Altitude-adaption in Tibetans is "Denisovan-like"

It seems that archaic humans left a small but critical legacy among us:

Emilia Huerta Sánchez et al., Altitude adaptation in Tibetans caused by introgression of Denisovan-like DNA. Nature 2014. Pay per view → LINK [doi:10.1038/nature13408] 

Abstract

As modern humans migrated out of Africa, they encountered many new environmental conditions, including greater temperature extremes, different pathogens and higher altitudes. These diverse environments are likely to have acted as agents of natural selection and to have led to local adaptations. One of the most celebrated examples in humans is the adaptation of Tibetans to the hypoxic environment of the high-altitude Tibetan plateau^{1, 2, 3}. A hypoxia pathway gene, EPAS1, was previously identified as having the most extreme signature of positive selection in Tibetans^{4, 5, 6, 7, 8, 9, 10}, and was shown to be associated with differences in haemoglobin concentration at high altitude. Re-sequencing the region around EPAS1 in 40 Tibetan and 40 Han individuals, we find that this gene has a highly unusual haplotype structure that can only be convincingly explained by introgression of DNA from Denisovan or Denisovan-related individuals into humans. Scanning a larger set of worldwide populations, we find that the selected haplotype is only found in Denisovans and in Tibetans, and at very low frequency among Han Chinese. Furthermore, the length of the haplotype, and the fact that it is not found in any other populations, makes it unlikely that the haplotype sharing between Tibetans and Denisovans was caused by incomplete ancestral lineage sorting rather than introgression. Our findings illustrate that admixture with other hominin species has provided genetic variation that helped humans to adapt to new environments.

Figure 3: A haplotype network based on the number of pairwise differences between the 40 most common haplotypes.
The haplotypes were defined from all the SNPs present in the combined 1000 Genomes and Tibetan samples: 515 SNPs in total within the 32.7-kb EPAS1 region. The Denisovan haplotypes were added to the set of the common haplotypes. The R software package pegas²³ was used to generate the figure, using pairwise differences as distances. Each pie chart represents one unique haplotype, labelled with Roman numerals, and the radius of the pie chart is proportional to the log₂(number of chromosomes with that haplotype) plus a minimum size so that it is easier to see the Denisovan haplotype. The sections in the pie provide the breakdown of the haplotype representation amongst populations. The width of the edges is proportional to the number of pairwise differences between the joined haplotypes; the thinnest edge represents a difference of one mutation. The legend shows all the possible haplotypes among these populations. The numbers (1, 9, 35 and 40) next to an edge (the line connecting two haplotypes) in the bottom right are the number of pairwise differences between the corresponding haplotypes. We added an edge afterwards between the Tibetan haplotype XXXIII and its closest non-Denisovan haplotype (XXI) to indicate its divergence from the other modern human groups. Extended Data Fig. 5a contains all the pairwise differences between the haplotypes presented in this figure. ASW, African Americans from the south western United States; CEU, Utah residents with northern and western European ancestry; GBR, British; FIN, Finnish; JPT, Japanese; LWK, Luhya; CHS, southern Han Chinese; CHB, Han Chinese from Beijing; MXL, Mexican; PUR, Puerto Rican; CLM, Colombian; TSI, Toscani; YRI, Yoruban. Where there is only one line within a pie chart, this indicates that only one population contains the haplotype.

See also this entry on Neanderthal introgression being subject to positive and negative selection.

Tibetans are most related to Yi peoples

A new paper on Tibetan autosomal genetics holds some information relevant not just for Tibetans but for other East Asian and in general human peoples:

Binbin Wang et al., On the Origin of Tibetans and Their Genetic Basis in Adapting High-Altitude Environments. PLoS ONE 2011. Open access.

The generic place of Tibetans within Humankind

This is maybe the information of most generic interest, as it requires to map not just Tibetans and neighbors but also peoples from all over the world, notably Eurasia.

For this, figure 1 holds nearly all the relevant information. Some sub-graphs follow:

Above, the global Frappe structure results (A) place Tibetans clearly within East Asian populations (green) but show a distinctiveness of their own since K=6 (purple). In spite of sharing Y-DNA macro-haplogroup D with Japanese, Tibetans show no particular affinity with these (JPT).

In the East Asian specific results (B), at K=6, Tibetans again appear on their own, as do the other ethnic groups, except the Yi and Mongolians, who are subsumed within their neighbors to a great extent.

In the neighbor-joining phylogenetic tree (above), we can see that Tibetans again fall fully within the East Asian group (right fan). This structure is more interesting at this point for the global context anyhow because it can explain, for example, why in some cases West Eurasians and Africans may cluster together versus East Asians, depending on sampling conditions and probably the presence or absence of Indians (only some Pakistanis represent South Asia in this graph, as in so many others) as well as the numbers of sampled African (typically low because they are used as control only). If you draw a median line in this NJ tree, East Asians, in spite of their tight affinity with each other, fall to one half and West Eurasians and Africans fall to the other together.

Whatever this means, we can easily see that East Asians share an ancestral founder effect (including also Melanesians per previous research). However I must warn that this is more genuinely apparent in the HUGO consortium paper than here, because of the lack of Indian samples in this case. See here, here and here, for my own old entries in this matter (it is particularly clear in this graph).

By comparison only very homogeneous groups share such marked apparent founder effects, for example Europeans, West Africans, Pygmies, some (but not other) Indians. All these in the HUGO paper, in this paper instead, we can see again Europeans (but only represented by CEU, what is less meaningful), most Mozabites, most Bedouins, the other Levant populations (Palestinians, Druze and some Bedouins) and, very markedly, the Kalash.

However in the haploid genetic aspect East Asians do not seem so extremely "bottlenecked" as they do appear with autosomal genetics, not at all. In fact they host huge diversity within Eurasian haploid genetics. This is hard to explain, admittedly, but it clearly sends an alert signal for us to be extremely cautious and try to comprehend what really happened in this part of the World.

Tibetans are most closely related to the Yi

The term Yi (Nuoso in one of their languages, Lolo in Vietnam and Thailand) is a catchall term from Chinese ethnography to refer to an array of Tibeto-Burman-speaking peoples from Yunnan and nearby areas.

The close affinity between Tibetans and Yi in the context of East Asian populations is apparent when we apply the microscope, so to say, to the NJ tree (pictured above), as I did here:

It is easy to appreciate that, excluding the Mongol-Daur-Yakut loose group (suspect of minor West Eurasian admixture), the narrow East Asian founder effect split soon in three groups (of those shown here): Tibetans+Yi, the main group (Chinese, Cambodian and Lahu) and the Japanese - each of which diversified rapidly from those specific roots. 

However this result is not coincident with the HUGO consortium tree (different method: maximum likelihood), where Cambodians fall in a SE Asian specific group and Chinese in a distinct SEA/EA/America shared one. So, as always, be careful before rushing to conclusions based only on one paper's data.

High altitude genes have been selected among Tibetans

Here we have another of those rare cases of selective sweeps in humans: adaption to high altitude among Tibetans. Two genes have been found to produce this striking adaption to hypoxia and confirmed in this paper: EGLN1 and EPAS1. The authors suspect that other genes, notably ANGPT1, ECE1, and LEPR, are probably also involved in this adaption to such a demanding ecology.