Age and origin of 17q21 inversion in humans

Gene Expression has a comprehensive post on this inversion whose age had been estimated as 3-million years old, but was downgraded by a couple of orders of magnitude by the current study.

The polymorphism is found at its highest frequency in Southern Europe and Southwest Asia, but Razib argues in favor of its ultimately African origin because of its existence at a low frequency in the "isolated" Mbuti:

If H2 arose in the Middle East its presence in Africa could be explained by back-migration. I immediately was skeptical of this model because H2 is extant at frequencies of 5% among the Mbuti Pygmies. The Mbuti are relatively isolated genetically from the Bantu farmers who have come to dominate their region. If there was any group which represented the ancient genetic variation of Central Africa, it is likely the Mbuti.

While the Mbuti are indeed fairly isolated, it is not right to think of them as a relic of African genetic variation. The distinction is crucial: while the Mbuti contain a large component of "ancient" (pre-farming) African genetic diversity, they are by no means pure, as can be seen by last year's comprehensive study on African variation.

In other words: the Mbuti are a good population to find ancient African variation in; but, they also have admixture with more recent populations, which may have served as a conduit for the introduction of extraneous genetic elements such as the inversion in question.

Getting back to the paper itself, the moral is clear: be doubtful of genetic age estimates for extremely old events (by which I mean anything predating the Neolithic).

This includes the age estimate in this study which is based on microsatellites. The long-term behavior of these markers is based pretty much on conjecture, as we normally have the ability to observe them only across a few (human) generations.

So, I'm not taking as granted the accuracy of the current paper's age estimate. Nonetheless, the study of the distribution of the inversion is quite useful. Its origin is probably in West Asia, a region which would explain its presence in both Europe and Africa.

AJHG doi:10.1016/j.ajhg.2010.01.007

The Distribution and Most Recent Common Ancestor of the 17q21 Inversion in Humans

Michael P. Donnelly et al.

Abstract

The polymorphic inversion on 17q21, sometimes called the microtubular associated protein tau (MAPT) inversion, is an ∼900 kb inversion found primarily in Europeans and Southwest Asians. We have identified 21 SNPs that act as markers of the inverted, i.e., H2, haplotype. The inversion is found at the highest frequencies in Southwest Asia and Southern Europe (frequencies of ∼30%); elsewhere in Europe, frequencies vary from less than 5%, in Finns, to 28%, in Orcadians. The H2 inversion haplotype also occurs at low frequencies in Africa, Central Asia, East Asia, and the Americas, though the East Asian and Amerindian alleles may be due to recent gene flow from Europe. Molecular evolution analyses indicate that the H2 haplotype originally arose in Africa or Southwest Asia. Though the H2 inversion has many fixed differences across the ∼900 kb, short tandem repeat polymorphism data indicate a very recent date for the most recent common ancestor, with dates ranging from 13,600 to 108,400 years, depending on assumptions and estimation methods. This estimate range is much more recent than the 3 million year age estimated by Stefansson et al. in 2005.

Link

3-million year old polymorphism in Europeans

A new study in Nature Genetics by a group of Icelandic scientists has found a 900kbp inversion whose origin appears to be 3 million years before present, i.e., during the time that Homo erectus existed on earth, or even before that time. The mutation is found in Caucasoids (~20%) almost absent in Mongoloids, and rare in Negroids. The authors also discovered that the presence of the mutation has an effect on women having more children and higher recombination rates [the two have been found to be related].

The presence of such an ancient mutation is still a mystery, but two alternative explanations are proposed. The first one is that the polymorphism has been maintained in the human gene pool through balancing selection, which would indicate that its fitness benefits in heterozygotes might have corresponding fitness costs in homozygotes, which remain to be discovered. Since the polymorphism is more frequent in Europeans, it may be the case that there is something in the European environment which allows the fitness benefit to manifest itself, similar to the malarial environments in many places of the world which allow sickle-cell alleles to persist.

The second explanation -which is more likely in my opinion- is that ancestral Caucasoids underwent admixture with a different type of hominin which survived in Western Eurasia and which partially interbred with incoming modern sapiens humans. The mutation subsequently may have spread in the Caucasoid population by balancing selection (since it has not been fixed), and its absence in other populations may indicate simply that they did not interbreed with the different type of hominin.

As far as we know, during the radiation of anatomically modern Homo sapiens, the only candidate species for hybridization with it would be Homo neandertalensis. It's possible then that this was the source of the mutation in question, but since Neanderthals are also a relatively young species (less than 1 million years old) it may be the case that they also received it from a previous hominin species.

After the contested Flores hominin and the recent discovery of possible hybridization of Mongoloids with Homo erectus, this new study presents a new mystery about the origin of modern humans. It remains to be seen how these developments will eventually affect the current picture about human origins which insists on a recent African origin for our species. mtDNA research on humans and Neanderthals suggests no significant hybridization between the two species, and the arguments of the multiregionalists have been severely criticized, but I suspect that in the end the Out-of-Africa theory will have to accommodate the presence of (at least limited) admixture from older forms of Homo in the origins of modern humankind.

For more info Genes Promoting Fertility Are Found in Europeans, Scientists Find Effect of Natural Selection on Human Genome, Gene Arrangement Makes Some Europeans More Fertile.

Nature Genetics (published online)

A common inversion under selection in Europeans

Hreinn Stefansson et al.

A refined physical map of chromosome 17q21.31 uncovered a 900-kb inversion polymorphism. Chromosomes with the inverted segment in different orientations represent two distinct lineages, H1 and H2, that have diverged for as much as 3 million years and show no evidence of having recombined. The H2 lineage is rare in Africans, almost absent in East Asians but found at a frequency of 20% in Europeans, in whom the haplotype structure is indicative of a history of positive selection. Here we show that the H2 lineage is undergoing positive selection in the Icelandic population, such that carrier females have more children and have higher recombination rates than noncarriers.

Link