This collaborative meeting between breeders, researchers in feline genetics, and students at UC Davis has entered its second year as an annual event. With generous sponsorship from the Winn Feline Foundation and Royal Canin. There were 165 attendees this year, almost double that of last year’s conference. The human and dog genomes have recently been sequenced. The cat is next in line. All mammals have the same 25,000 genes, just shuffled around. Cats are much closer to humans than dogs or mice.
Dr. Niels Pedersen started out with a summary of cellular biology and described what genes are and how they function. He also gave us insight into how the animal genetics lab gets funded: no donations go for Dr. Lyon's salary. Cats in their research colony get $20K from UC Davis for their care. To get a Ph.D. assigned to a project requires $34K a year for four years. Post-grads are $40-65K. Donations are essential for funding. Initial donations for a project provides the basis for NIH funding (the BIG bucks) to apply the research to humans. Without a link to a human disease, sufficient private funding is not sufficient to find a gene and develop a test for a feline disease.
Sphynx "Spasticity": The first student presentation was on inherited myopathy of the Sphynx cat. Breeders were observing cats at 10-16 weeks of age with an abnormal gait and sometimes tremors. Parents weren’t affected. The muscles are flaccid, so the term “spasticity” is inappropriate. Often these kittens die of aspiration, rather than the disease itself. The first step was to characterize this disease clinically. The symptoms could indicate an abnormality of the neuromuscular junction, diabetes, an infection, etc. They used electrophysiology and muscle nerve biopsy to determine the nature of the abnormality. Electromyography results were abnormal in these cats. Nerve conduction was examined and was normal. So this ruled out a neuropathy. The enervation of the muscles was normal and the nerves look normal on biopsy. The junction between the muscles and the nerves was also normal. These steps narrowed the problem down to a muscle disease. Abnormalities and cell death are seen in muscle fibers that is non-inflammatory in nature. Right now they are looking for a candidate disease in humans and other animals.
Dr. Diane Shelton continued with the subject of muscular dystrophies (MD). Most inherited diseases of this nature are not treatable, so a preceise diagnosis is needed to separate these diseases from treatable conditions. MDs can be recessive, dominant, or x-linked. Over 30 are identified in humans, but only a few in dogs and cats have been identified so far. There are a large number of proteins associated with muscles. Any one of them could "go wrong", so they first need to hone in on a candidate gene, then Dr. Lyon's lab takes it from there and tries to find the gene itself.
Dystrophin deficiency is a common form of human MD (Duschenne's). Calcium deposits build up in cells and cells degenerate. Immunofluorescence is used to probe the tissue to see which protein is missing. Ten different proteins can be probed.
There is an x linked MD in cats that has been already identified: feline hypertrophic muscular dystrophy. Calcium deposits can be seen on the tongue of affected cats. Also, a congenital MD with laminin alpha-2 deficiency has been seen in DSH, "Siamese" and Maine Coons. Symptoms include whole body rigidity and "lock-jaw".
Affected Sphynx have an alpha dystroglycan deficiency (60-70% of normal). But one Devon sample did not, so they are not yet convinced whether the Sphynx and Devon diseases are the same. Sequencing of this gene is in progress. No molecular weight change is seen, so it may not be a sequencing change. The FKRP gene is being sequenced as well.
The next presentation was on the examination of dystroglycan as a candidate gene for Sphynx MD. Disruption of the DAG1 gene causes muscle degeneration and weakness called Fukuyama MD in humans. This protein is essential in creating dystrophin-glycan complex in muscles. No mutation was found in the translated region of the DAG1 gene in affected cats. The mutation may, however, be in the untranslated region that determines how much of the protein is expressed. The protein is normal, just produced in lower amounts in these cats.
Next, they will be sequencing the untranslated regions with newly developed primers. If that work doesn't reveal a mutation, they will look at other genes.
Hypertrophic cardiomyopathy (HCM) was the topic of the next presentation. This is the most common heart disease in cats. The left ventrical has increased muscle thickness. Often there is also left atrial enlargement. Thromboembolism or congestive heart failure may occur. Treatment focuses on preventing progression to severe symptoms.
