X-factor Question

[aethervox]

I remember reading something about a geneticist at the University of Kentucky that was working with Haun on identifying the X-factor gene.

I'm no expert in this area, but I was under the impression that an RFLP test was fairly straightforward to develop if you had access to known positive and known negative blood samples. (RFLP stands for Restriction Fragment Length Polymorphism, I think. And I think that's the kind of test they use in paternity suits.)

Haun ran her hypothesis that the large heart is a sex-linked dominant trait by several professionals, including equine geneticist Dr. Gus Cothran, then of UKy now of TAMU. (Since specific information re. transmission and expression of the trait has would undoubtedly have considerable commercial value I'd be very surprised if it wasn't still under study somewhere.)

I asked Dr. Cothran via e-mail if any scientific papers had been done on the subject and he said they hadn't. They have DNA from a large number of horses, but no time or funding to do the analysis at this point. There's also not enough data to confirm the pattern of transmission via statistical analysis.

I also asked if any work has been done on the genetics of heart size in mammals, and he replied that the only studies that have been done are from the standpoint of pathology.

The lack of funding does not surprise me. After all, would people have bred as many mares to Mr. Prospector if it was known that his heart was 'normal' sized? (And where did that normal sized heart come from in Gold Digger's pedigree?) Or Bold Ruler, for that matter?

As far as heart size of heterozygous mares (i.e. one large and one normal heart size gene) Haun did say (in her second book) that single copy mares who did not express the large heart gene, still had hearts that were larger than mares with no copies.

I must admit that I have problems with the books because of the sloppy editing and Haun's tendency to change nomenclature in mid-book, making it difficult to follow. I wish she'd put up a web site with added information as it becomes available. For example, in her books, Tiznow is listed as a Blue Larkspur heart line stallion, but in a recent blog post, she says that Tiznow expresses Man o' War's heart as well has having his Y chromosome! It would be very nice to know what has changed!

[xfactor fan]

And of course big money in racing comes from breeders, and folks making money standing a successful stallion. IF the large heart theory is correct a great racehorse with the large heart is going to have a majority of great daughters, not sons. And in fact the sons are going to have a (roughly) 25% drop in quality across the board.

Just think of the advertising possiblities "breed to Mr Special and have dud sons, but great daughters." The major money is in the colts.

And if you are breeding to this theory, then you want the best runner with the smallest heart on the top, and a large heart on the bottom side of the pedigree.

Which of course pretty much matches the theory for breeding of "Speed on the top and class on the bottom"

And the third cell from the left was meant to be funny, kind of goes along with the image of the guy with the clip board handing out jobs.

[Pan Zareta]

I think there would need to be a single cell source for the developing heart. If it were truly a mosaic, you could have one group of cells developing into normal sized ventricles, say, while another line of cells tried to develop double or triple-sized atria. Seems like that would be problematic.

I'm not sure that all parts of the heart derive from the same germ cell layer. Even if they do, random X-inactivation occurs just before those layers are formed, so each is likely to include a combination of paternal and maternal X-inactivated cells.

So the X-inactivation is not truly random, but is slanted so that the paternal X is more often inactivated... And how does the cell know which is the paternal X - it was a maternal X in the sire after all.

Consistent preferential inactivation of the paternal X in extra-embryonic tissue is proven only in the mouse. The most that can be said of humans and other placental mammals is that X-inactivation of extra-embryonic tissue is skewed toward the paternal X. There is considerably less evidence for such skewing in actual embryonic tissue, but it is considered to be a probable factor in "manifesting heterozygotes" (in this context - females heterozygous for sex-linked recessive traits, but who display that trait in phenotype).

As far as heart size of heterozygous mares (i.e. one large and one normal heart size gene) Haun did say (in her second book) that single copy mares who did not express the large heart gene, still had hearts that were larger than mares with no copies.

If a hypothetically heterozygous mare has a larger heart than a mare hypothetically homozygous for a normal sized heart, then isn't she expressing the trait?

Thanks for contacting Dr. C. Interesting info. If indeed there's really no one working on this, then I'd say most equine geneticists have probably discarded the idea that larger than avg. equine hearts are transmitted anywhere near as simply as Haun proposed.

