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Extension or not; clarifying gene links and origins
Topic Started: Mar 7 2016, 06:18 PM (374 Views)
wildrabbits
Hopelessly Addicted to the Fuzz
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Does anyone happen to know the source and origin of the En broken gene? I don't remember if I had looked into this or not in the past...Was it derived from a dutch marked self-tort rabbit like ej was???

This link below makes me want to rethink some things
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1085547/?page=1

This quote from the result of the study posted below it is something I feel was not clarified enough; "The Rhinelander coat colour phenotype is determined by the English spotting locus and by the eJ allele at the extension locus. This extension allele was not characterized by Fontanesi et al. [31], therefore, here all animals of this breed were considered to carry the wild type E allele"
http://www.sciencedirect.com/science/article/pii/S0888754309002559

This following link brought up before by some brilliant types here on this forum also leaves far too many open ends and implications that ej just has dramatic effects on how A and E allele combination phenotypes...maybe it is just ignorance and misunderstanding on my part but I don't see anything anything proving that ej is in fact an extension gene in this study..only that it effects extension gene display;
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3236303/

I have a feeling one of my unmarked "eje" males I sold a while back from EeXEej cross was actually ee from one of the craigslist postings I saw not long ago...(This unmarked white male threw an entire chinchilla colored litter when crossed to an albino female yet none seemed to carry ej marking). I feel ej truly needs to be re-examined as not actually be an extension gene.

Let us look at this ej gene from the hypothetical point of view that it is not an extension gene for a minute and try to think of how it could be possible through other means...I am open to all possibilities and thoughts that come to mind!!! Please see that this is not intended as a debate. This is intended as a creative hypothetical subject for people to freely express open thoughts from a clean slate of mind =)
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twr
POWITH!!
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Um, you do seem to have significantly misunderstood those papers. I'll try to explain...

You mention 4 papers, I'll assign them numbers for my convenience:
[1] Castle, W.E. (1924) - Linkage of Dutch, English, and Angora in Rabbits ("PMC1085547")
[2] Fontanesi at al (2006) - Mutations in the melanocortin 1 receptor (MC1R) gene are associated with coat colours in the domestic rabbit (Oryctolagus cuniculus) (Referred to as "Fontanesi et al. [31]" in paper [3] below. Covers gene E, alleles ES and e)
[3] Fontanesi at al (2010) - Characterization of the rabbit agouti signaling protein (ASIP) gene: Transcripts and phylogenetic analyses and identification of the causative mutation of the nonagouti black coat colour ("S0888754309002559", focused on gene A, allele a, but has a lot on gene E too)
[4] Fontanesi at al (2010) - A composite six bp in-frame deletion in the melanocortin 1 receptor (MC1R) gene is associated with the Japanese brindling coat colour in rabbits (Oryctolagus cuniculus) ("PMC3236303", covers gene E, allele ej)

There is also a fifth paper that seems very relevant:
[5] Fontanesi et al (2014) - The KIT Gene Is Associated with the English Spotting Coat Color Locus and Congenital Megacolon in Checkered Giant Rabbits (Oryctolagus cuniculus) (Covers gene En, allele En)

Of these papers, all but [2] is freely available. [2] is paywalled. I have read it, but you can get the essentials from the abstract and the other Fontanesi papers, so you are not missing much.

So:
[2] identifies the E _gene_ as Mc1r (so "wild-type" Mc1r is _allele_ E) and identifies two mutations. They designate one as Del6 and identify it with the ES allele. They designate the other as Del30 and identify it with the e allele.
[4] identifies a further Mc1r mutation that correlates with the ej allele. The size of the deletion is the same as in their ES allele but the deletion is in a different place. So they redesignate the Del6 allele from [2] as Del6DS and designate the new ej allele Del6J. Look at figure 1 in this paper. It clearly shows the location of all 3 alleles in the Mc1r sequence.
[3] was published after [2] but before [4]. So at this point they know how to test for ES and e, but they can't distinguish between E and ej using a molecular test. That is what the quote about Rhinelander means.

