Archaic human admixture with modern humans
There have been arguments in favor of archaic human admixture with modern humans through interbreeding of modern humans with Neanderthals, Denisovans, and/or possibly other archaic humans over the course of human history. Neanderthal-derived DNA accounts for an estimated 1–4% of the Eurasian genome, but it is significantly absent or uncommon in the genome of most Sub-Saharan African people. In Oceanian and Southeast Asian populations, there is a relative increase of Denisovan-derived DNA. An estimated 4–6% of the Melanesian genome is derived from Denisovans. Recent noncomparative DNA analyses—as no specimens have been discovered—suggest that African populations have a genetic contribution from a now-extinct archaic African hominin population.
Nevertheless, there still are some doubts about the recent admixture events among a number of researchers. Ancient subpopulation structure ancestral to modern humans, Neanderthals, Denisovans, and other possible archaic humans has been proposed as an alternative explanation for the observed genetic similarities.
Through whole-genome sequencing, a 2010 draft sequence of the Neanderthal genome revealed that Neanderthals shared more alleles with Eurasian populations (e.g. French, Han Chinese, and Papua New Guinean) than with Sub-Saharan African populations (e.g. Yoruba and San). According to the study, the observed excess of genetic similarity is best explained by recent gene flow from Neanderthals to modern humans after the migration out of Africa. The proportion of Neanderthal-derived ancestry was estimated to be 1–4% of the Eurasian genome. In 2013, the same team of researchers revised the proportion to an estimated 1.5–2.1%. They also found that the Neanderthal component in non-African modern humans was more related to the Mezmaiskaya Neanderthal (Caucasus) than to the Altai Neanderthal (Siberia) or the Vindija Neanderthals (Croatia). In the modern human population, at least those of East Asians and Europeans, the total introgressed Neanderthal DNA found spans about 20% of the Neanderthal genome.
Although less parsimonious than recent gene flow, the observation may have been due to ancient population sub-structure in Africa, causing incomplete genetic homogenization within modern humans when Neanderthals diverged while early ancestors of Eurasians were still more closely related to Neanderthals than those of Africans to Neanderthals. On the basis of allele frequency spectrum, it was shown that the recent admixture model had the best fit to the results while the ancient population sub-structure model had no fit–demonstrating that the best model was a recent admixture event that was preceded by a bottleneck event among modern humans—thus confirming recent admixture as the most parsimonious and plausible explanation for the observed excess of genetic similarities between modern non-African humans and Neanderthals. A recent admixture event is likewise confirmed by data on the basis of linkage disequilibrium.
Recent studies have shown a higher Neanderthal admixture in East Asians than in Europeans. It indicated that most-likely at least two independent events of gene flow must have taken place into early modern humans and that the early ancestors of East Asians experienced more admixture than those of Europeans after the divergence of the two groups. This is estimated to have been an additional 20.2% (95%CI of 13.4–27.1%) of Neanderthal admixture in a second gene flow to East Asians. It is also possible, but less likely, that the difference was caused by dilution in Europeans by later migrations out of Africa. It may also be due to a lower negative selection in East Asians compared to Europeans. It has also been observed that there's a small but significant variation of Neanderthal admixture rates within European populations, but no significant variation within East Asian populations.
A 2012 study found that North Africans have a Neanderthal admixture rate lying between that of Eurasians (highest) and Sub-Saharan Africans (lowest). It has also shown a great variation within North Africans themselves, depending primarily on the amount of Eurasian versus sub-Saharan African ancestry. However, there are indications that their Neanderthal admixture is not solely contributed by Eurasian introgression.
Neanderthal contribution has been very scarcely but significantly found in the Maasai, an East African people. After identifying African and non-African ancestry among the Maasai, it can be concluded that recent non-African modern human (post-Neanderthal) gene flow was the source of the contribution as about an estimated 30% of the Maasai genome can be traced to non-Africans from about 100 generations ago.
Through the extent of linkage disequilibrium, it was estimated that the last Neanderthal gene flow into early ancestors of Europeans occurred 47,000–65,000 years BP (conservatively 37,000–86,000 years BP). In conjunction with archaeological and fossil evidence, the gene flow is thought likely to have occurred somewhere in Western Eurasia, possibly the Middle East.
