More on R1*-M173 bearers

Earlier here, the issue of R1*-M173 ancestry was examined by way of distribution patterns, and other areas of the genome outside of the Y chromosome, like in say an allele on the X chromosome [See R1*-M173 bearing chromosomes in Cameroon (clickable) - for review]. Well, now we will look at another correlation made between Y haplotype and lactose tolerance [which will be revisited here in the future] promoting alleles; to this end, we examine Mulcare et al.'s 2004 study, The T Allele of a Single-Nucleotide Polymorphism 13.9 kb Upstream of the Lactase Gene (LCT) (C−13.9kbT) Does Not Predict or Cause the Lactase-Persistence Phenotype in Africans:

The authors write...

We typed this polymorphism in 1,671 individuals from 20 distinct cultural groups in seven African countries. It was possible to match seven of the groups tested with groups from the literature for whom phenotypic information is available. In five of these groups, the published frequencies of lactase persistence are 25%. We found the T allele to be so rare that it cannot explain the frequency of the lactase-persistence phenotype throughout Africa.

They go onto say...

By use of a statistical procedure to take phenotyping and sampling errors into account, the T-allele frequency was shown to be significantly different from that predicted in five of the African groups. Only the Fulbe and Hausa from Cameroon possessed the T allele at a level consistent with phenotypic observations (as well as an Irish sample used for comparison). We conclude that the C−13.9kbT polymorphism is not a predictor of lactase persistence in sub-Saharan Africans.

This is the point of examination, wherein the authors find that C−13.9kbT polymorphism cannot be a predictor of lactose tolerance in sub-Saharan Africans, though the few exceptions wherein it seems to be predictor, appears to be amongst Fulbe and Housa groups of Cameroon; rather, alleles different from European [ where the −13.9kb*T marker appears to be the main predictor of lactose tolerance] variants seem to play the role of promoting lactase persistence. In any case, the seemingly anomalous presence of C−13.9kbT allele in Cameroonian groups, and given that they say that the European C−13.9kbT alleles seem to be common on the A haplotype of the LCT region [other haplotypes are B, C and U]—in particular, the extended A haplotype which seems to be most common in northern Europeans —while it isn't as common on many other A haplotype chromosomes, not to mention the "high expression of mRNA bearing the LCT transcription unit" encoded by LCT genes on non-A haplotype chromosomes also bearing single nucleotide polymorphism characterizing a C—>T transition at −13.9kb — thereby "suggesting that there may be heterogeneity of the cause of lactase persistence in Europe (Poulter et al.)", may have likely compelled the authors to make this reckoning:

It seems probable that the C-to-T transition at −13.9 kb occurred in a non–sub-Saharan African population that contributed to the current population of Europe. If this were the case, then its presence in Cameroon, and especially in people of Fulbe cultural identity or with Fulfulde-speaking ancestry, could be explained by introgression from outside sub-Saharan Africa.

Hence, the authors look to Y DNA for any possible clues to the possible "non-sub-Saharan African" source, wherein they typed in nucleotide sequences corresponding to haplogroup R. This is what they found in doing so:

The 92R7-derived haplogroup was extremely rare in the sub-Saharan African populations sampled. Most 92R7-derived chromosomes were found in Cameroon, with 8/42 in the Fulbe, 1/110 in Mambila, 1/65 Kwanja, and 5/113 “others.” Outside Cameroon, we found five 92R7-derived chromosomes in northern Sudan (3/11 Shaigi, 2/29 Ga’ali) and one in southern Sudan (1/72 “others”). The microsatellite haplotype diversity of 92R7-derived chromosomes in Cameroon was high, with 10 haplotypes observed among 15 individuals (h = 0.933, SE = 0.0449, average repeat size variance = 0.224).