I don't understand what your point is regarding [1]. It sounds as though the gene notation has confused you. In classical genetics, rabbit En is a distinct gene from gene E. It is not an allele of gene E. On forums, ES is often written Es for convenience, and that may make it appear that there is some connection between En and Es. In molecular genetics, gene En has been tied to gene Kit with high certainty (see the additional paper [5] above). Also, papers as old as [1] need to be read with caution, as they may be outdated. I've not read that specific paper yet, but the subject as described in the title is covered in the more recent Robinson, R. (1958) - Genetic Studies of the Rabbit, which I have read.

I hope that makes sense. I am glossing over a few fine points but I want to be sure we agree on the basics first.
Edited by twr, Mar 8 2016, 03:57 PM.
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twr
POWITH!!
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On the question of known origins of genes and breeds I have:
Dutch-marked rabbits: Very old, shown in paintings from the 1400's ("15thC").
Dutch as a show breed: First _recorded_ showing in 1870.

English spot: First version developed by 1850, from non-pedigree spotted rabbits.
Checkered Giant: Developed for meat in late 1800's, from non-pedigree spotted rabbits commonly kept in France at the time. Imported to the US in the 1900's ("early 20thC").

Harlequin: Developed as a show breed from tricolour dutch-marked rabbits. First shown in 1887.
Tricolour Dutch: First shown as a recognised colour within the breed in 1922. A version developed from crosses with Harlequins was first shown 1925.
Rhinelander: Developed from non-pedigree spotted rabbits and Harlequins. First shown in 1905.

From: Esther Verhoef-Verhallen "Rabbits and Rodents" (ISBN 90-366-1596-8)
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reh
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Hochstrasser already had the idea of a separate Japanese gene. Since he wrote about this topic in our rabbit journal, I investigated this by looking up a lot of this old papers. I ended up with a list of relevant pairings resulting in 400 kits with colors segregating fairly perfect for eJ being an extension allele.
Edited by reh, Mar 11 2016, 05:03 PM.
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wildrabbits
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Please keep in mind this thread is meant to be on theoretical point of view that ej is not an extension gene. It is open to all past thoughts and studies available though! Please freely provide as much info as possible that could absolutely prove and/or disprove anything!

twr your mention of paintings from the 1400's showing dutch marked rabbits does hint(from this theoretical point of view thread) that En and ej could indeed be linked mutations sourced from dutch genes as I tend to think..Do you happen to know if there is a common ancestor involved between dutch, english, AND harlequin rabbits?

I feel as though ej is a gene that heavily influences extension genes and maybe even ties itself into extension genes which may make it the easiest way to see it genetically yet, still may not actually be an extension gene at all..I hope you can understand my meaning here for I am NO geneticist and may be severely lacking the terms needed to explain.

reh can you show more on the study you mentioned? Does it involve rabbit breeding pair with genotypes such as EeXEej or EEXeje? Do the numbers provided from the study perfectly show 200 out of 400 rabbits being ej? What would make you say the number from the study would provide proof for ej being an extension gene?

Maybe these questions might help put things in different mind set.
Dudu genotype dutch mixed rabbit produces how many dutch marked kits when paired with DuDu?
Enen genotype rabbit produces how many spotted kits when paired with enen?
Eej genotype rabbit produces how many ej marked kits when paired with Ee?

Now consider these questions.
AaXAa produces how many aa rabbits?
EeXEe produces how many ee rabbits?
An unmarked eje(that appears ee from EejXEe parents) when bred to an ee, Ee, or EE produces how many kits carrying ej?

So far with my 3 different crosses involving EejXEe, ejeXee, and ejeXEe, all three litters have consistently had 25% ee phenotype offspring and 50%-75% ej marked offspring. I can think of no other extension gene that would display these kinds of ratios from a single gene...but with that said I also have never or really studied much into breeding any Es rabbits
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NeuBunny
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No study ever gives 'perfect' 200 out of 400. If I saw such, I would be suspicious that someone faked the data. That's what statistics are for - a very specific confidence in what ratios are 'not statistically significantly different' from 50-50. Mendelian ratios are the initial null hypothesis for all genetic studies ... burden of proof is that you must prove it does NOT fit the Mendelian ratio (within 95% confidence limits) first before progressing to test alternative hypotheses.

