Genetic Admixture in the History of Modern Humans

When anatomically modern humans left Africa between 200,000 and 150,000
years ago, they entered areas already populated by diverse and successful hominins.
Much of their interaction with these archaic species remains unknown: how closely they
lived, whether humans contributed to their extinctions, etc. However, it has become clear
that our ancestors interbred with some of the archaic hominins they encountered, and that
many modern humans continue to bear the genetic remnants of these admixtures. Recent
efforts to analyze human admixture has yielded a wealth of information, not only about
humans genetic history, but about the ranges of other hominins, the migrations of early
humans, and the adaptations that made it possible for humans to successfully spread
across the globe.

Neanderthals
In 1998, the skeleton of a strange child was discovered in the Abrigo do Lagar
Velho, located in western Portugal. The child, who seemed to have been ceremonially
buried, displayed a strange mixture of both human and Neanderthal traits. Given its
estimated age of about four years, the childs femur, trunk, and humerus more resembled
a Neanderthal than a human, but the mandible, many of the teeth and the femur appear
more similar the features of modern humans. Other features, such as the mastoid portion
of the temporal bone, appear intermediate between what would be expected of the two
hominins (Duarte et al. 1999).
This mosaic of features suggested the possibility of breeding between humans and
Neanderthals. However, the burial occurred between 24,500 and 25,000 years ago, at

least 3,000 years after the Neanderthals are believed to have disappeared from the Iberian
Peninsula. This led Duarte et al. to conclude that not only did the fossil represent the
product of Neanderthal-human admixture, it represented the visible influence of
Neanderthal genes on the human phenotypes thousands of years after the interbreeding
must have occurred. Such a result would suggest that, rather than occurring as an
anomaly, the interbreeding must have been common enough that the genes humans
gained would persist in their population for millennia (Duarte et al. 1999).
A decade later, the accessibility of DNA sequencing made it possible to more
empirically determine whether modern humans carried Neanderthal genes. Researchers
first studied mitochondrial DNA, but despite false alarms (Green et al. 2008), it has been
established that modern humans share no mtDNA with Neanderthals (Comas et al. 1997,
Briggs et al. 2009). However, the draft sequence produced by Green et al. (2010), found
regions of the nuclear genome shared between Neanderthals and many modern humans.
By sequencing the available DNA from three Neanderthals, the researchers were able to
form a draft sequence of over 4 billion nucleotides, which they compared to the DNA
sequences of chimpanzees and humans in order to establish that the DNA was not of
microbial origin. The resulting sequence was compared to the sequences of five
individuals: a San, a Yoruba, a Papua New Guinean, a Han Chinese, and a western
European. The difference between the Neanderthal and human genomes was greater than
the difference among any of the humans, and was used to establish that Neanderthals and
modern humans diverged between 270,000 to 440,000 years ago. Comparing a number
of Eurasian and African genomes, the researchers established that individuals of
European and Asian descent displayed shared more genes with the Neanderthals than

those of sub-Saharan African descent, further evidence that some human ancestors bred
with Neanderthals (Green et al. 2010).
All of the Eurasian genomes displayed an equal level of relatedness with the
Neanderthal genomes, suggesting that the Neanderthal admixture occurred before the
divergence of all Eurasian populations (Green et al. 2010). This distribution of genes
indicates that non-African populations diverged following their divergence from sub-
Saharan Africans, this conclusion supports the out-of-Africa theory that modern
humans evolved in Africa before radiating out to the rest of the planet, rather than leaving
Africa and then evolving into anatomically modern humans at a variety of places across
the globe. The interbreeding is most likely to have occurred very soon after humans left
Africa, probably in the Middle East, and the genes of interest surfed to fixation as the
population rapidly grew. Today, 1-4% of the DNA of most humans of European or
Asian descent is shared with Neanderthals, but no Neanderthal DNA is apparent in
populations whose ancestors are sub-Saharan Africans.
Though the presence of shared genes among Neanderthals and modern humans of
Eurasian descent is broadly accepted, some researchers remain unconvinced as to
whether this is the result of interbreeding or a product of the population dynamics. In a
paper published two years after Green et al. (2010), Eriksson and Manica (2012) present
the result of a simulation which produced a similarity between Neanderthal and human
genomes resembling what has been discovered, but did so without allowing genetic
admixture between the two groups. In their simulations, the genes that Neanderthals and
Eurasians share arose in the hominid population that included the common ancestor for
both groups. It first developed in an area of the populations range near that included to