No evidence of Neanderthal mitochondrial DNA has been found in modern humans. This would suggest that successful admixture with Neanderthals happened paternally rather than maternally on the side of Neanderthals. Possible hypotheses are that Neanderthal mtDNA had detrimental mutations that led to the extinction of carriers, that the hybrid offspring of Neanderthal mothers were raised in Neanderthal groups and became extinct with them, or that female Neanderthals and male Sapiens did not produce fertile offspring. A lack of mitochondrial DNA (mtDNA) evidence in modern humans does not discredit the admixture theory. A 2012 study produced a model which demonstrated exponential growth is compatible with the survival of a single mtDNA or Y chromosome lineage only if the growth rate is in a narrow supercritical interval. Thus, even if Neanderthals and anatomically modern Africans belonged to the same interbreeding population and even if this population was allowed to grow exponentially with a small rate, the more probable outcome would still be all humans being descendants either of a single woman (mtDNA) or a single man (Y chromosome). The model estimated in only 7% the probability that humans could have either mtDNA or Y chromosome of a Neanderthal origin. Whereas there was a 93% probability for the lack of mtDNA in modern humans.
Recent studies found the presence of large genomic regions with strongly reduced Neanderthal contribution in modern humans due to negative selection, partly caused by hybrid male infertility. These large regions of low Neanderthal contribution were most-pronounced on the X chromosome—with fivefold lower Neanderthal ancestry compared to autosomes—and contained relatively high numbers of genes specific to testes, meaning that modern humans have relatively few Neanderthal genes that are located on the X chromosome or expressed in the testes, consistent with the fact that male infertility is affected by a disproportionately large amount of genes on X chromosomes. It has also been shown that Neanderthal ancestry has been selected against in conserved biological pathways, such as RNA processing.
Genes affecting keratin were found to have been introgressed from Neanderthals into modern humans (shown in East Asians and Europeans), suggesting that these genes gave a morphological adaptation in skin and hair to modern humans to cope with non-African environments. This is likewise for several genes involved in medical-relevant phenotypes, such as those affecting systemic lupus erythematosus, primary biliary cirrhosis, Crohn's disease, optic disk size, smoking behavior, interleukin 18 levels, and diabetes mellitus type 2.
In a 2013 study, researchers found Neanderthal introgression of 18 genes—several of which are related to UV-light adaptation—within the chromosome 3p21.31 region (HYAL region) of East Asians. The introgressive haplotypes were positively selected in only East Asian populations, rising steadily from 45,000 years BP until a sudden increase of growth rate around 5,000 to 3,500 years BP. They occur at very high frequencies among East Asian populations in contrast to other Eurasian populations (e.g. European and South Asian populations). The findings also suggests that this Neanderthal introgression occurred within the ancestral population shared by East Asians and Native Americans.
Data from 2005 had previously shown that a group of alleles collectively known as haplogroup D of microcephalin, a critical regulatory gene for brain volume, originated from an archaic human population. The results show that haplogroup D introgressed 37,000 years ago (based on the coalescence age of derived D alleles) into modern humans from an archaic human population that separated 1.1 million years ago (based on the separation time between D and non-D alleles), consistent with the period when Neanderthals and modern humans co-existed and diverged respectively. The high frequency of the D haplogroup (70%) suggest that it was positively selected for in modern humans. The distribution of the D allele of microcephalin is high outside Africa but low in sub-Saharan Africa, which further suggest that the admixture event happened in archaic Eurasian populations. This distribution difference between Africa and Eurasia suggests that the D allele originated from Neanderthals. However, a 2010 study found that a Neanderthal individual from the Mezzena Rockshelter (Monti Lessini, Italy) was homozygous for an ancestral allele of microcephalin, thus providing no support to the theory that Neanderthals contributed the D allele to modern humans but does not exclude a possibility of a Neanderthal origin of the D allele. The 2010 Neanderthal genome study also could not confirm a Neanderthal origin of haplogroup D of the microcephalin gene.
A 2011 study found that HLA-A*02, A*26/*66, B*07, B*51, C*07:02, and C*16:02 of the immune system were contributed from Neanderthals to modern humans. After migrating out of Africa, modern humans encountered and interbred with archaic humans, which was advantageous for modern humans in rapidly restoring HLA diversity and acquiring new HLA variants that are better adapted to local pathogens.
