I'm not a geneticist, but I know there are several of you out there. So, if TVD is inherited in an autosomal dominant, incomplete penetrance fashion, will a genetic test be able to determine the penetrance? Would this be a test that simply indicates presence of TVD gene or no presence and then we'll have to assume that all dogs that have the gene *could* produce TVD with full penetrance? Are there modifier genes that could be discovered that would be responsible for the level of penetrance? Are there other diseases that have genetic tests when the mode of inheritance is "Autosomal dominant, incomplete penetrance"?

A friend was trying to explain this to me, but I didn't quite understand what she was saying. She didn't think it could be tested.

TIA, Cathy

From what I gather, in simple terms, they can test if a dog is affected, but they cannot test if a dog is a carrier, and may produce it. So, just because a dog gets a heart clearance does not mean there is no need to worry.

See, I understood the opposite. That the genetic test would categorize all carriers and affecteds together since "carriers" have the gene, but it's not fully "turned on". If the dog passes echo but has the gene, then he/she would be a carrier. If the dog doesn't pass echo and has the gene, then obviously, he is affected.

I think most of us are more worried about the "carriers", right? If it's autosomal dominant, then 50% of the offspring from a dog with the gene will have that gene. If the dogs have the gene but it's not fully penetrated, then they can still produce it?

"Are there other diseases that have genetic tests when the mode of inheritance is "Autosomal dominant, incomplete penetrance"?"

In horses, there is a DNA test for HYPP, which is inherited as an autosomal dominant trait... meaning the animal only has to receive one copy of the gene to be affected. The animal with one copy may not not exhibit any noticeable symptoms at all or symptoms may vary in severity in individuals, but it is still an "affected" animal. An animal with only one copy of the gene would be "heterozygous" (using the HYPP condition as an example, it would be "nH", n for one normal gene, H for one copy of the HYPP gene).
If the animal received two copies of the gene, one from each parent, it would be homozygous (HH, the H again representing a copy of the HYPP gene).
The only animal not considered affected, would be animals homozygous negative (nn, received a norducing an "affected" offspring. The thing to remal gene from each parent).
Here is a good chart for helping to understand the chances of promember here is that an nH is still considered an "affected" animal.
http://www.animalgenetics.us/HYPP.htm

Hopefully this helps understanding the mode of inheritance and possible percentages of producing an "affected" by giving an example of an actual autosomal dominant condition where a DNA test is actually available.

Don't know why this garbled, but I'll retype below:
The only animal not considered affected, would be animals homozygous negative (nn, received a normal copy of the gene from each parent).

Thanks, Val. That's exactly what my friend was saying. That we'd have dogs that pass echos, but have the gene and they would be considered "affected". Thanks!

Into horses or not... I think what's transpired in the last decade re health & breed type, resulting rulings/decisions by the AQHA re those health issues and breed "type" bears watching and studying, and possibly learning from it even if it doesn't directly involve our dogs... but maybe our breed club and registry could learn something, the good and the bad, what worked, what didn't.

If/when a DNA test becomes available for TVD, we as individual breeders and our parent club and registry could be facing the same moral and ethical decisions the QH breeders are facing.
Sorry, I keep referring to this as an example... I just find it fascinating and think there is so much to learn from following what's been going on in the American Quarter Horse Association .. it's almost like looking into parallel universe of what the Labrador breed could be facing.

Would it be a great article for the LQ?! Don't look at me though, I'm not gifted putting thoughts into words on paper. But the analysis and comparisons sure would be interesting reading I think.

I am not a geneticist, nor have I played one on TV. I do know of at least a couple of "dominant" traits that seemed to be a blind alley for DNA testing. Through years of research, at least one of these has identified a "recessive" trait that ALSO has to be present in order for the dominant to achieve full penetrance (for the dog to be symptomatically affected). The DNA test being worked on at the moment is for the recessive, which is easier to deal with. The downside of this is that dogs WITH even two copies of the recessive will NOT have the symptoms unless the other dominant gene (in another as yet unidentified locus) is also present. Dogs with two copies of the dominant gene will NOT have the symptoms unless the recessive gene is also present.