The mode of inheritance was established in a colony of affected Maine Coons. It is a dominant gene with 100% penetrance. Affected to affected breedings lead to more severe disease.
Sarcometric mutations in human HCM occur 1 in every 500 people. Mutations can occur in any of ten proteins. Most of these dominant mutations have incomplete penetrance in humans. Severity depends on both the mutation and what modifiers are present.
They are still working on identifying the mutation in Maine Coons. A few of the ten proteins have been ruled out so far. Maybe next year!
Echocardiology is traditionally used to determine LV thickness. Variability and asymmetry makes this challenging. This is a two dimensional assessment. LV mass, however, is a three dimensional assessment based on geometric assumptions for quantification. Cardiac MRI is used for a more accurate and reproduceable determination of LV mass. MRI can also detect differences in tissue characteristics, unlike echo. This technique is better at determining severity and serial assessment of treatment.
The researcher set out to determine if cardiac MRI was more accurate than 3D echo for determining LV mass in cats. They induced apnea for 15-22 seconds to get each 3mm image "slice". They then traced out the heart at various phases of the cardiac cycle to develop a measurement protocol.
They found that MRI at systole was more accurate than 3D echo. Echo consistently underestimated the LV mass. The difference between normal and affected hearts was more distinct with cardiac MRI, especially when controlled for the size of the cat.
This technique will never replace echo for screening in the near future, as it costs $1K and requires anesthesia, but it will be used in the research environment and possibly for clinical evaluation in the future.
Feral cats: The next presentation discussed the prevalence of FeLV/FIV in a cat colony in Maui, HI and how removal of positive individuals affects the incidence of the disease. None of the cats were vaccinated. They looked at population dynamics and geographic vs. genetic separation.
It is estimated that there are 500K feral cats on Maui. 300 cats per year are handled in a TTVAR program. Greater than 100 feral colonies managed, starting in 2000. There is only one low cost spay/neuter program. These cats have no natural predators. The tropical photoperiod allows for 3-4 litters a year. Poisoning has been considered as well as other trap and kill approaches.
They sampled 26 colonies of managed feral cats on Maui in different areas quite geographically separate. Cats are tattooed, ears notched following testing, altering, and tissues collected for future DNA analysis. Of 32 males and 32 females from 26 colonies. 97% were FeLV/FIV negative, with 3% FIV positive, mainly males. Removal of positive animals was followed by a spike of double the incidence of FIV the following year, possibly due to increased fighting amongst the males to re-establish dominance. DNA data on this population will be presented next year.
The Veterinary Genetics Laboratory: After DNA tests get developed in Dr. Lyons lab, they get turned over to the VGL for commercial availability. This is a non-profit lab, where the income goes directly to support more research.
VGL processed 200K samples last year. Parentage testing and DNA identification is a main focus. Integrity of pedigrees is maintained through cooperative work with breed registries. There are four equine coat color tests and tests for horse and canine genetic diseases.
The flow of samples and results was reviewed. Bar coding is used for the identification of samples. Automatic PCR processing and probing results in a fast sample turn-around time.
Parentage testing and DNA fingerprinting services are available now. In 2005 testing will be available for PKD, agouti, the albinism series (Siamese, Burmese, Tonkinese), and chocolate/cinnamon.
The next presentation was by a high school student. These exceptional students are part of the Young Scholars Program to encourage young folks to consider a career in research.
Sex-Linked Red:The MC1R gene controls the red/orange phenotype in all other mammalian species. But in cats this coat color phenotype is sex linked and is subject to x-inactivation during embryogenesis. This is a random phenomenon and is responsible for why the cloned patched tabby and white cat, CC, doesn't look exactly like her source "twin".
They went in search of a microsatellite near the orange gene to use to find the gene in cats. They used three primers on the x-chromosome to amplify different areas. Linkage analysis was used to determine if the microsatellites were close to the gene. The didn't find the gene, but they excluded certain portions of the x-chromosome. More primers will need to be developed for the x-chromosome in order to find this gene.
Tyrosinase related protein 1 (TRP-1): its effect on feline coat color. The biochemical pathway for eumelanin (black pigment) was presented. If you take away the trp1 protein, you end up with a reduction of eumelanin and a build up of the precursor protein.
