April 12, 2013

Haplotype that looks Neandertal-introgressed may reflect African population structure (Gokcumen et al. 2013)

From the paper:
Several scenarios can be envisioned to explain the unusual genetic variation observed at the NE1 locus: (1) recent Neandertal admixture exclusively with Eurasian populations, (2) back migration to Africa from Eurasia after Neandertal admixture with Eurasian populations, and (3) ancient African substructure maintained since before Human-Neandertal divergence (Figure 3A). 
...
The presence of African NE1 haplotypes does not support the first scenario of exclusive Neandertal admixture with Eurasian populations. Recent reports have suggested that Neandertals and Denisovans contributed their genetic material to present-day Eurasian populations and Melanesians, respectively [20], [21]. However, the variation that we observe at the NE1 locus is not consistent with direct archaic hominin admixture as discussed in these publications. We did not consider Neandertal admixture into ancient African populations because of paleoanthropological studies that only report interactions between Neandertals and modern humans outside of Africa [37].
Thinking about the last sentence, paleoanthropological studies only report interactions between Neandertals and modern humans in "parts of outside Africa", but the signal of Neandertal admixture exists all over "outside Africa". It is not incoceivable that Neandertal-admixed Eurasians back-migrated into Africa and introduced NE1 to African populations. Such hypothetical back-migrants would not appear Neandertaloid in tha paleoanthropological sense. The authors consider this possibility:
The second scenario assumes back migration into Africa from Eurasian populations after the admixture of Neandertal with Eurasian populations [38]. If such admixture occurred, the African NE1 haplotypes should represent a subset of Eurasian NE1 haplotypes. To test this, we again analyzed the phase 1 data of the 1000 Genomes Project, which includes 338 haplotypes from three African populations. Using this dataset, we found that variation within African NE1 haplotypes is significantly higher than variation within Asian and European NE1 haplotypes (p less than 10-15, Figure 3C, Figure S5). This result indicates that African NE1 haplotypes have a longer coalescence and, as such, the presence of the NE1 haplogroup among modern Africans cannot be explained by simple back migration and admixture of Eurasian haplotypes to African populations.
But, it is possible that the higher variation within African NE1 haplotypes may reflect introgression of short "Palaeoafrican" variants within the African NE1 haplotypes. Such variants would appear as excess variation, but would not be "provable" as introgression in the absence of a comparative archaic African genome. This is a recurring theme, that (part of?) the African-Eurasian diversity differential can be explained both in terms of loss of diversity in an Out-of-Africa bottleneck and a gain-of-diversity in In-Africa admixture events between divergent populations that must have lived in the large and ecologically diverse continent. Which brings us to scenario #3:

The third scenario represents the persistence of an old African substructure at the NE1 locus before the Human-Neandertal divergence (Figure 3A). This scenario explains the presence of NE1 haplotypes (that are similar to the Neandertal haplotype) among modern human populations as well as the deep, distinct lineages observed among African NE1 haplotypes. To corroborate this conclusion, we estimated the coalescence of NE1 haplotypes through network analysis (Figure S6) and found a coalescence time of between ~437 K and ~993 K years before present (YBP) for African NE1 haplotypes and ~134 K YBP and ~304 K YBP for European NE1 haplotypes. These observations collectively suggest that the most parsimonious explanation for the observed variation at the NE1 locus is that the NE1/nonNE1 haplogroups arose after the human-chimpanzee common ancestor, but before the Human-Neandertal split in Africa. As such, the variation at the NE1 locus has persisted within ancient African substructure and later spread to non-African populations.



  PLoS Genet 9(4): e1003404. doi:10.1371/journal.pgen.1003404

Balancing Selection on a Regulatory Region Exhibiting Ancient Variation That Predates Human–Neandertal Divergence

Omer Gokcumen et al.

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 less than 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.

Link

12 comments:

facb52 said...

See PLOS One

North African Populations Carry the Signature of
Admixture with Neandertals
Federico Sa´nchez-Quinto1., Laura R. Botigue´ 1., Sergi Civit3, Conxita Arenas3, Marı´a C. A´ vila-Arcos4,
Carlos D. Bustamante2, David Comas1", Carles Lalueza-Fox1"*

PLOS ONE | www.plosone.org 1 October 2012 | Volume 7 | Issue 10 | e47765

MOCKBA said...

If I get Fig. 4 right, all Yoruba have ancestral haplogroup, and all Luhya, NE1; and the Luhya haplotypes form a very distinct clade, apart from Eurasian NE1. So it really doesn't look like backmigration even though it's East African. But a distinct admixture event with a not-yet-identified African Neandertalides may be a possibility?