This is convoluted enough that the researchers want to test ONLY for the recessive (easier for prediction and eradication)and many dogs that would never have or produce a problem will be shunned from the breeding pool. The more we know, the more we realize how little we actually know. The watchword in this strange new world of the genome must be "Caution".

Maureen,

Thanks for that info. That's kind of what my friend was saying. That there's a second gene that turns on the first one and that dogs could be labelled as having the gene that really won't be affected. But it could be passed down if the mate had the gene that turns on the TVD gene? Does that make sense?

I'd like to donate to the research being done, but this type of information makes me wonder if that needle in the haystack is just buried too deep.
Cathy

"I'd like to donate to the research being done, but this type of information makes me wonder if that needle in the haystack is just buried too deep."

So, let's just leave things as they are and pretend
it will all go away. Stick your head in that haystack
along with your donation. If you are not part of the solution you ARE part of the problem. One tvd puppy
will change your mind about research, just one.

Just trying to research the feasibility of the testing for a disease with this type of heritabiliity, that's all.

Perhaps you haven't much experiences with researchers or charities in general, but when I donate to a fund, I like to know the vision of the project or group, the capabilities and knowledge of the people involved, and if the goal is truly attainable with the given funds. How many times have you heard that research was halted due to lack of funding?!? I've heard it a lot! I would love for there to be a genetic test for TVD, and elbow dysplasia, hip dysplasia, OCD, torn cruciates, retinal dysplasia, you name it. I'm thankful that I don't have any blood samples and pedigrees to submit to the TVD research, but I did have PRA samples and did submit. I had been warned by a friend that this might not be as easy as a $50,000 one year grant, that's all.
Cathy

Maureen, I find this very interesting. I teach genetics at the college level and am currently involved in research on a gene found in sea urchins, so I guess that makes me a geneticist. Is it that they cannot locate the dominant locus, or is it that no marker is available? The fact that it is dominant shouldn't make a DNA test more difficult.

For those who don't understand what the genetic test would do- it would look directly at the DNA- the gene itself. For a dominant gene, carrier status must refer to an individual who has the gene but does not express the phenotype (TVD), which is what incomplete penetrance means. A dominant gene with complete penetrance would not have any carriers, as all individuals that have the gene would be affected.

Here is what I understand from your description. If we call the dominant allele at the first locus A (allows TVD), the "normal", or noncarrier, condition would require the genotype aa. AA or Aa would be carriers or affected, depending on a second locus, the B locus. At the second locus a dominant B would prevent TVD and bb would allow it. So to have the actual condition, a dog would have to be AAbb or Aabb. Dogs with the A allele or with the bb genotype would be carriers and would have to bred carefully. Only aaBB would be noncarriers that could be bred to anyone. A dog with the A allele should not be bred to a dog that was Bb or bb. But you could breed a A_BB to another A_BB. Also you could breed an aabb to an aabb. Does this fit with your understanding?

I was just talking to my daughter when she was picking
up my granddaughter from her Montessori school where
she is in first grade. Leigh said, "woohoo, we've
raised 90% of the $50,000.00 for a new playground! The school is not asking for a specific amount of money from each family (85 families in the school) but that EVERY family participate." (a playground compared to TVD research....a playground compared to TVD research...85 families compared to the entirety of
the Labrador Retriever fancy...)

Wow, and the Labrador Community cannot find $50,000.00
to fund TVD Research? I am embarrassed and discouraged that it is taking this long to raise the funds!

The National Labrador Retriever Club recently sent $2,500.00 (plus $175.00 from private members) to Meg.
Hopefully, other Clubs and individuals will follow suit and at least the beginning of what may be the END of TVD in Labradors can be attributed to Labrador people who do have the best interest of our Breed in their hearts.

Becky, your analogy is not very strong because the parents of the children at that school can easily realize that the monies they donate will build a playground, and I bet you'll be able to report in a year that your granddaughter is playing on it!