And they point out that their finding is consistent with R1*-M173 chromosomes findings by Cruciani et al. in their 2002 study:

Our Y-chromosome data corroborate the results of Cruciani and colleagues (2002) in finding high frequencies in our Cameroonian samples of a haplogroup that is generally absent from sub-Saharan Africa. Phylogeographic arguments suggest that this haplogroup (R1*, by use of the nomenclature of the Y-Chromosome Consortium [2002]) has a non-African origin. Cruciani and colleagues (2002) found R1* Y chromosomes at an average frequency of 40% in several northern Cameroonian groups, including one Fulbe group.

With this in mind, they go onto point out that:

We found evidence for the same haplotype (typed by use of a marker that appears phylogenetically identical in this part of Africa) in our samples from central Cameroon, with a particularly high frequency (19%) in the Fulbe group that was tested.

It doesn't take much imagination to notice that the authors seemed rather eager to examine the Y DNA marker from only one of two possibilities—that is "non–sub-Saharan African population's contribution" [the alternative of course, being "African"], a role which they apparently assumed would be desirably played by the R1*-M173 chromosomes, but what the authors appear to brush aside, as noted before, is the virtual rarity of these undifferentiated R1* chromosomes outside of Africa, with the only other region with noticeable frequencies being in the Dead Sea region of Jordan; fairly low frequencies were found in an Omani sample, which is not surprising, considering that their Nile Valley neighbor [Egypt] have these undifferentiated R1*-M173 chromosomes. As a previous posting [link posted above] on this issue examined, R1*-M173 in the Dead Sea could very well likely represent African ancestry, given the geographical clines observed in its distribution therein, along with other markers indicative of African ancestry. On the other hand, the authors are apparently aware that Europe is not the source of these chromosomes, which prompts them to reckon in this manner: It seems probable that the C-to-T transition at −13.9 kb occurred in a non–sub-Saharan African population that contributed to the current population of Europe.

*Being aware of the prospect that Europe could well not be the source of the Y DNA, the authors applied the wording "non–sub-Saharan" source, rather than otherwise just assume that it was a "European source".

For a moment there, it would appear that the authors saw a correlation between R1*-M173 bearers and the prevalence of the −13.9kb*T allele. However, they run into this:

However, haplogroup R1* is also found at high frequencies in several non-Fulbe groups in the Extreme North Province of Cameroon, where the −13.9kb*T allele is found at low frequencies

And they write:

Thus, the demographic processes leading to the presence of the −13.9kb*T allele in Cameroon may not be the same as those leading to the Y-chromosome introgression but could instead relate more specifically to Fulbe migration history

The authors are right when they reckon that demographic processes, which were likely responsible for the relative prevalence of the lactose promoting allele in one segment of African R1*-M173 bearers and its absence or rarity in another segment, were distinct. However, this finding compelled the authors to re-examine the pattern of the highest prevalence of the −13.9kb*T allele in the Fulbe samples vs. its low prevalence in other high-frequency bearing R1*-M173 Cameroonians, and reconsider the role of Y DNA in explaining the presence of the C-T 13.9kb allele in the said few African groups in which it was identified.

Because of this preconceived eagerness to only explore a possible non-African ultimate source of R1*-M173 chromosomes, which as their own wording makes clear—is still tenuous and debatable, they overlooked the possibility that the mutation had originally occurred in R1*-M173 bearing Africans who were probably a highly mobile bunch, as one with think in terms of nomads, before finally settling in certain locales. Given this, the relatively low prevalence of the −13.9kb*T allele in other groups—which share high frequencies of R1*-M173 with the authors' Fulani sample—versus that of said Fulani sample, could well be explained by the possibility that the African R1*-M173 bearers with none to low −13.9kb*T are remnants of the ancestral R1*-M173 population, wherein the mutation associated with the −13.9kb*T allele had not yet occurred! Hence, if only a segment of this population—wherein the new mutation occurred and started off at low frequencies—were to migrate elsewhere and then expand, the chance of the −13.9kb*T allele (or precursor allele) bearing members rising within the population thereof, would be greater. Alternatively, if the non-Fulbe Hg R-bearing bunch in the extreme North Province of Cameroon had subsequently lost the allele type upon situating themselves due to lack of lactose-rich diet, along with gene flow from groups with weak lactose-tolerance, and assuming that said locus was/is under some other form of natural selection in the latter or other genetic contributors as well, then it is conceivable that through the act of genetic drift that allele numbers went considerably down. This latter scenario would have to be envisioned in a time frame postdating the earliest signs of cattle domestication. Remember, these are considerations only if one were examining an unequivocal or a strong correlation between the presence of Hg R bearing Y-chromosomes and the C-T 13.9kb allele.