According to a study in 2012, the extinction of Neanderthals may even be attributed to African ancestors of Eurasians interbreeding with the Middle Eastern Neanderthal. Although one hypothesis is that the brutish hominins were simply no match for cultured, intelligent Homo sapiens and quickly became extinct, there is some evidence shown in the 2012 study that interbreeding may have caused the Neanderthal to become extinct simply due to the random mixing of their genes through sexual reproduction. The model produced by Neves and Serva's suggests that the 1-4% genetic mix present in the Eurasian genome could have come about with one interbreeding every 10 to 80 generations. These low rates of interbreeding could theoretically have led to the extinction of Neanderthals through a genetic lottery.
According to a 1999 study, the early Upper Paleolithic burial remains of a modern human child from Abrigo do Lagar Velho (Portugal) featured traits indicating Neanderthal admixtures with modern humans dispersing into Iberia. Considering the dating of the burial remains (24,500 years BP) and the persistence of Neanderthal traits long after the transitional period from a Neanderthal to a modern human population in Iberia (28,000–30,000 years BP), it was suggested that the child may have been a descendant of an already heavily-admixed population.
In a 2006 study, researchers found that the early Upper Paleolithic modern human remains from Peştera Muierilor (Romania) of 35,000 years BP have the morphological pattern of European early modern humans, but possesses archaic and/or Neanderthal features, suggesting European early modern humans' admixture with rather than a full replacement of Neanderthals. These features include a large interorbital breadth, a relatively flat superciliary arches, a prominent occipital bun, an asymmetrical and shallow mandibular notch shape, a high mandibular coronoid processus, the relative perpendicular mandibular condyle to notch crest position, and a narrow scapular glenoid fossa.
In a 2003 study, researchers found that the early modern human Oase 1 mandible from Peștera cu Oase (Romania) of 34,000–36,000 14C years BP presented a mosaic of modern, archaic, and possible Neanderthal features. It displayed a lingual bridging of the mandibular foramen, not present in earlier humans except Neanderthals of the late Middle and Late Pleistocene, thus suggesting affinity with Neanderthals. Concluding from the Oase 1 mandible, there was apparently a significant craniofacial change of early modern humans of those from at least Europe, possibly due to some degree of admixture with Neanderthals.
A 2007 study found that the earliest (before about 33 ka BP) European modern humans and the subsequent (Middle Upper Paleolithic) Gravettians, falling anatomically largely inline with the earliest (Middle Paleolithic) African modern humans, also had traits that are distinctively Neanderthal, suggesting that a solely Middle Paleolithic modern human ancestry was unlikely for European early modern humans.
In March 2013, new data from the late-Neanderthal jaw from the Mezzena rockshelter (Monti Lessini, Italy) indicated possible interbreeding in late Italian Neanderthals. The jaw (more specifically, a corpus mandibulae remnant) falls within the morphological range of modern humans, but also displayed strong similarities with some of the other Neanderthal specimens, indicating a change in late Neanderthal morphology due to possible interbreeding with modern humans.
A 2015 study reported about the Manot 1, a partial calvaria of a modern human that was recently discovered at the Manot Cave (Western Galilee, Israel) and dated to 54.7±5.5 kyr BP. The finding represent the first fossil evidence from the period when modern humans successfully migrated out of Africa and colonized Eurasia. It also provides the first fossil evidence that modern humans inhabited the southern Levant during the Middle to Upper Palaeolithic interface, contemporaneously with the Neanderthals and close to the probable interbreeding event. The morphological features suggest that the Manot population may be closely related or given rise to the first modern humans who later successfully colonized Europe to establish early Upper Palaeolithic populations.
The hypothesis, variously under the names of interbreeding, hybridization, admixture or hybrid-origin theory, has been discussed ever since the discovery of Neanderthal remains in the 19th century, though earlier writers believed that Neanderthals were a direct ancestor of modern humans. Thomas Huxley suggested that many Europeans bore traces of Neanderthal ancestry, but associated Neanderthal characteristics with primitivism, writing that since they "belong to a stage in the development of the human species, antecedent to the differentiation of any of the existing races, we may expect to find them in the lowest of these races, all over the world, and in the early stages of all races".
