Department of Haematology, Royal Albert Edward Infirmary, Wigan.
Although it is extremely rare amongst the indigenous population, we have previously identified several British individuals with alpha-thalassaemia. It was to be expected that the underlying molecular defect in these individuals would result from racial admixture; however, we found that many of them share a specific, previously reported determinant of alpha-thalassaemia, referred to as --BRIT (Higgs et al. 1985). Several of these individuals with the --BRIT determinant originated from the North West of England and therefore a more extensive survey of individuals from this area was undertaken. We identified 14 individuals with the --BRIT determinant out of 200,000 individuals studied. These, together with all other known examples bring the total number of cases identified to 36. It seems likely that this almost exclusively British determinant of alpha-thalassaemia (--BRIT) has become established through genetic drift in this population.
PMID: 2605871 [PubMed - indexed for MEDLINE]
Are they saying here that the alpha-thalassaemia found in Britons is (a) of indigenous origin, or (b) that it is of external origin but has been isolated long enough so as to become its own strain? I believe the latter.
I think that they are saying that they expected (a) but actually found (b). That the specific alpha-thalassemia-causing mutation described is unique to Britain. Perhaps the earlier study (Higgs 1985) makes this clearer. There are lots of ways to produce thalassemia. The hemoglobin molecule is huge and complex. It comprises a cage made of four interconected protein chains that physically trap and hold an atom of iron, which then chemically binds to two oxygen atoms enabling them to be carried to where they are needed. Any small glitch in any of the four hemoglobin chains interferes with its ability to hang onto the iron atom, but also interferes with malaria. I think they make the point that the prevalence of this particular mutation must be due to drift (random chance), rather than adaptation, because England is too cold for malaria to take hold.
Joined: 30 Mar 2005 {Posts: 1082 } Location: New Jersey
Posted: Thu 23 Feb 2006 19:37 Post subject:
Frank wrote:
I think that they are saying that they expected (a) but actually found (b).
I'm assuming you mean the reverse of the above?
So, in other words, thalassemia doesn't necessarily indicate Asian admixture, but it can? I always thought it definitely did, just like HbS definitely indicates sub-Saharan admixture.
Frank wrote:
I think they make the point that the prevalence of this particular mutation must be due to drift (random chance), rather than adaptation, because England is too cold for malaria to take hold.
Drift means random chance? I never was quite sure what genetic drift means, and dictionary definitions left me kind of dry. In other words, this strain of thalassemia just erupted entirely on its own, in their opinion?
I have read accounts of malaria having existed in Britain.
Correct. I wrote it backwards. They expected that the thalassemia "would result from racial admixture" but found it to be indigenous instead. Sorry.
William wrote:
So, in other words, thalassemia doesn't necessarily indicate Asian admixture, but it can? I always thought it definitely did, just like HbS definitely indicates sub-Saharan admixture.
The problem is that "thalassemia" is a generic term meaning genetic "malfunction of one of the globin chains." But the chains have many links and so can suffer from many different defects. Some specific kinds of thalassemia are indigenous to Asia, some are indigenous to the Mediterranean, and the one mentioned here is evdently British. HbS, on the other hand, is a specific single-nucleotide mutation. Technically speaking, I guess you could say that HbS is one of the thalassemias.
William wrote:
Drift means random chance?
Yes. Mathematically it is drunkard's walk. Those few adaptively neutral polymorphisms that die out by sheer are gone forever. The others, equally neutral, continue. Hence, eventually there will be only one left. This is the same random Brownian movement propagation that produces those small Welsh villages where everyone has the same last name. In a very large population such a dramatic result would take millions of generations. But in a small population drift can result in an allele becoming extinct or "fixed" (everybody having the same allele) in just a few generations.
William wrote:
In other words, this strain of thalassemia just erupted entirely on its own, in their opinion?
Every mutation that has ever existed "erupted entirely on its own." The difference is what happens thereafter. If it is maladaptive it dies out. If it is adaptive, it spreads quickly throughout a population. If it is neutral, its fate lies in the hands of the gods of drift.
Joined: 30 Mar 2005 {Posts: 1082 } Location: New Jersey
Posted: Fri 24 Feb 2006 15:05 Post subject:
Thanks for the thalassemia explanation. It's nice to know someone who can explain the unknowns to me. Occasionally, I've written to and gotten responses from the geneticists performing the tests, but usually they're too busy.
Frank wrote:
But in a small population drift can result in an allele becoming extinct or "fixed" (everybody having the same allele) in just a few generations.
This is interesting. I wonder if the fixing of an allele through drift has ever been mistaken for selection? Would they know whether it's selection or drift based upon the marker being investigated?
Am J Hematol. 1988 Feb;27(2):139-41. Related Articles, Links
Beta S gene in Sicily is in linkage disequilibrium with the Benin haplotype: implications for gene flow.