TRP1 has 8 exons that are well conserved between species. They designed primers in areas of high homology with other species' TRP1 and sequenced these regions in black cats. They sequenced same regions in “brown” cats and found two mutations, but these didn't correlate with the chocolate phenotype in Persian cats. So they went back and worked using intron specific primers to get ENTIRE sequence of TRP1. This gene now has been sequenced in black cats (controls). This took two years. As a result, they found the cinnamon (bl) mutation. They are still working on a test for chocolate.
White spotting: KIT was examined as a candidate gene for white spotting. KIT mutations cause dominant white in mice and the piebald phenotype in humans, cattle, horses, and pigs, but not in dogs. Ednrb and Edn3 are other genes causing white spotting, but these also cause health problems.
KIT codes for a transmembrane transport protein expressed in melanocytes, blood cells, and germ cells. This gene is comprised of 21 exons. The microsatellites available were not very helpful. Five and a half exons were examined and no difference was found between normals and white spotted cats. Analysis was difficult because of the different grades of white seen in cats.
Are different types of white spotting the same gene or not? This isn’t known yet. It could be a multigene additive trait. Research will continue on this gene and other candidate genes.
Albinism Unmasked: Albinism mutations are found in mice, rabbits, and humans. The responsible gene, tyrosinase, is found on feline chromosome D1. There are five published alleles (C, c, cs, ca, and c), although the existence of c (pink-eyed white) is debatable.
The Burmese mutation was found on exon 1and the Siamese on exon 2. Both were found in the mink Tonkinese. These mutations were confirmed in a variety of cat breeds. They can now test for Siamese allele carriers and Burmese allele carriers.
Albino cats have blue eyes with "red flash". They first developed a pedigree for cats segregating for albino. A nonsense mutation was found in exon 2, causing the protein to be truncated. This mutation probably came from a non-pointed cat sometime in history, because it is found on the wild type strand, not the Siamese associated strand. The albino strand of DNA digests like a non-pointed cat. So the test cannot distinguish between a solid and an albino cat, but can identify the difference between a pointed or Burmese and an albino cat and can identify if a Siamese or a Burmese is carrying albino.
The Pointed gene in Korats: breeders sent in samples to confirm the presence of the Siamese mutation in their breed. There was a lot of cooperation with European Korat breeders.
The Siamese mutation was identified in ten breeds, some of them fixed for points, like the Himalayan, Ragdoll, Birman, and Siamese and other breeds segregating for points. Some breeds want to eliminate Siamese allele carriers. 85 Korat samples (1/4 from US, 3/4 from Europe) were received. 18% of tested cats were pointed carriers and 2% were pointed Korats. 15% of the Russian Blues tested were pointed carriers. However, this is biased data based on self-sampling by breeders… the samples were NOT randomly obtained.
Failures in testing were primarily due to insufficient sample collection. Sampling from young kittens can be difficult. Cat cooperation is needed for buccal (“cheek”) swab collection.
Feline Parentage Testing: This technique was developed as part of the feline diversity project started by looking at the genetic diversity of the Havana Brown, where inbreeding depression was suspected. The breeders were seeing reduced fecundity and high coeffcients of inbreeding. Diversity is necessary for the function of the immune system, fecundity, and minimization of recessive mutation based diseases.
Parentage testing (and DNA fingerprinting) is done using microsatellites. But the technique is not standardized between labs, so information can not be compared between labs. They wish to standardize the markers used internationally. The markers are chosen on the basis of comprehensive chromosomal coverage, high PIC values, and high level of heterozygosity. There must be no linkage between markers.
Different markers work better for different breeds, so they chose a wide variety of markers. They use 19 markers for their parentage testing panel. Samples are needed from all potential parents involved to determine parentage. The test works through exclusion, rather than strict identification. You can only say a cat can NOT be a parent, not definitively that a certain cat IS. Testing was evaluated independently by 20 labs in 16 countries worldwide. The test cats were related Persians. 10 labs have responded. 9 got the parentage questions correct. One lab had two females bred together (and this couldn't occur in real testing). That is because x linked markers had low heterozygosity. A few microsatellites didn't work as well as they needed to. To solve these problems, they will be looking at using mitrochondrial DNA to determine maternal vs. paternal lineage and will develop more microsatellites to refine the panel.