portion of the population that would eventually split off to become Neanderthals, and
when Neanderthals split off from the ancestors of modern humans, they carried this gene
with them, and it spread through their population. When the ancestors of Eurasians left
Africa, they too carried this gene, which, after passing through the genetic bottleneck this
migration created, became fixed in the population. The gene died out in sub-Saharan
Africa, making it appear that the shared genes came from interbreeding between
Neanderthals and Eurasians, rather than being inherited from their most recent common
ancestor. Eriksson and Manica do not argue that their research demonstrates that
population dynamics were responsible for the genetic distribution that we observe in
modern humans, rather that interbreeding is not the only possible explanation, and that
scientists who support the idea of admixture bear the onus of providing genetic or
archeological evidence that their ideas are best explained by interbreeding.
Other research has sought to use tools that are better able to distinguish between
to the possibilities. According to Yang et al. (2012), genetic similarity produced by
interbreeding would result in a different tree depth than if it were produced by population
dynamics. Tree depth can be measured using a tool called site frequency spectrum, and
by testing this metric, the researchers determined that the excess of rare alleles among the
Neanderthals and Eurasians but not Africans upholds admixture as the more
parsimonious explanation. Further evidence for admixture was provided by a study from
Sanchez-Quinto et al. (2012), which measured the relative levels of genes thought to be
from Neanderthals in various North African populations. They found that the levels of
Neanderthal DNA was proportional to the populations levels of admixture with
European and Middle Eastern groups, making it most probable that these genes were

acquired by these groups after they had left Africa, and passed back to North Africans
through interbreeding. If Eriksson and Manica are correct, these genes would already
have existed in the ancestors of the North Africans the population Neanderthals split
from and need not have been acquired from Eurasian populations. Though these data
are not entirely incompatible with the population-dynamic hypothesis put forth by
Eriksson and Manica, they are much more parsimoniously explained by interbreeding
with Neanderthals.

Denisovans
In 2008, a finger bone was found in Denisova Cave, in Siberia. The low
temperature of the cave had allowed for unusually complete preservation of the DNA,
which revealed the individual to be a previously unknown hominin species (Krause et al.
2010, Reich et al. 2010). DNA analysis indicates that Denisovan and Neanderthal
lineages split after they had split from the ancestors of modern humans. However, the
two have distinct population histories; all sequenced Neanderthal genomes have a
common ancestor more recent than the one they share with Denisovans, a result of a
strong population bottleneck the Neanderthals experienced following their split with the
Denisovans (Reich et al. 2010).
Unlike the Neanderthals, whose genes can be found in nearly all humans of
European or Asian descent, the genes of Denisovans are conspicuously absent from most
modern Europeans excepting those genes that they share with Neanderthals (Reich et
al. 2010). Instead, they can be found in a number of East Asians, contribution 4-6% of
the DNA of most Melanesians.

Research conducted by Reich et al. (2011) has more precisely determined the
distribution of Denisovan genes in modern human populations. Varying levels of
Denisovan DNA were found in Aboriginal Australians, Polynesians, Near Oceanians,
Fijians, Eastern Indonesians, and the Mamanwa; however, none was found among
mainland East Asians, Western Indonesians, the Onge, or the Jehai. Based on which
populations the Denisovan DNA was found in, as well as the relative strength of the
DNA in these different populations, researchers were able to better estimate where the
admixture occurred. Human-Denisovan interbreeding is most parsimoniously explained
as having occurred in Southeast Asia, which would mean that the Denisovans who have
so far only been discovered in Siberia had an extremely large range. Additionally, the
dispersal of archaic genes in human populations provides an excellent opportunity to
study human migrations. The data gained by this paper are consistent with the out of
Africa theory, and support the idea that humans left Africa in one wave, but dispersed
into Asia in multiple waves. The first wave contained the ancestors of the Australians,
New Guineans, Onge, Jehai, and Memanwa the second contributed the ancestors of
many East Asians and Indonesians (Reich et al. 2011).


Archaic African Admixture
Though modern humans of sub-Saharan descent carry no Neanderthal or
Denisovan genes, it has been found that they nonetheless bear the remnants of their
ancestors admixture with an archaic hominid population (Hammer et al. 2011). Unlike
the other admixture studies discussed in this paper, this work was made more difficult by

the fact that nothing is known about the archaic population with which admixture may
have occurred, making it impossible to compare the DNA sequence of humans and the
archaic hominins. Using both coding and noncoding regions of the genome, the
researchers measured polymorphism and linkage disequilibrium among extant
populations, including the hunter-gatherer populations of the San and Biaka Pygmies.
The researchers created models to test various explanations for the observed pattern of
genes, and, after running maximum likelihood-tests, found that the null model of no
admixture was unlikely to produce the data observed (P value of 0.0493). Instead, there
were two peaks in the maximum-likelihood surface. The first indicated that a hominin
population split off from human ancestors around 700,000 years ago and interbred with
them roughly 35,000 years ago, contributing ~2% of their DNA. The second peak
corresponds to an archaic population diverging from human ancestors about 375,000
years ago, then mating with them around 15,000 years ago and contributing ~0.5% of
their genome. However, based on the dates of divergence they estimated for other
African populations, the first peak represents the contributors to the African genome
(Hammer et al. 2011).


