Response just in from USMARC's Dr. Mike Heaton which addresses Darroll's and my curiosity about the numbering system for this new test. Be sure to check out the link re scrapie genetics, too, which should be of special interest for those whose breeds are short on RR genotype.
Dr. Heaton writes:Your question is a really good one that I'm happy to try to answer. If I understand it correctly, folks are wondering "Why were TMEM154 haplotypes given those particular numbers?"
I'll start by saying this is really a bit of inside baseball.
The numbering of complex haplotypes like TMEM154 gives researchers a shorthand way of identifying and tracking the most common gene variant and comparing it to the less common variants. As you saw from TMEM154 it can get complex quickly.
To help simplify things, we start by trying to identify the most common gene variant in a set of U.S. sheep DNA sequences and naming that variant "haplotype 1". In TMEM154, the most common variant turned out to be the K35 variant. The second most common variant in our data set was "haplotype 2" and the third most common variant was "haplotype 3". The ancestral gene variant turned out to be haplotype 3. Identifying the ancestral haplotype is important because it gives us clues about the gene's natural history and function.
Keep in mind that at the time that we discover these haplotypes, we typically have no information about their impact on a trait or which are the ancestral variants. That information comes later. In fact, we expect that most haplotypes of a gene will have NO impact on a trait. So most haplotype numbers usually never leave the laboratory.
With the more common haplotypes (like 1, 2, and 3) our confidence in their accuracy is high because we have lots of animals that have them and we can easily check segregation in families. For example, we can show that K35 is on the same chromosome as N70 and not I70.
As additional rare mutations are discovered, it becomes harder to verify which haplotype these mutations arise on. The problem is that we don't have many animals with these rare mutations and we often don't have segregation information. The bottom line is we get some haplotypes assigned incorrectly early on in the process.
So instead of renumbering all the other haplotypes when we find a mistake, we simply drop the number of the incorrect haplotype and move on. This is why the 5, 7, and 8 are not present in the TMEM154 haplotype numbering system. They were rare and incorrectly assigned in the early days of the research.
In a perfect world we'd know the sequences of all the haplotypes, where they occur, and their relative effect. Then they could be named sensibly with regards to how they might be used. As you already appreciate, we're not quite there yet.
I hope this long winded explanation helps shine some light on your question. You are correct that this story is more complex than folks are used to. However, I think the ovine TMEM154 story illustrates the current state of the art in host genetics of infectious disease and gives a glimpse of what may be possible in the future. It’s now recognized that even the familiar ovine prion gene is actually much more complex than just A136, R154, and R171 (see Figure 1, http://www.biomedcentral.com/1746-6148/6/23
). My hunch is that we’ll see more examples like these as time goes on and they will provide the opportunity to make genetic improvements in livestock.
Again, thanks to Mike for his patience with our many questions!