Annie Mouse said...

There is a big difference between analysing whether or NE1 is a subset of European NE1, and looking at relative diversity. If African NE1 is a subset it came from Europe, no matter how diverse it is.

It is not clear to me whether or not this paper is saying that they actually looked to see if it is a subset, or whether they just looked at relative diversity. It looks like the latter, which would be inconclusive.

If European NE1 WAS a subset of North African NE1, that truly would be interesting.

Lank said...

At first sight, the NE1 haplotype looks very much like it introgressed from Neanderthals. It's very rare in Yoruba (0.27%), has a minor presence in East Africans (2.78% in Luhya and 8.19% in the more Eurasian-admixed Maasai 8.19%). However, it is found at 13% in the Mbuti Pygmy, who show the strongest signs of archaic admixture in a previous study, but was apparently absent in the Biaka Pygmies and other Africans from the HGDP.

Considering how this haplotype was found in both Neanderthals and the Denisovan, who are not that much more closely related to each other than to modern humans, NE1 seems to be extremely old. The high African NE1 coalescence dates support this. So the question is if selection in Eurasians explains the variation between populations at this locus, rather than recent differential archaic admixtures. Some findings in the paper would support such a scenario:

"To understand the genomic composition upstream of the APOBEC3 locus, we first examined the phase I SNP data from the 1000 Genomes Project [30] and identified an unusually strong linkage disequilibrium (LD) block spanning approximately 36 kb (NE1 locus, hg18 - chr22:37,600,063–37,636,026) (Figure 1). This LD block is evident in Eurasian (CEU and CHB/JPT) populations but is absent in the Yoruban (YRI) population (Figure S1). Even though long stretches of LD can be indicative of selection, high LD can also result from a lack of recombination in the absence of selection [31], [32]. "

"Furthermore, we performed a genome-wide investigation to identify regions that show π (>0.002), LD (R2>0.5), Tajima's D (>4.5) and FST (>0.2) similar to that of the NE1 locus (Figure 4B). We identified four other regions in the entire human genome that have a pattern similar to that of the NE1 locus (Table S6). Interestingly, three of these regions either overlap or are adjacent to environment interaction genes, such as the olfactory receptors, the innate immunity gene, OAS1, or the keratin associated proteins involved in hair formation. Indeed, a recent study reported that OAS1 shows signatures of both Neandertal and Denisovan admixture [44], suggesting that loci that cluster with NE1 may have unusual evolutionary histories."

The NE1 locus seems to be have a role in antiviral immunity. So the high frequency and relatively limited variation seen in Eurasians may simply be explained by selection. Neanderthals (and Denisovans) would have gone through similar processes in Eurasia.

This is something that authors need to be wary of when looking at single loci in modern Eurasians that appear to have introgressed from Eurasian archaics. If a particular haplotype is present in Africans, even at a low frequency (and does not appear derived from Eurasian archaics), it remains possible that Out-of-Africans went through selection in their new environment, and that previous Eurasian archaics went through similar but separate evolution processes. Of course, this could be solved simply by examining if Eurasian haplotypes are closely related to Neanderthals or the low frequency variant in Africans.

terryt said...

"we estimated the coalescence of NE1 haplotypes through network analysis (Figure S6) and found a coalescence time of between ~437 K and ~993 K years before present (YBP) for African NE1 haplotypes and ~134 K YBP and ~304 K YBP for European NE1 haplotypes. These observations collectively suggest that the most parsimonious explanation for the observed variation at the NE1 locus is that the NE1/nonNE1 haplogroups arose after the human-chimpanzee common ancestor, but before the Human-Neandertal split in Africa".

What about the possibility that the 'Africans' and 'modern humans' are both descended, at least in part, from a population that split from Neanderthal ancestors 'between ~437 K and ~993 K years before present' and moved INTO Africa from Eurasia? After all there is no obvious reason why we must assume that 'modern humans' descend from a species that had been confined to Africa since Homo habilis times.

Annie Mouse said...

From Figure 2, the "normal" non-NE1 is more closely related to the chimpanze sequence than "neanderthal" NE1. Non- NE1 differs from chimp by 2 SNP whereas NE1 differs by 11 out of 12 SNP. On the face of it the "normal" non-NE1 looks more archaic than neanderthal. I suppose this reasonable if the NE1 source population diverged very early and Out of Africa represents the folk who emerged later from those who remained behind in the main archaic-interbreeding African population.

To me Denisovans and Neanderthals NE1-type sequences look like descendents from NE1, not parents of NE1. They appear to diverge differently away from NE1.