Dudu x DuDu gives NO Dutch rabbits ... du is a recessive gene.

Enen x enen gives 50-50 litters of broken and solid. En is co-dominant, such that EnEn gives kits with less than 10% color. Not all Enen are 'spotted'. Patterns can be booted, blanket, spotted, or false charlie... plus/minus butterfly, spine stripe and other specifics. Modifiers are incredibly important to expression of a specific pattern.

En and E are separate loci. If they were not, broken tort would be impossible. So I'm not sure how En is relevant in this context... other than it does have a very apparent interaction with ej ... tricolor rabbits do not show the alternation of large patches (bands and bars) within their colored portions.

Harlequin have been demonstrated biochemically to have cell lines that are lacking MC1R receptors (and other cell lines with the receptors) - this is the basic biochemical difference between the patches. The E locus codes for the MC1R receptor.

Eej x Ee - > 25% EE, 25% Ee, 25%Eej, 25% eje. Appearance of Eej and eje depend on genes at the A locus (which codes for agouti signalling protein). A-Eej may be 'harlequinized chestnut', aaEej will be black. A-eje will be harlequin. aaeje will be 'torted harlequin'. These odds are the 'chance per kit' ... when you hit kit numbers substantially above 100 kits, this will converge toward the population statistics. Anything less than 25 kits, random chance is going to give you actual 'population' ratios all over the place... just as flipping coins on average you get 50% heads and 50% tails, but it isn't particularly hard to flip 2 or even 10 heads in a row.

Aa x Aa gives 25% aa .... but not every litter is going to be exactly 1 kit in 4. Lots of litters will be all agouti, some will be all all self. The odds for getting a litter of 4 self pups from a Aa x Aa is actually 0.25^4 = 0.3% (not zero - it is expected to happen in 3 of every 1000 litters ... lol and Murphy's law says that will happen exactly when you don't want it to).

Ditto.

we need to know what's going on at the A locus on the rest to be able to calculate odds.

How many total kits in each of your 3 litters. Unless total kit number is over 25 for each type of cross, I don't think you have the resolution for statistical significance.

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twr
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Regarding papers with ej numbers in, the ones I'm aware of are:
[6] Castle, W.E. (1924) - Genetics of the Japanese rabbit
[7] Punnet, R.C. (1924) - On the ‘Japanese’ rabbit
[8] Punnet, R.C. (1926) - Note on a chinchilla-Japanese cross in rabbits

If I remember correctly the really high numbers are for eje x ee and eje x eje, but [7] and [8] also have other crosses. [7] actually has two sets of numbers in it, the ones by Punnet in the main article text and some more by Haldane in a note at the end. These papers don't use the modern notation consistently because they were in the process of working things out at the time. eg "recessive black" in some places actually means the E allele. [6] and [7] were published together and are the ones that concluded that Japanese/Harlequin is an allele of the E gene.

Regarding statistical significance: Human intuition simply can't be trusted with statistics. We see patterns and strange coincidences that are not really there (or rather not strange - just a natural consequence of randomness). That is why when people say they are seeing something odd, we often concentrate on nailing down just what their evidence actually is.

wildrabbits
 
twr your mention of paintings from the 1400's showing dutch marked rabbits does hint(from this theoretical point of view thread) that En and ej could indeed be linked mutations sourced from dutch genes as I tend to think..Do you happen to know if there is a common ancestor involved between dutch, english, AND harlequin rabbits?
I don't see the connection. As far as I can see nothing I've posted suggests a common origin for harlequin and english spotting. By "dutch genes" do you mean "the" dutch gene or do you mean the dutch breed more generally?

Regarding the "what if" of assuming that ej is not an e allele: I have played with a few combinations to see how they stack up against the information in papers [4], [6] and [7]. (Note that papers [1], [2], [3] and [5] don't tell us anything about the Japanese pattern. I just haven't got around to using paper [8] yet.) So, for the sake of the following I'm going to pretend that there is a gene J, with a dominant allele J that causes Japanese pattern and a recessive wild-type allele j.

