Download To what extent did Neanderthals and modern humans interact?

BIOLOGICAL
REVIEWS
Cambridge
Philosophical Society
245
Biol. Rev. (2009), 84, pp. 245–257.
doi:10.1111/j.1469-185X.2008.00071.x
To what extent did Neanderthals and modern
humans interact?
Kristian J. Herrera1, Jason A. Somarelli1,2, Robert K. Lowery1,2 and Rene J. Herrera1*
1
Department of Human and Molecular Genetics, College of Medicine, Florida International University, 11200 SW 8th Street,
Miami, FL 33199, USA
2
Department of Biological Sciences, Florida International University, 11200 SW 8th Street, Miami, FL 33199, USA
(Received: 14 May 2008; revised: 23 October 2008; accepted: 28 November 2008)
ABSTRACT
Neanderthals represent an extinct hominid lineage that existed in Europe and Asia for nearly 400,000 years.
They thrived in these regions for much of this time, but declined in numbers and went extinct around 30,000
years ago. Interestingly, their disappearance occurred subsequent to the arrival of modern humans into these
areas, which has prompted some to argue that Neanderthals were displaced by better suited and more adaptable
modern humans. Still others have postulated that Neanderthals were assimilated into the gene pool of modern
humans by admixture. Until relatively recently, conclusions about the relationships between Neanderthals and
contemporary humans were based solely upon evidence left behind in the fossil and archaeological records.
However, in the last decade, we have witnessed the introduction of metagenomic analyses, which have provided
novel tools with which to study the levels of genetic interactions between this fascinating Homo lineage and
modern humans. Were Neanderthals replaced by contemporary humans through dramatic extinction resulting
from competition and/or hostility or through admixture? Were Neanderthals and modern humans two independent, genetically unique species or were they a single species, capable of producing fertile offspring? Here,
we review the current anthropological, archaeological and genetic data, which shed some light on these questions
and provide insight into the exact nature of the relationships between these two groups of humans.
Key words: archaic Homo lineages, extinction, admixture, acculturation, hybridization, ancient DNA,
introgression.
CONTENTS
I. Introduction ......................................................................................................................................
II. Anthropological data ........................................................................................................................
(1) Archaeological results .................................................................................................................
(2) Analyses of fossil data .................................................................................................................
III. Investigations using modern human dna .........................................................................................
IV. Evidence from the neanderthal mitochondrial genome ..................................................................
(1) The first mtDNA sequences from Neanderthals .......................................................................
(2) Older, more diverse Neanderthal mtDNA sequences ...............................................................
(3) Issues involving the mtDNA sequences .....................................................................................
V. Evidence from the neanderthal nuclear genome .............................................................................
(1) The earliest large-scale sequencing efforts .................................................................................
(2) Issues relating to the genomic studies ........................................................................................
(3) Searches for genes .......................................................................................................................
VI. Conclusions .......................................................................................................................................
VII. References .........................................................................................................................................
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* Address for correspondence: Tel: 305 348 1258; Fax: 305 348 1259; E-mail: [email protected]
Biological Reviews 84 (2009) 245–257 Ó 2009 The Authors Journal compilation Ó 2009 Cambridge Philosophical Society
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I. INTRODUCTION
Homo sapiens neanderthalensis was one of the closest relatives of
modern humans. This extinct group of hominids first
appeared in Europe about 400,000 years before present
(YBP) (Stringer & Hublin, 1999). Fossil evidence indicates
that approximately 150,000 YBP (Bar-Yosef, 1998; Grün &
Stringer, 2000) Neanderthals extended their range into the
Middle East and Asia, spreading as far east as Teshik-Tash,
Uzbekistan (Debetz, 1940) and the Altai Republic in Russia
(Krause et al., 2007a) (Fig. 1). They proliferated to the
greatest extent in Europe, with sites from Gibraltar in the
Iberian Peninsula (Finlayson et al., 2006) to the Caucasus
Mountains in Russia (Golovanova et al., 1999) (Fig. 1). The
vast majority of Neanderthal locations have been detected
south of the Alps, France and the Iberian Peninsula; while
several additional sites are situated further north in
Germany and even into Wales (Green & Walker, 1991)
(Fig. 1). For nearly 400,000 years, Neanderthals were the
dominant hominid group in Europe and West Asia. Yet,
fossil evidence indicates that approximately 50,000 YBP
Neanderthals may have gone extinct in Asia (Klein, 2003),
and about 34,000 YBP suffered a dramatic decline in
number in Europe (Svoboda, 2005). About 2,000 years
later, much of the Neanderthal population throughout
Europe had disappeared (van Andel, Davies & Weninger,
2003). The remaining Neanderthals are thought to have
survived in isolated refugia, including the Iberian Peninsula,
for another few millennia (Finlayson et al., 2006). One
finding in Gibraltar, for instance, suggests that Neanderthals
may have existed in southern Iberia as late as 28,000 to
24,000 YBP (Finlayson et al., 2006).