I think we are looking at evidence for an early population of humanoids that left the main african interbreeding group very early and diverged into NE1. This could have been in North Africa, the near East or some other place. A segment of this population moved north and became neanderthals. A segment moved east and became the Denisovans. Then Out-of Africa emerged carrying its more chimp-like sequence (non NE1) and interbred with this parental population of NE1 folk (most probably in the Near East). Some of these folk also interbred with the Denisovans as they moved east. Seems to fit with the other stuff we know.

Possibly increased African diversity in NE1 is because of population flow from close to the source of the parental NE1 population (eg Near East/North Africa)

Kristiina said...

Mbuti Pygmies have mixed with other groups, as have Biaka pygmies, so we do not know if Pygmies originally lacked NE1. Their original y haplogroup seems to be ydna B (various shared and unshared clades), but on maternal side their common origin is not so obvious, as Biaka have L1c, but Mbuti L5 and L2. On paternal side, both share also pan-African E M2 (DYS271), but Mbuti carry also a haplogroup that used to be called E2b (M75/M98/M85/M200) (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC447595/).

So, it is still possible that Mbuti Pygmies got their NE1 from people who had their origin elsewhere in Africa. It is interesting that Wikipedia says that the most basal lineages, paragroup E-M96*, have been found in a single Bantu-speaking male from South Africa, amongst pygmies and Bantus from the Cameroon/Gabon region, and in two individuals from Saudi Arabia. Here we could enter into the debate whether haplogroup E came into contact with Neanderthals in the Middle East or somehow indirectly. If there was contact, interbreeding was not very extensive or was diluted, as the haplogroup E carrying males in Sub-Saharan Africa seem to have the nonNE1 variant.

terryt said...

"but on maternal side their common origin is not so obvious, as Biaka have L1c, but Mbuti L5 and L2".

From information I have accumulated over the years I see I have noted: "western Pygmies; L1c1a, eastern Pygmies L0a2b, L2a2 and L5ac1". I don't know how reliable that information is today. But that fits your comment.

eurologist said...

What about the possibility that the 'Africans' and 'modern humans' are both descended, at least in part, from a population that split from Neanderthal ancestors 'between ~437 K and ~993 K years before present' and moved INTO Africa from Eurasia?

Terry, I agree with you.

The ~437 to ~993 K ybp time frame is exactly when widely apparent parallel evolution happened in Africa, extreme West Asia, and Europe - indicating significant bi-directional gene flow. And the ~134 to ~304 K ybp time frame for European NE1 haplotypes is exactly what you would expect from Neanderthal differentiation versus the more generalized and wide-spread heidelbergensis.

So, NE1 appears to be a European development, from the European portion of ergaster --> heidelbergensis and back-migrating into Africa, while Denisovans did not participate in the specific Neanderthal differentiation.

German Dziebel said...

A different take on what the data presented in the paper is telling us can be found here:
http://anthropogenesis.kinshipstudies.org/2013/04/an-out-of-america-signal-as-seen-through-human-regulatory-genes/

terryt said...

Interesting commentary German. You wrote:

"But despite the higher variation within African NE1 haplotypes, the frequency of those haplotypes are the highest outside of Africa and, especially in America. This means that diversity is no indication of a population’s age. Plain simple".

I think you are wrong there. Diversity would be a direct function of time if there is no selection reducing that diversity. You must take that into consideration for your hypothesis. You also seem to be ignoring the probability that non-NE1 looks to be closer to the ancestral condition. It has fewer mutations from Chimpanzee, and the difference may be a result of mutation within the chimps.

I notice from your map that Americans actually have roughly equal proportions of homozygous non-NE1, homozygous NE1, and heterozygous individuals. Doesn't that indicate a variety of source populations into the region rather than indicating a source itself?

German Dziebel said...

"Diversity would be a direct function of time if there is no selection reducing that diversity."

I assume selection would be the first thing to consider in the case of regulatory genes and, as the authors themselves indicate, we do see some indications that it indeed happened (e.g., levels of LD in different populations).

"I notice from your map that Americans actually have roughly equal proportions of homozygous non-NE1, homozygous NE1, and heterozygous individuals. Doesn't that indicate a variety of source populations into the region rather than indicating a source itself?"

No, I think the maps show that America has homozygous NE1 and heterozygous NE1/non-NE1 at higher frequencies than other regions. Non-NE1 homozygotes are there as well but this is plesiomorphy found on all continents and has no indications of origins. There are too few NE1 homozygotes in Asia to suggest any recent migration to the Americas, and any multiple migration scenario is even harder to imagine.