Cloning was the next topic, and this was presented by ACRES (an endangered species research group). Many species of cat are becoming more endangered every year from killing for food or goods, disease from introduced species and inbreeding, loss of habitat and weather catastrophes. Habitat must be preserved and maximum reproduction obtained. Artificial insemination (AI) is being used in cranes followed by reintroduction.
There are two techniques being used to reproduce cats artificially. In the first technique, hormone stimulation is followed by oocyte aspiration, embryo production by in vitro fertilization (IVF), with intra-cytoplasmic sperm injection (ICSI ) used if the sperm has low motility or a high rate of abnormalities. The other technique is nucleus transfer (cloning)
With hormone induced ovulation and oocyte recovery by laparoscopy about 20 eggs per procedure can be obtained, twice a year. They can get up to 50 eggs on young cats up to 1 year old.
Semen collection can be done with the use of an artificial vagina. The cats are trained, no electro-ejaculation is used for domestic cats. However, you get four times as much with electro-ejaculation.
Fertilized embryos are implanted at 12-14 days. About 50% result in pregnancy, with only one live birth following 7 procedures implanting fishing cats in domestics. Both fresh and frozen embryos have been tried. With caracals in DSH, 2 live births from one female out of six procedures in three different females. There are big differences between species in the success rate. They haven't been successful in lions or fishing cats yet with ICSI.
Nuclear transfer (cloning) is the method of last resort when an animal is too old for IVF or dead. This technique allows "clean-up" of disease infected animals by using clean tissue. They can use any nucleated cell, but skin cells are ideal. Refrigerated tissue is good for a week. They create a fibroblast monolayer in culture and freeze the cells. The nucleus is injected into a DSH oocyte, electrical stimulation given, followed by embryo transfer. This is easier said than done, however! Only 2% of male and 4% of female embryos successfully implant. 50% of implanted embryos result in kittens to term and half of those survive (twice as many females survive than males). They currently have 11 live cloned DSH kittens and half a dozen cloned african wildcats.
The ultimate goal is to create embryos and implant them in wild cats in wildlife reserves to be raised naturally. Then they need to make sure the clones can breed naturally. More research still needs to be done on premature aging and increased telomere length in clones.
Dr. Susan Little gave a presentation on breed specific reproduction and kitten health projects. Little breed specific data is available in the literature. Most information is from research colonies. Most data on pedigreed cats is for Persian and Siamese only and is dated. There is a need for up-to-date surveys for a wide variety of breeds.
Litter size, stillbirths, birth weights, congenital defects, causes of kitten illness/death, survivability, length of gestation, age of queen and tom are some of the parameters examined. Historical values for litter size are 3.3 to 4.6, with stillbirths reported as 3 to 22% in various reports.
Breeds with broad heads or long thin heads have a higher risk of c-sections. Birth weights average 100g. The average mortality rate, including stillbirths, with the breeds Dr. Susan examined is around 10-14% at 4 weeks. Mortality rates more than 20% in the first 4 weeks of age should be investigated. Congenital defects seen in many breeds have been umbilical hernias, cleft palates, tail kinks, syndactyly, and flat chests. Dr. Susan sees an overall incidence widely varying between breeds for the presence of these defects.
Corneal dermoids and tremors in Birmans; flat chests in Bengals and Burmese; pectus excavatum in Ocicats; and skin tags, split eyelids, and cleft palates in Ragdolls are standouts in breed specific incidence. Data analysis is underway. Interim reports can be found on her website at http://catvet.homestead.com.
Wobby kittens have been seen since the 1990's in Birmans. Found in several countries and with many breeders. There is a mild to severe presentation of tremors. Signs are absent when kittens are resting or sleeping. In severe cases kittens stumble and fall. Onset is at 2-3 weeks of age. Symptoms last a few days to several weeks and resolve by 10-12 weeks. These cats are normal as adults, so they are used in breeding, knowingly or unknowingly. The hind end ("bounce") is affected, with the front end much less affected.