There are several interesting theories that offer explanations for the disappearance of Neanderthals from the fossil
record. Some have speculated that sudden or repeated
global climate change drastically reduced their habitats and
limited the land that was suitable for hunting (Hublin, 1998;
van Andel & Davies, 2003; Musil, 2003; Finlayson, 2004;
Steudel-Numbers & Tilkens, 2004; Finlayson et al., 2006;
Jimenez-Espejo et al., 2007; Finlayson & Carrion, 2007).
However, recent advances in palaeoclimatology seem to
suggest that the generally accepted dates for the Neanderthal extinction between 32,000 and 28,000 YBP fail to
coincide with any severe climatic event (Tzedakis et al.,
2007). This implies that one or more other factors instead
of or in addition to climate change may have been involved
in the Neanderthal extinction (Tzedakis et al., 2007).
Hypotheses of these additional factors have included
cave-associated contaminants such as smoke (Stormer &
Mysterud, 2006). Consistent exposure to pollutants released
from fires contained in caves would possibly lead to various
health issues, including increased sterility among males
(Stormer & Mysterud, 2006). Yet, it is not clear why this
would be an issue 30,000 YBP and not at any other time.
Cannibalism among Neanderthals has also been suggested
(Defleur et al., 2006; Underdown, 2008). According to
Underdown (2008), cannibalism may have led to the spread
of lethal transmissible spongiform encephalopathies (TSEs),
which could also be transmitted by the sharing of tools
Kristian J. Herrera and others
between sick and healthy individuals. Considering that
infections are usually triggered by a number of circumstances and are subject to de novo genesis, the appearance of
a novel deleterious or lethal strain at any given place and
time would not be unlikely. Such an epidemic would have
greatly weakened the Neanderthal population in a manner
similar to that observed in the Fore of Papua New Guinea
(Farquhar & Gajdusek, 1981). Along these lines, it is also
possible that just as Native Americans were impacted and in
some instances decimated by infections transmitted by
European settlers, Neanderthals could have been the
recipients of a number of deadly plagues from invading
modern humans that spread through immunologically
vulnerable individuals. Given that mass-scale death is
facilitated at high population densities, it is possible that
seasonal gatherings and subsequent dissemination of
individuals may have negatively impacted a significant
portion of the Neanderthal population in some locations.
The decline and eventual disappearance of Neanderthals
throughout Asia and Europe occurred subsequent to the
arrival of Homo sapiens in these areas, approximately 100,000
and 40,000 years ago, respectively (Valladas et al., 1988;
Mellars, 1992; Tishkoff et al., 1996). This has led to the
postulation that modern humans may have contributed to
the extinction of this archaic hominid (Finlayson, 2004).
Some have proposed that modern humans were more
adaptive, with greater ecological fitness than Neanderthals
(Finlayson, 2004; Kuhn & Stiner, 2006). The appearance of
another hominid group in Western Asia and Europe may
have increased competition within the same ecological
niche, with the more successful and adaptable modern
humans out-competing and eventually replacing the
Neanderthals (Flores, 1998).
A lack of evidence for natural selection favouring modern
human morphology over that of Neanderthals seems to
suggest that behavioural and technological differences
rather than anatomical adaptations gave humans their
advantage (Weaver, Roseman & Stringer, 2007). It has been
suggested that modern humans developed superior hunting
techniques and tools, giving them a greater advantage in
procuring adequate nutrition (Mellars, 1998). One of these
possible advantages may have been a division of labour,
a strategy seemingly lacking in Neanderthals, whose females
joined males in hunting (Kuhn & Stiner, 2006). Not only
would this have put child-bearing female Neanderthals at
risk of injury, but may also have prevented females from
gathering vegetation, thereby restricting the Neanderthal
diet (Kuhn & Stiner, 2006). The idea of a restricted diet is
further supported by isotope analyses of Neanderthal fossils
and nearby fauna (Richards et al., 2000). These investigations indicate that although marine resources were used
around the Mediterranean, the majority of the Neanderthal
diet was meat based (Richards et al., 2000). Additionally, the
development of more technically advanced weaponry by
modern humans, including long-range projectiles combined
with a higher distal-limb/body ratio might have made
modern humans more successful hunters in steppe environments, allowing them to spread further north (Finlayson,
2004). It is also possible to imagine that competition from
Biological Reviews 84 (2009) 245–257 Ó 2009 The Authors Journal compilation Ó 2009 Cambridge Philosophical Society
Neanderthal/modern Human interactions
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Fig. 1. Range expansion of Neanderthals and modern humans. Neanderthals existed throughout much of Europe for nearly
400,000 years. Their range is indicated in pink. Red dots are representative sites delineating the range of Neanderthals. Blue arrows
represent the migration of modern humans out of Africa and into Europe (Luis et al., 2004; Rowold et al., 2007; Underhill &
Kivisild, 2007).
expanding modern human groups combined with any of
the previously mentioned factors of climate fluctuation, cave
pollutants, cannibalism and/or disease, may have led to the
decline of the Neanderthals.