It seems that the explanation the authors thought was most plausible to them, was to build a storyline around Fulani/Fulbe migration, as the agent for spreading the relatively limited frequencies −13.9kb*T alleles that they were able to come across in their overall African sample:

Thus, the demographic processes leading to the presence of the −13.9kb*T allele in Cameroon may not be the same as those leading to the Y-chromosome introgression but could instead relate more specifically to Fulbe migration history. Further studies on the distribution of the −13.9kb*T allele and of other genetic markers in this part of Africa are required to resolve this question.

Apparently, the authors are well aware of the fairly tenuous nature of their hypothesis, hence thereby acknowledging the need for further DNA studies to "resolve this issue". The fact that they aren't too confident about specific Fulani geographic-origins either, plays no small role in giving their theory its tenuous character...

The origins of the Fulbe are the subject of debate, but the group is thought to be from outside Cameroon; on the basis of ethnic traditions and linguistic similarities between Fulbe languages and Tukulor (Toucouleur), an origin in the Futa Toro region of the Senegal river basin has been proposed (Newman 1995).

Why Fulani origins would be a subject of debate, is beyond the present author of this blog. Both their oral traditions and primary gene pool is consistent with west African origin, as any other west African group.

There are two possible ways of looking at the origin of the situation, if one is to correlate it to the shared R1*-M173 Y DNA marker between the two African camps: a) “Convergent evolution” amongst geographically distant R1 bearing populations which had adopted a pastoral lifestyle and became lactose digesters, or b) a UEP in one geographical locale, which would imply genetic introgression ultimately from the source population to a recipient population, in which case, any correlation to the shared Y DNA R1*-M173 marker between the two tested camps, could well weaken; and if this mutation didn’t necessarily occur in some R1* bearing population, then the question arises: could it be better correlated to another marker(s)?!

And now, delving into an area with some degree of speculation...

This lactose tolerance promoting allele would not have been prominent in the original R1*-M173 bearers in their early geographical spheres of influence, even in the "Near East", through which they would have had to ultimately enter Europe. The beginning of their [R1*-M173 bearers] most outstanding expansions likely came along in or around Asian Minor, wherein those that then headed to the west would expand to give rise to R1b bearers, and those that proceeded to eastern Europe-central Asia, would eventually—at a latter time than the expansion in western Europe—give rise to R1a bearers. By this time, the −13.9kb*T allele would still not have gained any prominence, presuming that it is strongly linked to lactose tolerance promotion, as no cattle domestication had yet occurred. However, not only after cattle domestication and dairy farming, but also as a result of the persistence thereof in applying milk as a significant source of nutrition, the mutation in western Europe underwent a selective sweep that would make the type very frequent in north Europe, particularly around the Funnel Beaker region. If one were to assume that the C−13.9kbT allele occurred in R1 bearing populations, and that Europe could not have been the source of the allele in the few Africans wherein the above mentioned authors had found it, then it [the C−T 13.9kb allele] would have to have been the product of convergent evolution in geographically distant pastoral populations which descend from the same MRCA. However, if one were to absolutely rule out convergent evolution, and given that ancestral R1*-M173 chromosomes in Africa are virtually absent in Europe, then one would have to come to the conclusion that the above author's had come to—in that, the emergence of −13.9kb*T allele doesn't correlate with R1* ancestry:

Thus, the demographic processes leading to the presence of the −13.9kb*T allele in Cameroon may not be the same as those leading to the Y-chromosome introgression but could instead relate more specifically to Fulbe migration history. Further studies on the distribution of the −13.9kb*T allele and of other genetic markers in this part of Africa are required to resolve this question.