If you and the researchers can convince the fanciers (or just me) that the money we (or I) donate will result in a mutation or reliable marker test for TVD, the money will fly in (at least a little from me). Did you donate toward PRA testing development? Some of the older labrador fanciers have been burned, and we are cautious now.

Is there a budget? Have the geneticists isolated genes with similar inheritance? Is it published data? Perhaps the researcher can post here directly for us all to read?
Cathy

Becky, your analogy is not very strong because the parents of the children at that school can easily realize that the monies they donate will build a playground, and I bet you'll be able to report in a year that your granddaughter is playing on it!
......................
It's the analogy that came to mind while reading this thread and talking to Leigh on the phone. The same amount of monies in record time from such a few individuals...Yes, Ammi will be playing on the playground next year. WHEN will the TVD research begin and we see results? Not till the monies come in, that's for sure.

A small sum from each of us will break nobody...but, it would equal the $50,000.00 needed by Dr. Sleeper.
Or, or what, what is the alternative??? You ask me to
"convince" the fancy .... impossible.... IF the fancy is not already CONVINCED there is a problem that we MAY be able to correct, there is nothing that I nor any other club member can do. I have a very limited knowledge base of this research, and prcd/PRA research...but, I am gleaning ALL the benefits of those who were courageous enough to put their money into the unknown that is now our Optigen marker test.

WHAT IF? What if we could eliminate TVD from our gene pool? Hey, I'm not even a minnow in this pond and I know that doing nothing accomplishes nothing. Keep your caution...keep TVD...I choose to try to raise funds for what may very well be an answer. Trust, yes, I DO trust Dr. Sleeper and her staff. Caution is thrown to the wind!
........................
If you and the researchers can convince the fanciers (or just me) that the money we (or I) donate will result in a mutation or reliable marker test for TVD, the money will fly in (at least a little from me). Did you donate toward PRA testing development?
.........
No, I started testing a few years ago after the gene
marker was delineated.
.............
Some of the older labrador fanciers have been burned, and we are cautious now.
...........
The marker was found, BECAUSE of the continued research and funding! Those of you who participated should be very proud of yourselves!
...............
Is there a budget? Have the geneticists isolated genes with similar inheritance? Is it published data? Perhaps the researcher can post here directly for us all to read?
...........
There is a letter from Meg, to the Labrador community,
outlining the specifics of this research. You can find the letter on http://www.nationallabradorretrieverclub.com.

I am one small voice hollering as loud as I can. Please don't take my exhuberance as disrespect for those who have already paid their dues. I feel very blessed to have Labradors AND the Labrador community as part of my life.

Hi,

I am not a geneticist, but Meg is and I'm guessing she would be perfectly willing to discuss any questions you have with her. I have corresponded with her several times via e-mail. She has been very available and I'm imagining that she would be willing to discuss with you what questions you have.

Please let us know what she says. If you have questions, I'm sure others do also.

As far as the money goes, the quote I received says "The estimated cost for DNA isolation, initial sample analysis, and salary support for one year would be approximately $50,000."

She's at:

Meg Sleeper, VMD, DACVIM-Cardiology
Section of Cardiology
MJR-VHUP
3900 Delancey Street
Philadelphia, PA 19104
sleeper@vet.upenn.edu

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Replying to:

Becky, your analogy is not very strong because the parents of the children at that school can easily realize that the monies they donate will build a playground, and I bet you'll be able to report in a year that your granddaughter is playing on it!

If you and the researchers can convince the fanciers (or just me) that the money we (or I) donate will result in a mutation or reliable marker test for TVD, the money will fly in (at least a little from me). Did you donate toward PRA testing development? Some of the older labrador fanciers have been burned, and we are cautious now.

Is there a budget? Have the geneticists isolated genes with similar inheritance? Is it published data? Perhaps the researcher can post here directly for us all to read?
Cathy

So figuring roughly, with what has been donated through the NLRC, 1900 people would need to donate $25/each to reach the $50,000 figure.

Becky, is it possible to have a Paypal link on the NLRC site to donate for TVD research? I just looked quick to see if there was one but didn't find it (maybe I missed it though), saw where a check can be mailed, but maybe having a PayPal link would be an idea.

