April 14, 2013

'Neanderthal' allele that is probably not Neanderthal in modern humans

This is a generally well finished study on an allele shared by (some) modern humans, Neanderthals and "Denisovans" but which the authors properly gouge to be probably not Neanderthal in origin among us.

Omer Gockumen et al., Balancing Selection on a Regulatory Region Exhibiting Ancient Variation That Predates Human–Neandertal Divergence. PLoS Genetics 2013. Open accessLINK [doi:10.1371/journal.pgen.1003404]


Ancient population structure shaping contemporary genetic variation has been recently appreciated and has important implications regarding our understanding of the structure of modern human genomes. We identified a ~36-kb DNA segment in the human genome that displays an ancient substructure. The variation at this locus exists primarily as two highly divergent haplogroups. One of these haplogroups (the NE1 haplogroup) aligns with the Neandertal haplotype and contains a 4.6-kb deletion polymorphism in perfect linkage disequilibrium with 12 single nucleotide polymorphisms (SNPs) across diverse populations. The other haplogroup, which does not contain the 4.6-kb deletion, aligns with the chimpanzee haplotype and is likely ancestral. Africans have higher overall pairwise differences with the Neandertal haplotype than Eurasians do for this NE1 locus (p<10−15). Moreover, the nucleotide diversity at this locus is higher in Eurasians than in Africans. These results mimic signatures of recent Neandertal admixture contributing to this locus. However, an in-depth assessment of the variation in this region across multiple populations reveals that African NE1 haplotypes, albeit rare, harbor more sequence variation than NE1 haplotypes found in Europeans, indicating an ancient African origin of this haplogroup and refuting recent Neandertal admixture. Population genetic analyses of the SNPs within each of these haplogroups, along with genome-wide comparisons revealed significant FST (p = 0.00003) and positive Tajima's D (p = 0.00285) statistics, pointing to non-neutral evolution of this locus. The NE1 locus harbors no protein-coding genes, but contains transcribed sequences as well as sequences with putative regulatory function based on bioinformatic predictions and in vitro experiments. We postulate that the variation observed at this locus predates Human–Neandertal divergence and is evolving under balancing selection, especially among European populations.

The paper discusses an allele (NE1) of APOBEC3G, a gene arguably related to anti-viral immunity, which is found primarily in its derived variant among non-Africans (especially South Asians, Europeans and Native Americans). In similar cases other similar studies have claimed that it should be a Neanderthal introgression, ignoring the presence of the relevant allele at low frequencies in Africa. The authors of this study do not commit this error but finding it at low frequencies not just among the Maasai and the Luhya but also among Pygmies, they consider that there is a high likelihood of the allele found among Eurasians and Native Americans to have originated among Homo sapiens in Africa and then maybe favored by natural selection or other mechanisms outside the ancestral continent. 

Figure 3. Ancient African origins of the NE1 haplogroup.
(A) Models of scenarios that could lead to NE1 haplotypes observed in humans and Neandertals. The frequency of the NE1 haplogroup is depicted in red and the frequency of the nonNE1 haplogroup in yellow. The red corresponds to higher frequencies, whereas yellow corresponds to lower frequencies of the NE1 haplotypes in the population. The arrows represent the direction of possible admixture events. The left panel represents a model, under which the NE1 haplotypes admixed into Eurasian populations (Asn and Eur) after Human-Neandertal divergence. The second model, which is depicted in the central panel, is similar to the first model, except with the addition of more recent back migration of Eurasian NE1 haplotypes into Africa (Afr). The right panel shows the third model, under which the NE1 haplotypes among humans are explained by persistence of ancient African substructure. All these scenarios were based on the assumption that the NE1 haplotype occurs at high frequency or is fixed in the Neandertal population given that the available Neandertal sequences align well to the NE1 haplotype. (B) Geographical distribution of the NE1 haplogroup. We estimated the proportion of chromosomes that carry the CNVR8163.1 deletion from various sources described in Materials and Methods. The dark red portion of each circle represents the frequency of the homozygous nonNE1 genotypes, the white represents the homozygous NE1 genotypes and the light red represents the frequency of heterozygote genotypes. Note the existence of the NE1 haplotypes (i.e., as heterozygotes, light red) among sub-Saharan African populations (e.g., LWK and ASW) as well as the high frequency of heterozygotes (light red) in the European populations. (C) The pairwise distances between the African (Afr) NE1 haplotypes, the Asian (Asn) NE1 haplotypes, and the European (Eur) NE1 haplotypes, calculated using phase 1 data from the 1000 Genomes Project. p-values were calculated by the Mann-Whitney test.
Figure 4. Selection acting on the NE1 locus.
(A) Maximum likelihood tree based on select NE1 (red) and nonNE1 (blue) haplotypes, with the chimpanzee haplotype as an outgroup. The gray-box indicates the estimated interval for the Human-Neandertal divergence between 400,000–800,000 years ago [51]. Note that the coalescence at this locus is extremely long and very unlikely to have evolved under neutral conditions as modeled here. (B) Comparison of FST and Tajima's D values of 10 kb intervals across the human genome. The red to dark blue gradient indicates decreased density of observed events at a given location in the graph. The NE1 locus, and other loci with similar profiles, are highlighted in white.

While the Neanderthal-Sapiens divergence estimate they use (fig. 4A) is clearly more recent than I would gladly accept (I'm more into 1.3-0.9 Ma BP, based on archaeological and paleoanthropological data), it does not seem to matter for the conclusions, as they estimate that the two main haplotypes in chromosome 22 related to this allele diverged much earlier, at the beginnings of the history of the genus Homo. 

Chimpanzees by the way have the non-NE1 allele, which is therefore considered ancestral.

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