Hans Peder Steensby in the 1907 article Racestudier i Danmark ("Race studies in Denmark") rejected that Neanderthals were ape-like or inferior, and, while emphasizing that all modern humans are of mixed origins, suggested interbreeding as the best available explanation of a significant number of observations which by then were available.
In the early twentieth century, Carleton Coon argued that the Caucasoid race is of dual origin consisting of Upper Paleolithic (mixture of H. sapiens and H. neanderthalensis) types and Mediterranean (purely H. sapiens) types. He repeated his theory in his 1962 book The Origin of Races.
A 2010 study has shown that Melanesians (e.g. Papua New Guinean and Bougainville Islander) share relatively more alleles with Denisovans when compared to other of the studied Eurasians and Africans. It estimated that 4% to 6% of the genome in Melanesians derives from Denisovans, while no other Eurasians or Africans displayed contributions of the Denisovan genes. It has been observed that Denisovans contributed genes to Melanesians but not to East Asians, indicating that there was interaction between the early ancestors of Melanesians with Denisovans but that this interaction did not take place in the regions near southern Siberia, where as-of-yet the only Denisovan remains have been found. In addition, a 2011 study has also shown a relative increased allele sharing between Denisovans and Aboriginal Australians, compared to other Eurasians and African populations, consistent with relative high admixture between early ancestors of Melanesians and Denisovans.
In 2011, a study produced evidence that the highest presence of Denisovan admixture is in Oceanian populations, followed by many Southeast Asian populations, and none in East Asian populations. There is significant Denisovan genetic material in eastern Southeast Asian and Oceanian populations (e.g. Aboriginal Australians, Near Oceanians, Polynesians, Fijians, eastern Indonesians, Philippine Mamanwa and Manobo), but not in certain western and continental Southeast Asian populations (e.g. western Indonesians, Malaysian Jehai, Andaman Onge, and mainland Asians), indicating that the Denisovan admixture event happened in Southeast Asia itself rather than mainland Eurasia. The observation of high Denisovan admixture in Oceania and the lack thereof in mainland Asia suggests that early modern humans and Denisovans had interbred east of the Wallace Line that divides Southeast Asia.
However, in contrast to the previous results, more-recent research found indications that mainland Asian and Native American populations had 0.2% Denisovan contribution, albeit twenty-five-fold lower than Oceanian populations. The manner of gene flow to these populations is currently unknown. After Oceanians, it has been observed that particularly Southeast Asians in general have affinity to Denisovans.
Findings indicate that the Denisovan gene flow event happened to the common ancestors of Aboriginal Filipinos, Aboriginal Australians, and New Guineans. New Guineans and Australians have similar rates of Denisovan admixture, indicating that interbreeding took place prior to their common ancestors' entry into Sahul (Pleistocene New Guinea and Australia), at least 44,000 years ago. It has also been observed that the fraction of Near Oceanian ancestry in Southeast Asians is proportional to the Denisovan admixture, except in the Philippines where there is a higher proportional Denisovan admixture to Near Oceanian ancestry. Reich et al. (2010) suggested a possible model of an early eastward migration wave of modern humans, some who were Philippine/New Guinean/Australian common ancestors that interbred with Denisovans, respectively followed by (1) divergence of the Philippine early ancestors, (2) interbreeding between the New Guinean and Australian early ancestors with a part of the same early-migration population that did not experience Denisovan gene flow, and (3) interbreeding between the Philippine early ancestors with a part of the population from a much-later eastward migration wave (the other part of which would become East Asians).
It has been shown that Eurasians have some but significant lesser archaic-derived genetic material that overlaps with Denisovans, stemming from the fact that Denisovans are related to Neanderthals—who contributed to the Eurasian gene pool—rather than from interbreeding of Denisovans with the early ancestors of those Eurasians.
The skeletal remains of an early modern human from the Tianyuan cave (near Zhoukoudian, China) of 40,000 years BP showed a Neanderthal contribution within the range of today's Eurasian modern humans, but it had no discernible Denisovan contribution. It is ancestral to many Asian and Native American populations, but post-dated the divergence between Asians and Europeans. The lack of a Denisovan component in the Tianyuan individual suggests that the genetic contribution had been always scarce in the mainland.