Males and females are equally affected. This appears to be an autosomal recessive inherited trait. Birman cat distal polyneuro-pathy (axonopathy) has been reported in the literature as a slowly progressive hind end ataxia. Clinical signs are not well described in the literature and no age of onset is stated. The pathology is axon degeneration of the peripheral and central nervous system. NCV studies are normal and the EMG abnormal. Myelin abnormalities and exon death is seen.
Other potential causes that must be considered when first studying a disease of this nature are inflammatory disease, infectious disease, toxins, cerebellar diseases, neuroaxonal dystrophy, lysosomal storal diseases and hypo/dysmyelinating diseases.
In order to properly identify and evaluate these cases, characterize the clinical and pathological changes, avoid euthanizing affected kittens (they get better) but don't use affected kittens in a breeding program, collect pedigrees and confirm the mode of inheritance, and eventually work to develop a test from research.
For breed studies, Dr. Little is getting 50-70% compliance with the program. She needs 20-30 breeders for a breed study to really work. For each project, there is a usually a key breeder or two that motivates other breeders and keeps the project on-line. She won't start a project unless a perception of motivated compliance is established.
Dr. Leslie Lyons lead a discussion about future projects. NIH will sequence the feline genome. This will be an excellent tool for exploring genetic diseases. The limiting factor is getting enough samples and detailed information linked to them. Parentage testing to validate pedigrees is being used by other species. Their lab is getting better and better at using smaller amounts of DNA. Sending in samples for parentage testing, PKD or color testing supports other studies and provides banking of data for future investigations.
If you can set up a breed club or registry with a contract for testing, the price comes down considerably. From an anonymous voice in the crowd the comment was made: "We need to get Colonel Delabar inspired and Tom Dent liquored up to think about going the direction of VERIFIED pedigrees in CFA." Lorraine Shelton volunteered to author an amendment to the CFA by-laws to require buccal swab submission prior to the recognition of all DMs in order to put the spotlight on this and to get the delegates thinking in this direction.
Keep in mind that this material is available to researchers worldwide. One submission can go a long way.
Certification of PKD status, for example, or other genotypes by a registry, if linked to parentage testing, means that genetic data can become part of a pedigree. This may ultimately need to be linked to microchipping or eye scanning.
It is recommended to keep in your possession buccal swabs from every cat in your cattery. We can decide later what to do with them. Buccal swabs can be stored indefinitely for when they are needed for a study.
Manx, Fold, Dwarfism, and the Rexes are other genes planned for study. Dominant traits like these that are not fixed in a breed are easier to map than when a breed is homozygous for a particular trait. Samples from folded ear cats and their straight coated littermates are needed, for example.
Feline Infectious Peritonitis: Dr. Niels Pedersen gave a presentation on the genetic aspects of feline infectious peritonitis (FIP). FIP is a complicated disease that he started studying in 1964. The causative agent of SARS is a coronavirus, renewing interest in feline enteric coronavirus (FECV).
FIP is caused by a mutation of a benign enteric coronavirus. A 5-10% likelihood of this mutation occurs, mainly during primary FECV infection (when kittens not fully immunocompetent). Only half or less of kittens with the FECV mutation get FIP. Mutation occurs as a simple deletion or insertion in the 3c gene. It allows the virus to infect macrophages, spreading the virus everywhere in the body. The disease symptoms of FIP are caused by the cat's immune attack on these macrophages.
Cats with FIP do not spread the mutated virus to other cats, but rather secrete the parent coronavirus. Coronavirus strains from each cattery are identical, but distinguishable from strains in other catteries. FIPV strains are always identical to the FECV strains in the same environment.
Are some strains more apt to mutate and cause FIP than others? We don't know yet. All catteries with more than six or so cats have FECV infected cats. The number of cats kept over 8 does not affect the incidence of FIP.
FECV has strict tropism, it only grows in the tips of the epithelium of intestinal villi. FIPV has strict tropism to macrophages and is highly pathogenic. Antibody mediated immunity helps to clear FECV from intestines.
Ten days to two weeks after FECV infection, the cat’s titer raises. There is no fever associated with this. Dr. Pedersen wants us to stop using the phrase "feline coronavirus" and instead say "feline enteric coronavirus". The virus is shed at extremely high levels in feces and spread through fecal to oral transmission. Litterpans contaminate the environment efficiently. Shedding varies, some cats are non-shedders (they shed for a little bit, then are immune), some are chronic shedders ( they never clear the virus), but most cats cycle through shedding, clearing and then reinfection.