The key points I take from paper [4] are:

  • All rabbits with allele J that have been tested for E alleles have a specific E allele (one per J allele) that is not found in other patterns. This indicates that there is a strong linkage between J and E (i.e. these genes are located on the same chromosome and are quite close to one another). By itself this doesn't allow us to put a firm number on just how close the linkage is.
  • Allele J disables the nearby copy of gene E at the transcription level in regions that are orange in the Japanese pattern (see fig 3).
I treat these as a given, so before I launch into any details of what I've considered based on the above, does anyone want to dispute or otherwise discuss either of those points? Also note that nothing I've looked at could make extra ee-looking rabbits in anything close to a 3:1 ratio. The most I can make is somewhere less than 1 in 16 (I've not yet worked out how much less).

EDIT: Added stuff from the quote on down.
Edited by twr, Mar 20 2016, 06:14 PM.
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reh
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Get the Duct Tape, Stat!
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http://www.kaninchenwissen.de/bilder/japanerKreuzungen.pdf
http://www.kaninchenwissen.de/bilder/JapanerWeb.pdf (german)

G = Agouti, B = Extension
schwarz = black, loh = tan, wild(farbig) = agouti
gelb = red/yellow, keine gelben/thüringer = no yellow/tortoise kits
Edited by reh, Mar 21 2016, 12:57 PM.
www.rabbitcolors.info - Images and Gene Codes
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twr
POWITH!!
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Reh, the first link is broken for me.

I've not read the 2nd link yet, but the 4x4 grid looks similar to one option I looked at (true-breeding harlequin being e'e'JJ and aggregating numbers from [7] experiments A and B as F2 from aaeeJJ x aaEEjj). I didn't get a 9:3:3:1 ratio though because I treated J as disabling E when it is on the same chromosome (per [4] fig 3) and because the aa makes both agouti and agouti-harlequin come out as self.
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reh
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Get the Duct Tape, Stat!
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Link corrected.
The punnet squares are to show it is eJ and not e + J, because in the latter case there have to be some yellow guys, which is not the case.
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wildrabbits
Hopelessly Addicted to the Fuzz
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Neubunny why would you say DuduXDuDu gives no dutch marked rabbits? I have seen du marking carry on for 2 generations crossed with DuDu...
My total ej litter count amounts to exactly 25 between the 3 litters of first time mothers with 6 dead before 1 month age.
EejXEe=12 kits, 4 ej marked, 2 ee phenotypes which from modern theory had to be eje
ejeXee=4 kits, 3 ej marked, 1 ee black tort..2 obvious dutch marked from father
ejeXEe=9 kits, 5 ej marked, 1 ee phenotype(Still need to verify if Ee or EE) From the one ee ermine phenotype he threw I am guessing Ee but litter number one leaves some wonder as to what ej does.. Verification will come from crossing this Chinchilla male to a born ee pearl lop female to confirm if he is EE or Ee.

twr your mention of paintings of dutch rabbits in the 1400s says to me that from the time frame En, du, and ej may have been mutations sourced from a single ancestor and/or related lines. du and ej are already said to have been reportedly sourced from the same rabbits if I remember right..

The genetic ratio from these 3 genes seems to be identical to me as well.. Enen produces roughly 50% En offspring, Dudu produces roughly 50% du marked offspring, ej produces roughly 50% ej effected offspring...notice how other genes don't seem to change these ratios much either?...
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NeuBunny
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admittedly, I don't do Dutch and so my understanding is only what I have read, but I'm under the impression that Dutch is completely recessive - only dudu has Dutch marks - which means the kits have to get the gene from both parents. A Dudu kit is not Dutch. A Vv vienna marked kit can look dutch, as can a DuduVv. But maybe I'm wrong and it is co-dominant?

I know I see solid pattern rabbits listed as Du- and dutch listed as dudu in most resources. But now that I'm actually looking, I don't see anything specific about Dudu in those ... and I do see references to 'partial Dutch' in others (without going into the gene codes).
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