A 2011 study, exploring the immune system's HLA alleles, suggested that HLA-B*73 introgressed from Denisovans into modern humans in western Asia due to the distribution pattern and divergence of HLA-B*73 from other HLA alleles. In modern humans, HLA-B*73 is concentrated in western Asia, but it is rare or absent elsewhere. Even though HLA-B*73 is not present in the sequenced Denisovan genome, the study noted that it was associated to the Denisovan-derived HLA-C*15:05 from the linkage disequilibrium, consistent with the estimated 98% of those modern humans who carried B*73 also carried C*15:05.
The Denisovan's two HLA-A (A*02 and A*11) and two HLA-C (C*15 and C*12:02) allotypes correspond to common alleles in modern humans, whereas one of the Denisovan's HLA-B allotype corresponds to a rare recombinant allele and the other is absent in modern humans. It is thought that these must have been contributed from Denisovans to modern humans, because it is unlikely to have been preserved independently in both for so long due to HLA alleles' high mutation rate.
A 2014 study found that a EPAS1 gene variant was introduced from Denisovans to modern humans. The ancestral variant upregulates hemoglobin levels to compensate for low oxygen levels—such as at high altitudes—but this also has the maladaption of increasing blood viscosity. The Denisovan-derived variant on the other hand limits this increase of hemoglobin levels, thus resulting in a better altitude adaption. The Denisovan-derived EPAS1 gene variant is common in Tibetans and was positively selected in their ancestors after they colonized the Tibetan plateau.
Archaic African hominins
Rapid decay of fossils in African environments has made it currently unfeasible to compare modern human admixture with reference samples of archaic African hominins.
In 2011, after finding three candidate regions with introgression by searching for unusual patterns of variations—indicating a different origin—in 61 non-coding regions from two hunter-gatherers (Biaka Pygmies and San, shown significant for admixture in the data) and one West African agricultural group (Mandinka, shown not significant for admixture in the data), researchers concluded that roughly 2% of the genetic material found in some Sub-Saharan African populations was inserted into the human genome approximately 35,000 years ago from archaic hominins that broke away from the modern human lineage around 700,000 years ago. After a survey for the introgressive haplotypes across Sub-Saharan populations, it was suggested that the admixture event happened with archaic hominins that possibly once inhabited Central Africa.
In 2012, researchers studied high-coverage whole-genome sequences of fifteen Sub-Saharan hunter-gatherer males from three groups—five Pygmies (three Baka, a Bedzan, and a Bakola) from Cameroon, five Hadza from Tanzania, and five Sandawe from Tanzania—finding signs that the ancestors of the hunter-gatherers interbred with one or more archaic human populations, probably over 40,000 years ago. They also found that the median time of the most recent common ancestor of the fifteen test subjects with the putative introgressive haplotypes was 1.2–1.3 mya.
In a 2013 study, the researchers suggested that the observed genetic affinities between archaic and modern human populations are mostly explained by common ancestral polymorphisms (inherited from Homo heidelbergensis) —and not admixture—followed by genetic drift, explaining that the differences in the observed genetic affinities among modern human populations are most-likely a result from different retention rates of these polymorphisms among the modern human populations. However, they also stated that the study did not completely rule out archaic introgression to modern humans.
According to A. Eriksson and Andrea Manica, the attempts to detect hybridization based on patterns of linkage disequilibrium have found a possible signal, but these approaches rely on simplistic demographic models with assumptions that are not testable. These researchers stated that for both measures of shared polymorphisms between Neanderthals and modern humans, the patterns observed in the data could be generated by their spatial model that included ancient population structure of a strength that is compatible with the modern distribution of genetic diversity, even in the complete absence of hybridization.
Though they did not claim that anatomically modern humans never admixed with other hominins, their results imply that current evidence for such admixture events is inconclusive at best. Future tests, to be convincing, would need to show that the genetic patterns used to invoke hybridization cannot be explained by population structure, for which there is both genetic and archaeological evidence.