Effects of admixture with archaic hominins
Comparatively little research has been done on admixtures effects on human
evolution: whether modern humans acquired beneficial genes, and to what extend the
genes they acquired were spread by natural selection or genetic drift. This is especially
true for the Denisovans, whose contribution to the human genome was discovered only

very recently. However, a paper published by Abi-Rached et al. (2011), demonstrated
that Denisovans admixture contributed to the modern human immune system, and that
this contribution has been broadly spread by positive selection. The human leukocyte
antigen (HLA) system is our species major histocompatibility complex, a vital
component of our immune system. Sequencing of the Denisovan genome has found that
it carries several of the HLA class I alleles found in modern humans. It is possible that
the alleles evolved before the populations split, but given the rapid evolution of diversity
among HLA alleles, it is more probable (and parsimonious) that humans acquired the
genes from interbreeding with Denisovans. Analyzing the distribution of various HLA
alleles, Abi-Rached et al. conclude that at a minimum, humans gained either the
A*11:01-C*12 haplotype or the A*11:01-C*15 haplotype from Denisovan admixture.
Additionally, HLA-C*15 and HLA-C*12:02, are found in both Denisovan and human
genomes. Modern human HLA haplotype diversity is much greater in Asia than in
Africa, which is unusual for human genes, as the population bottleneck created by our
ancestors out-of-Africa migration usually produces a lesser diversity outside of Africa.
This surprising imbalance in haplotype diversity is best explained if humans first
acquired these genes outside of Africa, after which a portion spread back to Africa.
Another HLA allele, HLA-B*73 is found most commonly in western Asia, leading
researcher to suspect Denisovan origins. It has not been found in Denisovan DNA, but
its linkage disequilibrium with HLA-C*15 alleles is high: worldwide, roughly 98% of
individuals with B*73 also carry C*15:05, and in some regions of Africa, the portion
reaches 100%. This suggests that the B*73 shares the same origin as HLA-C*15:
interbreeding with Denisovans (Abi-Rached et al. 2011).

Other HLA alleles have been found in Neanderthal genomes: both HLA- B*07
and HLA-B*51 as well as an allele that is one of the closely related HLA-A*26 and HLA-
A*66. Based on the distribution of these genes in modern human populations, Abi-
Rached et al. determined that two HLA- B*07 and HLA-B*51 were acquired from
Neanderthals, as well as HLA-C*07:02 and HLA-C*16:02, which were found by
combining genetic distribution and linkage disequilibrium (Abi-Rached et al. 2011).
When modern humans left Africa, they were exposed to a plethora of pathogens
they had not yet encountered. By this point, archaic hominins had been living in Eurasia
for over 200,000 years, and many of the differences in their immune systems were almost
certainly adaptations to allow them to better resist these threats. After being received
from Neanderthals and Denisovans, the increased resistance these genes likely provided
cause them to be spread through the population by positive selection. Additionally,
because of their role in fighting pathogens, HLA class I alleles experience balancing
selection, and the infusion of new alleles would have increased the low genetic diversity
of a group that had just passed through a population bottleneck. Among the first research
into the evolutionary effects of human admixture, Abi-Rached et al. have demonstrated
that our ancestors may have benefitted enormously from their interbreeding with other
hominins.

Conclusion
The first Neanderthal fossils were discovered in 1856, three years before the
publication of On the Origin of Species. Fifteen years later, in The Descent of Man, and
Selection in Relation to Sex, Darwin argued, based on anatomy, that Neanderthals were

not the ancestors of modern humans. Though his reasoning was correct, it was not until
the advent of genetic sequencing that a more nuanced view could be developed.
Scientists now understand that Neanderthals, Denisovans (not yet discovered in Darwins
time), and an archaic African hominin (not yet discovered in our time) have all
contributed to the human genome. Their contributions have been small, and have
affected only subsets of the global human population, but some of them have been
significant, providing humans with pathogen resistance, and perhaps other genes, that
helped them as they left Africa and spread out across the globe. Most of the genetic
analysis on human admixture presented in this paper has been conducted in the past four
years, and research on the issue is accelerating. Though understanding our inheritance of
archaic hominin genes is important for understanding human origins, evolution, and
migration, we are only just beginning to understand the ways admixture affected us.






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