As for the different hearts defined by sire line, and the notion that there might be any difference between the three TB Y chromosome lines...

[xfactor fan]

Actually I don't think the implication is that the heart size follows the Y sire line, but since the stallion will express only one X, this is the "pure" expression of what the gene is going to do.

So the Princequillo heart line would zig zag down the bottom side of the pedigree, and his maternal grandson Kris S. could have and express the same X. So would Secretariat, and so on.

Some of Haun's science is bad, but not that bad.

[aethervox]

As far as heart size of heterozygous mares (i.e. one large and one normal heart size gene) Haun did say (in her second book) that single copy mares who did not express the large heart gene, still had hearts that were larger than mares with no copies.

If a hypothetically heterozygous mare has a larger heart than a mare hypothetically homozygous for a normal sized heart, then isn't she expressing the trait?

Not really, because her heart is still smaller than that of a heterozygous mare who is expressing the large heart gene. As an example, Winning Colors was heterozygous for the large heart gene because Halo didn't have it, but she did express the large heart gene. If she had two full sisters, one heterozygous but not expressing the gene and one homozygous for the normal sized heart, Winning Color's heart would be the largest, followed by her heterozygous sister who isn't expressing the gene, followed by her homozygous sister who doesn't have the gene at all.

I think the heart size being named after sires isn't so much to link the heart size to the Y chromosome, but to give the various size mutations a name that the racing public would recognize. Supposedly the Princequillo heart is the largest, and the Blue Larkspur heart the smallest of the four major sire lines.

Regarding the genetics behind the large heart, the impression I got from Dr. Cothran was that he'd suggested that the gene might be sex-linked but that there were also other possibilities that needed to be looked into.

Does that clear things up or make things murkier?

[Pan Zareta]

Mea culpa. I'm well aware that under Haun's hypothesis transmission of the large heart has nothing to do w/ the Y. I should have said labelled by sire name, not defined by sire line.

My eyes tend to roll back in my head when there's discussion of the "[sire name] heart"s. Yes, there's scientific proof of considerable variation in heart size among TBs, QHs, and perhaps other horse breed. The scientific proof ends there. Ten+ years after publication of the first X-factor book, during which time the equine genome has been fully sequenced, Haun's hypothesis is still based solely upon circumstantial evidence. But it's now been refined to include sire-specific variants or mutations?!? As far as I know, the identification of these variants is based on, again, circumstantial evidence and an extremely limited number of heart scores that would not even come close to passing scientific muster as a representative sample.

[aethervox]

At the moment yes, it's circumstantial evidence. There may be similarities in QRS traces between family members, but until someone does the statistics...

I suspect that by writing a pair of 'popular' books, Haun has put off a lot of scientists who would have helped out. I know, from working with academics, how difficult it is to get new theories accepted by mainstream science, even if you are a first class scientist yourself, which Haun is not.

[xfactor fan]

And of course it didn't help that the original research was done in Australia. Who were looking at Phar Lap their national equine hero.

So when these folks from down under came to present the new idea that rocked the boat for the stallion owners, and breeders, and pretty much the whole industry they were not very welcome.

And of course I know that there is perfectly good science being done in Australia--they were the ones that figured out the very complex genetics of sex influenced chromosomes where a gene is expressed if it passed on via one sex, but not the other. Autosomes mind you, nothing easy like X's and Y's.

New ideas in science aren't usually welcome. Don't know if anyone remembers the early days of the K-T mass extinction theory, (giant meteor kills the dinosaurs) where this geology guy took a very close look at the boundary between these two strata, and noticed like everyone else that it was black. But he took it a step farther and noticed that it was made up of soot, shocked quartz, and iridium which is not found on earth, and is found in meteors.

The howling from the paleontology guys was epic. How dare this geology guy come in and tell them anything. As luck would have it, Dr. Walter Alvarez is the son of Nobel Prize winning Physicist Dr. Luis Alvarez. And in part because his father got involved in the research, the two of them were able to survive the academic firestorm with reputations intact. And now of course the location of the impact has been found, and the process of exactly what happened has been worked out in a fair amount of detail.