R. Lowery and his peers criticize the researches carried out by Green et al. and Reich et al. in 2010, in which D-statistics were compared among contemporary human populations using the frequencies of derived alleles in single nucleotide polymorphisms (SNPs), also present in the archaic genome of interest. Those sets were defined under the assumption that in SNPs where the derived state is present in both archaic hominid and contemporary human populations, the derived alleles are most likely to include products of introgression. These analyses suggested that non-Sub-Saharan Africans contain 1–4% higher Neanderthal derived allelic frequencies than Sub-Saharan-Africans. The potential explanation for these observations that was provided by Green et al. in 2010 is that modern human populations admixed with Neanderthals near the time of or shortly after migrating out of Africa. However, as Lowery points out, simply because a contemporary human SNP allele is not seen within the chimpanzee genome but is found within the Neanderthal lineage does not mean that the mutation necessarily first occurred within Neanderthals. Such mutant alleles could have originated any time between the divergence of the chimpanzee and hominin lineages, 4–7 million years ago, and the split between Neanderthals and modern humans (400,000 to 800,000 years ago). Such derived alleles may have survived (without reaching fixation) to enter the gene pool of a recent common ancestor of Neanderthals and contemporary humans. In more technical terms, the possession of these mutations in both archaic groups and contemporary humans may represent common ancestral polymorphisms. Reich et al. (2010) in their analyses of the Denisova genome, found evidence supporting 6–8% higher frequencies of Denisova derived alleles in the Melanesian population relative to other contemporary groups, and suggested that this is the result of admixture between Denisovans and the Melanesians ancestors as they migrated from Africa along the “Southern Coastal Route” of Southern Asia. Regarding this hypothesis too, the alternative to introgression as an explanation for the observed affinities between archaic hominins like Neanderthals or Denisovans and contemporary humans is the existence of ancestral common polymorphisms that managed to infiltrate multiple lineages. In terms of the differences in the level of genetic similarities to Neanderthal between non Sub-Saharan Africans and Sub-Saharan Africans, it is possible that regional differentiation in Africa within the common ancestral population of all modern humans occurred at a time early enough for some human populations to be genetically closer to Neanderthals or Denisovans than other populations. This could have been facilitated by the existence of ancient genetic sub-population structure within modern humans prior to the spread of modern humans out of Africa. Recent simulations of the different demographic models that account for a potentially older divergence time indicated that the D-statistic differences observed between non Sub-Saharan Africans and Sub-Saharan Africans are, in fact, compatible with a model that does not incur admixture.
In their study, Lowery and his peers examine the possible origins of genetic similarities between groups of contemporary humans (n = 827 individuals belonging to 11 metapopulations) and archaic hominins by exploring their patterns of genetic relatedness. SNP-based genetic diversity was divided into four SNP subsets that are likely to have originated at different time points in recent human evolution. These four subsets include SNPs that are derived in the Neanderthal and ancestral in the Denisovan (NdDa), those that are ancestral in Neanderthals but derived in the Denisovan (NaDd), those that are derived in both Neanderthals and the Denisovan (NdDd) and those that are ancestral in both Neanderthals and the Denisovan (NaDa). By so doing, the point was to examine sets of SNPs most likely to stem from the common ancestors with modern humans. They also examined the genetic affinities between the archaic hominins and contemporary human wherein the ancestral component is not edited out. The conclusion of the study was that, although the observed clinical degree of similarities seen in the Structure analysis could result from introgression followed by demic diffusion, the data is easier explained by common ancestral polymorphisms shared between the ancestors of Modern Europeans and Neanderthals, followed by demic diffusion eastward. In particular, if Neanderthal admixture with modern humans is responsible for the 65.4% of the European nuclear genome shared with Neanderthals, it contrasts the complete lack of Neanderthal contribution to the European mitochondria or Y-chromosomes. Regarding Melanesians, they are thought to descend from a population of modern humans that reached Melanesia earlier than the peopling of most Eurasia. As a result, it is possible that Melanesians have retained more genetic material from the common ancestral gene pool than Eurasians. Therefore, the D-statistic-based results indicating that Melanesians possess a greater number of NaDd and NdDd alleles is more congruent with a model in which common ancestral polymorphisms followed by genetic drift.