It used to be thought that breeders could prevent infection with early weaning. This isn’t true. Kittens can start shedding before three weeks of age; they just don't have a titer until their maternally derived immunity wanes. It is not practical for catteries to keep FECV out.
They looked at shelter situations by studying cats at the Sacramento county animal shelter. No cats less than eight weeks of age were infected with FECV. All cats from 8-56 weeks old were. Only half of cats over 56 weeks of age were infected. The virus is everywhere.
To get an idea of how easy this virus is spread, a grain-of-wheat sized particle of feces can have up to 100 MILLION virus particles! One week after primary exposure in kittens the heaviest level of shedding occurs. Shedding in adult cats increased after their entry into the shelter. Stress increases infectivity. More virus in the environment may mean more mutation episodes. In nature, where litters are more isolated than in catteries, kittens are infected later. Kittens shed 100-fold more virus than adults.
Experimental FIP is 70-100% fatal. Disease signs appear when antibodies develop. Antibodies are not protective, but cause worse disease. FIPV is not found outside of the body, and therefore is not spread from cat to cat. 10-12 days after FIPV infection, fever and antibodies develop.
Weight loss, spiking fevers, and peritoneal effusion are the symptoms of "wet FIP". Dry FIP shows as uveitis or other isolated, localized disease. This is a sign that the cat’s immune response almost worked. Lately it seems that vets are seeing more dry FIP than wet FIP. FIP was not reported before about 1955, corresponding with when people started to keep litterboxes and cats inside. Cats may be evolutionarily developing more resistance, resulting in more dry FIP than wet.
Risk factors for FIP include age (6-18 months is the period of highest risk); catteries, shelters, or other high density environments; and genetic predisposition. Don't use males that have “thrown FIP”. This doesn’t mean that FIP is sex-linked to males, but if the males are controlled, the females don't have to be as much. Female cats are not as influential genetically.
The incidence of FIP in catteries comes and goes. An epidemic one year may suddenly go away the next year. Depopulation is useless, just stay the course. Do different breedings and wait for a "hot strain" to die out. STAY CALM in the face of FIP. Don't overreact.
Antibody response is correlated with fecal shedding. Fecal shedding is very erratic. Some cats shed for a while and seem to never shed again. Single timepoint titers are inaccurate and meaningless. Recovery is usually associated with a drop in titer. Titers over 1:100 or 1:400 are usually associated with shedding. But these numbers fluctuate. Be careful with interpreting titers.
Genetics: different cats respond to infection differently. There is probably a genetic influence in this. Genetics of the immune system is VERY complex. The vaccine is worthless, no drugs effectively treat FIP, so genetics are the only real hope.
The cytokine response in vaccinated cats exposed to FIP was different between cats. Immunity to FIP is cell mediated, while immunity to FECV is antibody mediated. The vaccine was proven worthless, but they observed that surviving cats had high interferon gamma (IFN-g) response and no tumor necrosis factor (TFN) response, while FIP cats had no IFN-g response but a high TNF response. Mice with their gene for IFN-g knocked out die of an FIP like disease following coronavirus exposure.
Selective breeding is happening naturally for FIP resistance. There generally seems to be less FIP than there used to be. No effective vaccine will ever exist for FECV/FIP. This is because if a cat can't wage an adequate immune response to the native virus, it can't form an effective immune response to the vaccine strain either.
There is now a shelter medicine program at UC Davis. There is a lot to learn about the effect of husbandry on overall cattery health... It isn't all genetics!
Use of interferon is an expensive placebo in his opinion. In catteries, don't get involved in getting titers done on your cats. You'll spend thousands of dollars for a bunch of meaningless numbers. The definitive test for FIP is immunohistology of macrophages, but FIP is really not a difficult disease to diagnosis if you look at the whole picture.