Other folks haven't been so lucky.

[skennedy]

...
Not really, because her heart is still smaller than that of a heterozygous mare who is expressing the large heart gene. As an example, Winning Colors was heterozygous for the large heart gene because Halo didn't have it, but she did express the large heart gene.

Was there a measurement of heart size for Winning Colors, and, if so, where do you find this kind of info? I would love to see some real quantitative data about this stuff. According to the database here, Halo (Caro?) had a 25% chance of getting the gene from Life Hill. But let's assume WH was heterozygous.

If she had two full sisters, one heterozygous but not expressing the gene and one homozygous for the normal sized heart, Winning Color's heart would be the largest, followed by her heterozygous sister who isn't expressing the gene, followed by her homozygous sister who doesn't have the gene at all.

Why would the heterozygous sister who is not expressing the gene have a larger than normal heart? If WH is "expressing the gene" in the strict Mendelian sense, then she would have a large heart. If the gene is really X-linked and mosaicism (right word?) comes into play, I can see how WH could have a larger than normal heart, but not as large as a son of hers that got the gene. If the gene is not being expressed, then it can't contribute to the development of a larger than normal heart, can it?

I know of a gene that confers large muscle size in mice. Actomyosin is over-produced, so each individual muscle cell is "beefier" than normal. It would be interesting to know whether an X-factor heart has bigger individual cardiac muscle cells or more of them, or both.

BTW, I think if I post a few more times, my status will be upgraded to "Suckling". Gee whiz, that will be such an honor.

[aethervox]

...
Not really, because her heart is still smaller than that of a heterozygous mare who is expressing the large heart gene. As an example, Winning Colors was heterozygous for the large heart gene because Halo didn't have it, but she did express the large heart gene.

Was there a measurement of heart size for Winning Colors, and, if so, where do you find this kind of info? I would love to see some real quantitative data about this stuff. According to the database here, Halo (Caro?) had a 25% chance of getting the gene from Life Hill. But let's assume WH was heterozygous.

Per this article http://www.circledhorses.com/The%20X-Factor.htm Winning Colors' heart was measured and was found to be large. Her sire, Caro, had a normal sized heart - his was measured during autopsy.

If she had two full sisters, one heterozygous but not expressing the gene and one homozygous for the normal sized heart, Winning Color's heart would be the largest, followed by her heterozygous sister who isn't expressing the gene, followed by her homozygous sister who doesn't have the gene at all.

Why would the heterozygous sister who is not expressing the gene have a larger than normal heart? If WH is "expressing the gene" in the strict Mendelian sense, then she would have a large heart. If the gene is really X-linked and mosaicism (right word?) comes into play, I can see how WH could have a larger than normal heart, but not as large as a son of hers that got the gene. If the gene is not being expressed, then it can't contribute to the development of a larger than normal heart, can it?

There's been a lot of recent research about incomplete inactivation of genes on the X-chromosome. There's an overview of how it works in humans at http://www.pnas.org/content/96/25/14180.full They are also discovering that, in some cases, one copy of the X-chromosome is preferentially inactivated (i.e. the same X is inactivated more than the other one). In marsupials, it's always the paternal X-gene that is deactivated.

I know of a gene that confers large muscle size in mice. Actomyosin is over-produced, so each individual muscle cell is "beefier" than normal. It would be interesting to know whether an X-factor heart has bigger individual cardiac muscle cells or more of them, or both.

BTW, I think if I post a few more times, my status will be upgraded to "Suckling". Gee whiz, that will be such an honor.

I agree, it would be interesting to know why the heart is larger

Keep on posting and you'll get there. This has been an interesting topic!

[skennedy]

Per this article http://www.circledhorses.com/The%20X-Factor.htm Winning Colors' heart was measured and was found to be large. Her sire, Caro, had a normal sized heart - his was measured during autopsy.

Another Haun article. Is there any source of hard data? I would love to see a histogram of male thoroughbred heart weights. In the males, the gene expression is all-or-none, and I've seen estimates that say maybe as many as 15-20% of thoroughbreds have the large heart gene. If that is true then you ought to be able to see 2 populations of heart sizes in the histogram of males. It should look like a bell curve centered around 8 lbs, and a smaller bump on the right tail at maybe 14 lbs.