If there was only one source of the distribution of the −13.9kb*T allele found in the African samples as a product of UEP, and this happened to be of north European origin, then some other ancestry, aside from R1*-M173 of the said African groups has to be accounted for, to explain the occurrence in said African populations; if so, could this be learned from mtDNA? It certainly won't hurt to examine the prospect, given the said conditional premise. In any examination to learn whether or not the C−T 13.9kb allele—as the precise examples found in the few African samples, and in any correlation with R1*ancestry—could have been a product of convergent evolution, it would also serve to test the few R1*-M173 bearers of the Dead Sea region, and other haplogroup R1 (xR1b) bearing lactose digesters for that matter [it wouldn't be unreasonable to include even R1 (xR1b) bearing groups which are not known to have lactose-rich diet in the screening process, which one would assume, should have already been done to some degree or another at this point], to see if said −13.9kb*T allele is prevalent. What is clear from all this, is that the C−13.9kbT sequence is low to rare in the African landscape, and hence, all these guessing games on the provenance of the source of the few C−13.9kbT polymorphisms that have been found in African samples. Furthermore, the tenuous character of this whole affair about −13.9kb*T transition model being an unequivocal causal agent and/or one presumably of UEP or yet, a monophyletic lineage, is related by observations like these:

— contrasting observations, and deviations from expected results...

In a series of 48 London patients of various ancestry, from whom intestinal biopsies were obtained, the correlations of lactase activity and sucrase/lactase ratio with −13.9kb*CT and −13.9kb*TT genotype were not as tight as might have been expected for a cis-acting causal change. In contrast to this, in a recent Finnish study, the 13.9kb*CT heterozygotes did have activity intermediate between the 13.9kb*CC and 13.9kb*TT homozygotes (Kuokkanen et al. 2003).

— and to repeat: divergent monophyletic LCT-gene markers...

In a few rare individuals, high expression of the mRNA transcript, encoded by the LCT allele of a non-A haplotype chromosome, has been observed (Poulter et al. 2003). In particular, a single individual in a United Kingdom cohort was interpreted as being heterozygous for the A and B haplotypes, as well as for C−13.9kbT, and showed high expression of lactase from both transcripts, suggesting that there may be heterogeneity of the cause of lactase persistence in Europe (Poulter et al. 2003).

— multiple LP allele loci indicators...

A comparison of the occurrence of this allele, as well as alleles at other recently described loci that subdivide the A haplotype (such as G−22kbA, [Enattah et al. 2002]), suggests that−13.9kb*T is the most recent (Poulter et al. 2003).

...possibly summed up by...

It is possible that the C−13.9kbT transition occurred more recently than another (as yet unknown) mutation that is the true causal change both in Africa and Europe. Recent transfection studies do, however, suggest a functional role for C−13.9kbT (Olds and Sibley2003; Troelsen et al. 2003).

Yes, the T allele, as the transitions are so-called, may well have some "functional" role in the LCT gene that needs to be established, but apparently not as a predictor of lactase-persistence in Africa [including its R1* bearing groups, wherein some communities lacked the T allele, while others had it], which if we recall, is something that the authors themselves were observant about.

*Last modified on 2/27/2010.
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References*

—As already cited.

Other reading:

R1*-M173 Chromosomes in Africa 

R1*-M173 Chromosomes in Africa - II

Mitochondrial DNA M1 haplogroup: A Response To Ana M. Gonzalez et al. 2007

Lactose Tolerance Phenotypes in Africa