Polycystic Kidney Disease (PKD): PKD is the most common inherited disease of cats. The hypothesis was that it is the same gene as in humans and the goals was to see if cats could be used for human drug trials. Another goal was to reduce the incidence of PKD in the Persian population. Screening by ultrasound has been used, but its success is dependent on the skills of the technician. PKD is caused by an autosomal dominant gene.
PKD-1 occurs in 1 in 1000 humans. This is the most common human genetic disease. Symptoms begin at age 40, with end stage renal disease occurring at 60. Four candidate genes for ADPKD in humans have been identified: PKD-1 has 46 exons, (52kb), while PKD-2 is much smaller, so was hoping it might be PKD-2. A linkage analysis was performed.
Holding PKD clinics led to obtaining a large sample size, pedigrees, and ultrasound diagnoses. They picked markers around known PKD genes, and combined this with parentage analysis to verify the pedigrees. The sample set consisted of 528 cats, 413 of these were Persians, 39% of which were positive. They developed a dozen large families for analysis and found a marker that implicated PKD-1. PKD-2 was definitely excluded. A human genetics group started sequencing PKD-1 exons for mutations. They got a hit on the ninth one tested out of 46!! This was VERY lucky.
All cats tested so far have the same mutation. In over 300 samples, no cats have been found with cysts in their kidneys that have tested negative by this test! No normal cats have been found with the mutation. No homozygous cats have been found. They are currently taking test and turning it into a fluorescence test for the automated parentage testing machine.
New mutations could occur in the future. This test will only work for THIS mutation. Genetic counseling is key. Don't wipe out 40% of the Persian breed through an overzealous test and alter program. If the gene had a low frequency in a large population, you could test and eliminate, but that isn’t the case here.
Genetic Counseling: by Jerome Bell DVM. The goal of a breeding program is to breed better cats overall. Look at entire animal. A secondary goal should be to minimize genetic disease and to try not to produce affected cats. Eventually, the goal is to decrease the frequency of a disease causing allele in the breed.
When a heritable disease is identified and a test is available, breed known carriers to normal cats. Replace the carrier parents with genetically normal offspring. Select against other carriers for breeding SLOWLY. If you decided you wanted to use a cat for breeding, USE THAT CAT. But breed it to a normal cat and replace it with a non-carrier.
Phenotype tests (PKD ultrasound screening) can be used for screening or DNA based tests. Linkage DNA tests are used if the exact gene mutation has not been sequenced. This type of DNA test is NOT 100% reliable, unlike tests like the new PKD one that is based on the actual mutation.
If no DNA test is available, you need to look at the history of your cats and your cat’s relatives. But be careful not to restrict the gene pool and destroy the breed through careless elimination of cats based on pedigree only.
Managing recessive traits: When there is no test for carriers, test known or high risk cats to lower risk cats and work away from known carriers with each generation. Each generation away from a known carrier reduces the gene’s incidence by half. Replace known carriers with only POSSIBLE carriers.
Determination of the relative risk of a certain cat requires an open health registry with large participation by breeders and a known mode of inheritance. This allows reduction and understanding risks. But it can select against entire families and eliminate many normal cats, reducing genetic diversity.
OFA is a model of an open genetic registry. A breeder can research lines and look at sibling information, not just information about the cats in the immediate pedigree. Breeders can't continue to hide problems. Secrecy leads to poor health in your breed. Breeders must assess their own breeding program.
Managing dominant genes. Replace affected cats with normal siblings, a parent or older offspring. Try not to produce any more affected cats. Balance the elimination of the defective gene with maintaining breed lines.
Managing sexed linked genes. Use a normal male to maintain the line.
Managing polygenetic disorders. A breadth of pedigree data and phenotype analysis is needed. You don’t just need information on a cat’s parents and grandparents, but their siblings as well. In a polygenetic threshold disorder, don't forget that BOTH parents are contributing to the expression of the trait.
Genetic diversity equals breeder diversity. Don't do the same breedings and selection as everyone else. A groups of people line-breeding in one direction with others line-breeding in another direction is more effective than constant outcrossing. Genetic diversity does not need to be reflected in a single cat, but across the entire breed!
Do not continually multiply the number of carriers by spreading a defective gene throughout the breed. Work away from a defective gene. There is no need to hybridize with another breed to work away from a defective gene. You may just bring in another defective gene into the population.