Surely Haun and her doc friend have such data (at least for "heart score" since they've measured "thousands of hearts"). I find the fact that they haven't shown it to be suspicious.

There's been a lot of recent research about incomplete inactivation of genes on the X-chromosome. There's an overview of how it works in humans at http://www.pnas.org/content/96/25/14180.full They are also discovering that, in some cases, one copy of the X-chromosome is preferentially inactivated (i.e. the same X is inactivated more than the other one). In marsupials, it's always the paternal X-gene that is deactivated.

OK, that article talks about incomplete inactivation of the X. Very interesting, but that is not the same thing as the gene not being expressed. Gene expression is the synthesis of a gene product (usually a protein) dictated by the information contained in the gene.

If the X is not inactivated, then the gene can be expressed in that cell. So heterozygous females (with incomplete X-inactivation) could have both X chromosomes expressing their gene product - one normal and one X-factor.

BTW, I think if I post a few more times, my status will be upgraded to "Suckling". Gee whiz, that will be such an honor.

Keep on posting and you'll get there. This has been an interesting topic!

That was intended to be "wry humor". Actually I would be completely happy to skip right over the stage where I am labelled a "Suckling".

And yes, this has been very interesting. Thanks for your posts.

[Pan Zareta]

Another Haun article. Is there any source of hard data? I would love to see a histogram of male thoroughbred heart weights. In the males, the gene expression is all-or-none, and I've seen estimates that say maybe as many as 15-20% of thoroughbreds have the large heart gene. If that is true then you ought to be able to see 2 populations of heart sizes in the histogram of males. It should look like a bell curve centered around 8 lbs, and a smaller bump on the right tail at maybe 14 lbs.

Surely Haun and her doc friend have such data (at least for "heart score" since they've measured "thousands of hearts"). I find the fact that they haven't shown it to be suspicious.

I've no doubt the data exists, and in quantity. The project was reported in industry publications well before Haun's first book was released. They (several scientists acknowledged by Haun) measured TB hearts at many, maybe most, of the major KY farms. Access was undoubtedly conditional, not unrestricted. It may be that one or more of those conditions precludes release of the amount and type of hard data we'd all like to see, tho' obviously a few owners did grant Haun permission to publish results clearly identified by name and pedigree.

[sharmila 75116]

Actually I don't think the implication is that the heart size follows the Y sire line, but since the stallion will express only one X, this is the "pure" expression of what the gene is going to do.

So the Princequillo heart line would zig zag down the bottom side of the pedigree, and his maternal grandson Kris S. could have and express the same X. So would Secretariat, and so on.

Some of Haun's science is bad, but not that bad.

Hello Everyone
am sry to re-start this debat.
It's years am reading this site and never wanted to get into this x-factor issue.
I'm french-trotter breeder.
My heart always told me to marry mothers to mothers. I personally thought at that time was the great laws of breeding.(and up to today still)
As we breeders off forums would say"whenever you have a great mare she will always produce even with a jackass"

My story is that this same x-factor(as we call it here today)
I did it and it worked for me.
here's my blodmare pedigree
http://blodbanken.nu/servlet/GetBBData? ... rm&lang=fr
I wanted to inbreed one of the mares in the pedigree who's name is "Dame d'Atout"
and I used this stallion(here's his pedigree)
http://blodbanken.nu/servlet/GetBBData? ... rm&lang=fr

and this is what came out in finale
Redemption Song
http://blodbanken.nu/servlet/GetBBData? ... ption+song

When Redemption Song was a yearling then I bought the Haun book.
I felt comforted with her story.
But things wasn't so easy with my horse .....I had a good trainer who did really good work on my horse.....and she became a Groupe II runner and nearly a Groupe I titled horse.

Also my girl-friends made one of Norways big prized trotter in this same way
his name is "Bullchip"
http://blodbanken.nu/servlet/GetBBData? ... r=bullchip

My friend she said she wanted to inbreed the mare " Rosemary"
and she went BINGO

ps Xfactorfan .....am fan of yours