Wang and Li also criticize the supporters of the admixture theory, who concluded that about 1-4% of non-African genomes in Europeans are derived from Neanderthals, and that they have detected gene ﬂow from Neanderthals to modern humans but no gene ﬂow from modern human to Neanderthals (Green et al., 2010). They argue those conclusions are quite controversial, especially issues pertaining to regional afﬁnities and the assumed direction of gene ﬂow. As Wang and Li indicate, one obvious drawback of this study is data quality. Draft sequences consist mainly of 30e100 bp-long reads that only provide 1.3 fold genomic coverage. De novo sequence assembly is not possible with such a low-coverage data. All Neanderthal reads were aligned to the human and chimpanzee reference genomes using megablast. These analyses have largely been limited to detecting lineage-speciﬁc substitutions and small insertions or deletions (indels). Sequencing errors are also inevitable due to low coverage. For instance, Neanderthal-speciﬁc substitutions are about 30 times higher than on human lineages, largely due to transitions caused by cytosine deamination in the Neanderthal DNA. Green et al. disregarded transitions to reduce contamination and sequencing errors and to provide evidence of low contamination rates. Although removing transition would not cause a negative result to positive, this disregard most likely resulted in the loss of useful information.
The poor quality of the data makes it difﬁcult to detect signals of gene ﬂow and might cause bias in subsequent analyses. To estimate Neanderthal ancestry in European genomes, this study analyzes the biallelic SNPs, focusing on those SNPs with different alleles in modern Europeans and Africans and with derived allele in the Neanderthals. Although the sequenced Neanderthal genome has derived alleles, SNPs may be polymorphic in other Neanderthals.
Using D statistics when Neanderthal sites with derived alleles are controlled, the authors observed the same derived allele in modern humans as in Neanderthals, meaning that they share the same lineage. With low coverage in Neanderthals, derived alleles in heterozygotes tend to be lost. Since results between Africans and non-Africans within these sites are deﬁned by demographic events, the lost data is not correlated with distribution of derived alleles in Africans and non-Africans. Taken this into consideration, low coverage will cause bias in conclusion of gene ﬂow direction. In addition to this ﬁnding, Durand et al. (2011) argues that the D-statistic used by Green et al. to test for admixture was insensitive to confounding factors, such as sequencing errors, ancient DNA damage, and human/Neanderthal population sizes.
Green et al. estimated the proportion of Neanderthal ancestry in non-Africans between 1% and 4% (Green et al., 2010). However, Hodgson et al. dissents with the admixture theory supporters, by stating that interbreeding between Neanderthals and modern humans may not have been possible during this time because they would not have made contact (i.e. The accepted southern route of out-of-Africa migration took Neanderthals through the southern Arabian Peninsula, thus preventing contact). Hodgson et al. also proposed that modern humans might have returned to Africa after initial admixture with Neanderthals due to climatic shifts .
By examining haplotypes of the DYS44 segment in a sample of 6092 X-chromosomes. Speciﬁcally, haplotype B006, which is the closest to the ancestral one, is common outside Africa but virtually absent in sub-Saharan Africa. Yotova et al. concluded that Neanderthal admixture occurred very early or prior to the worldwide expansion of modern humans’ African common ancestors (Yotova et al., 2011). However, neither of the two papers by Green et al. and Hodgson et al. could rule out that genetic substructure of Neanderthals’ and modern humans’ African common ancestors was already formed by the time Neanderthal ancestors left Africa to settle western Eurasia. If this is so, some ancient African modern human populations might have more afﬁnities with Neanderthals than others. If these populations were also the source of modern humans’ out-of-Africa expansion, then present-day non-Africans would be more closely related to Neanderthals than Africans in some genomic regions. As a conclusion, Li and Wang state that the draft sequence of the Neanderthal genome might have provided evidence against strict versions of both multiregional continuity and Out-of-Africa replacement models. It suggested the model emphasizing the role of Out-of-Africa expansion could be coupled with the low levels of assimilation of regional late archaic hominids. Such a model might be realistic if the hypothesis of regional afﬁnities and the relevant data was reliable. However, in order to know whether Neanderthal to modern human gene ﬂow took place, deeper sequencing as well as more sampling representing population structure on Neanderthals is necessary.
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