation we are in today, and we just need to move ahead without continuing to get stuck in the Great Divide.

Kathy Rutledge, CFA Breed Council Secretary





 



 

 


 


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