Ragusa A, Lombardo M, Sortino G, Lombardo T, Nagel RL, Labie D.
INSERM Unite 15, Paris, France.
Hemoglobin beta-like gene cluster haplotypes defined by restriction enzyme polymorphic sites are useful in determining the origin of the beta S gene found in several human populations. We present here evidence that the beta S gene found among Sicilians is associated with the same haplotype observed among sickle cell anemia patients from Central West Africa. In addition, this haplotype is either nonexistent or very rare among normal Sicilian individuals. We conclude that the beta S gene was introduced to Sicily from North Africa and that the gene flow originated in Central West Africa and traveled north through historically well-defined trans-Saharan commercial routes.
PMID: 2893541 [PubMed - indexed for MEDLINE]
Firstly, I'm assuming that Beta S is HbS. Correct? What is linkage disequilibrium?
We already know that the strain of HbS in Sicily and the rest of the Mediterranean originated in Benin, which this study also confirms. But are they saying that the HbS in Sicilians occurs together with the haplotype from Central West Africa (Benin), and this is how this particular study goes about proving the Benin connection?
And when they say this...:
Quote:
[...]the beta S gene found among Sicilians is associated with the same haplotype observed among sickle cell anemia patients from Central West Africa. In addition, this haplotype is either nonexistent or very rare among normal Sicilian individuals.
...do they mean that the Central West Africa haplotype is not or rarely found in Sicilians without HbS (in other words, this is what they mean by "normal Sicilian individuals")?
Indicentally, I discovered new studies that confirm the Greek-Ethiopian relatedness. To me, it seems that since sub-Saharan HLA alleles were found in Greece (and that genetic distances between Ethiopians and Greeks were closest), that is that, and nothing can be said against it, no matter who whines about it. Alleles don't lie. I'll post the studies later, with observations I've made.
I wonder if the fixing of an allele through drift has ever been mistaken for selection?
Sure. Happens all the time. In The History and Geography of Human Genes, Luigi Luca Cavalli-Sforza suggests that northern European depigmentation was merely drift. (His other two alternative explanations involve adaptation.)
William wrote:
Would they know whether it's selection or drift based upon the marker being investigated?
Not by just looking at the marker of interest, but linkage disequilibrium can resolve this.
Oops. Gotta go. Mary Lee and I have to leave for the airport now. I shall continue when I can find a hot spot. In the meantime, read the section titled "The Percentage Rate Has Remained Relatively Steady over the Years" in The Rate of Black-to-White “Passing”. It explains linkage disequilibrium.
Joined: 30 Mar 2005 {Posts: 1082 } Location: New Jersey
Posted: Mon 27 Feb 2006 14:40 Post subject:
Frank wrote:
In the meantime, read the section titled "The Percentage Rate Has Remained Relatively Steady over the Years" in The Rate of Black-to-White “Passing”. It explains linkage disequilibrium.
That is an excellent article. Well, all of your essays are excellent. But this one I must have missed. The information on "Whites" designated as "Black" "passing" through maroon communities is fascinating. Not only were the maroon people themselves "passing," but others were passing through them.
The redesignation of South African Colourdes as Whites (which seems to have happened quite often) didn't require such stealth, apparently.
Okay. I am back. I am in a hotel in Las Vegas with some free time. My point was not that linkage disequilibrium can distinguish between random drift and selection per se. I do not know of any way of distinguishing between them directly. But linkage disequilibrium can tell you whether a mutation is native to a given population (and so most likely drift) or an intrusion from an immigrant population (and so most likely adaptive). It works because the chromosome recombination that takes place during meiosis is very coarse. When an immigrant gene (HbS, say) intrudes into a population, it drags along hundreds of alien genes and tens of thousands of alien intron polymorphisms that got swept along for the ride.
So if you find an "out of place" gene, like the Brit thalassemia, you look at the few thousand nucleotides adjacent to the odd-ball. If they are all normal Brit polymorphisms, then you conclude that the strange one arose locally, and so is most likely drift (since malaria does not seem to have been endemically lethal enough to sift a British population). But if you find that the adjacent several thousand polymorphisms are from India or the Arabian Gulf, then you conclude that the alien gene was a immigrant (and so most likely adaptive).
Joined: 30 Mar 2005 {Posts: 1082 } Location: New Jersey
Posted: Thu 02 Mar 2006 15:43 Post subject:
I see, thank you. So, regarding the Sicily study in this thread, the HbS exists in Sicily in unison with other intron polymorphisms that are specific to Central West Africa (Benin), and this is how this particular study establishes the Benin origin of the HbS in Sicily.
We'll discuss this further when we both have time. You're in Las Vegas, and I'll soon be snowed in if I don't leave work, so I better do just that!
'
FAQ
Search
Register
Log in