Maybe we can get the LRC or the AKC's Canine Health Foundation involved. I would like to see our club donate also.

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Replying to:

So figuring roughly, with what has been donated through the NLRC, 1900 people would need to donate $25/each to reach the $50,000 figure.

Just went back and searched deeper... found this about how to use PayPal and the email address to send it to:
http://www.geocities.com/nlrc_reports/tvd_funding1.html

Is there anyway though to make a direct link for using PayPal and more easily spotted?

Val

Okay... I just checked out using the email address and donating through a PayPal account.... it's pretty easy to do! Just copy the email addy,
login to your PayPal account, go to your account and click on the "Send Money" tab, fill in the form with the email addy specified on the NLRC site for making a donation, specify the amount you want to donate, be sure to list you name/address in the memo section... SUBMIT! Real easy to do!

I see on the NLRC site it tracks donors... so we can see the progress being made to reach the goal!!

Here's the link for List of Donations, so you can check in; I assume they are only the ones donated through the NLRC.

http://www.geocities.com/nlrc_reports/tvd_donations.html

"So, if TVD is inherited in an autosomal dominant, incomplete penetrance fashion, will a genetic test be able to determine the penetrance?"

No unless they can identify several genes that work in conjunction with the main mutation. The penetrance would be determined based on the phenotype of the dog ie dogs with normal color doppler echocardiograms are not affected whereas dogs with abnormal results indicating presence of the syndrome would be affected. Both would look the same at the genetic level.

"Would this be a test that simply indicates presence of TVD gene or no presence and then we'll have to assume that all dogs that have the gene *could* produce TVD with full penetrance?"

Yes. But the number of dogs with the gene who are normal and pass the gene to offspring who are also ALL normal is unknown.

"Are there modifier genes that could be discovered that would be responsible for the level of penetrance?"

In my opinion yes.

"Are there other diseases that have genetic tests when the mode of inheritance is "Autosomal dominant, incomplete penetrance"?"

Yes there are many. It's nothing new in human genetic research.

When I get a chance I would like to do some more research into the information out there and what exactly the team of geneticists are doing and hope to accomplish. My biggest concern is that TVD is actually polygenic (requiring many genes be present that work together)and so if they find the main mutation and put out a genetic test for breeders to do and many send in samples and this gene is identified in dogs that are normal and have never produced TVD then we have more questions than answers. Of course it's a worthy venture however sometimes rushing to put out a DNA test doesn't produce the results intended.

Your description was excellent, but my concern was about the EFFECT on the population of testing based only on the modifier gene (the recessive) instead of the more specifically causative gene (the dominant). This is not TVD, but another research project that has been ongoing (about 20 years) that I have been tracking. As a breeder, it disturbs me that in order to extinguish a problem DIRECTLY related to a dominant gene action, we are going to be given the opportunity to select against another gene that MAY have many other purposes and only tangentally affects the problem.

Yes, both a dominant on gene A and a recessive at gene b are required to produce the overall problem, but that "modifier" may modify other functions that have not been identified. For those who visualize in computer terms, when you delete a program from your computer, you get a warning that "this element may be accessed by other programs" so that you can decide if you REALLY want to delete that element. The "other" affected program may be a game that you never play - or it might be your financial software with all your tax information! Without knowing what else it affects before making the choice of "deleting" the gene, we may be selecting for a different troublesome issue down the line. As I said earlier, I think the watchword has to be "caution" while we sort out some of these new genetic discoveries.

It seems to me that it would be highly desireble to have a test for both genes in this hypothetical situation. After all, only two of all the possible genotypes would be affected, and, depending on how widely spread the contributing alleles are in the population, you could be eliminating alot of dogs, especially if no one knows which of the two contributing alleles is more widely distributed. You might be developing a test for the common one, while the rarer one would be the better target. And if more than two loci are involved, as I suspect is the case for HD and some other orthopedic problems, then the situation gets really complicated. People are working on how to deal with these complex genetic diseases in humans. Maybe some day we'll have a better way to do it.