Another explanation for the disappearance of Neanderthals is that they were not driven to extinction through the
mechanisms described above, but rather by assimilation into
early modern human populations. It has been suggested that
some Neanderthals might have hybridized with the
invading modern humans, and became integrated into the
modern human population through introgression and
admixture, gradually reducing the number of pure
Neanderthals by diluting their DNA in an overwhelmingly
modern human gene pool. This idea necessitates that
modern humans and Neanderthals were capable of
reproducing successfully and giving birth to fertile offspring,
thereby allowing for gene flow (Duarte et al., 1999; Smith,
1999; Smith, Jankovic & Karavanic, 2005; Trinkaus, 2007).
It is possible, however, that any putative matings between
the two groups would have been incapable of yielding fertile
offspring, rendering such hybrids of Neanderthals and modern
humans evolutionary dead-ends. Given the long period of
coexistence between modern humans and Neanderthals in
Europe (approximately 10,000–15,000 years) and Western
Asia (as much as 40,000 years), it seems reasonable to assume
that a number of interactions might have occurred between
the two groups (Shreeve, 1995). As illustrated by Shreeve
(1995), the presence of a similar hominid group in an area
being colonised by modern humans and prolonged cohabitation would almost certainly have led to interactions
between the two groups; however, the nature and significance
of these encounters remains debatable. Some prehistoric
population estimates have human and/or Neanderthal
densities at 65 persons per 10,000 km2, which would make
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potential encounters rare (Shea, 2007). Considering the
geographic expanses as well as the diversity of terrain and
habitat within the ranges of modern humans and Neanderthals, it would be expected that the nature of any interaction
would have been mosaic-like in time and space.
Potential modern-human/Neanderthal admixture has
implications for understanding both the evolution of
contemporary human populations as well as Neanderthal
extinction. The occurrence of such events would imply that
an archaic hominid group may have played a role in the
shaping of current human populations, and that possibly
some selectively advantageous traits were acquired from this
group. For over a century, investigators in the fields of
anthropology and archaeology have generated a substantial
body of knowledge on Neanderthals. Unfortunately, the
fossil record is far from complete, and much of the evidence
can be interpreted in various ways. Considering the recent
advances in molecular biology and genomic analyses,
perhaps more concrete evidence for or against introgression
can be uncovered by comparing Neanderthal and modern
human DNA. With the advent of in vitro DNA amplification
by the polymerase chain reaction (PCR) as well as recent
advances in molecular biology techniques, researchers are
capable of probing the genomes of both groups in search of
genetic evidence to answer the question of Neanderthal/
modern human admixture. Here, we review the available
evidence regarding introgression between these two hominid groups.
II. ANTHROPOLOGICAL DATA
(1) Archaeological results
Although modern humans and Neanderthals may have had
different ecological needs and exhibited relatively low
population densities that kept them from direct constant
competition, it is difficult to envision the complete lack of at
least sporadic interactions. According to evidence produced
by several archaeological studies, interactions between the
two groups may have been frequent enough to allow the
transfer of technology, particularly from modern humans to
Neanderthals (Mellars, 2004). For the majority of their
existence, Neanderthals practiced the Mousterian toolculture. This culture almost exclusively involved the use of
stone in crafting weapons and other instruments (Bordes,
1961). The most advanced non-stone implements they
created were instruments crafted from splinters of bone
(Bordes, 1961) and probably spears crafted from wood.
Although it has been suggested that the Aurignacian culture
may not necessarily be of modern human origin (HenryGambier, Maureille & White, 2004), modern humans are
known to have developed more sophisticated cultures in
Europe and Asia (Stringer, Hublin & Vandermeersch,
1984). The Aurignacian culture featured the earliest known
widespread use of bone, teeth, and ivory for jewellery and
tools (Bar-Yosef, 2004). Around the time that modern
humans arrived in Europe, Neanderthal technologies in
some areas of Europe experienced a change from the
Kristian J. Herrera and others
Mousterian tool-culture to technologies such as the
Châtelperronian, which featured the usage of bone, ivory,
and body ornaments similar to that of the modern human
Aurignacian culture (Hublin et al., 1996). This seemingly
sudden revolution in implement design and ornamentation
within several Neanderthal populations taking place with
the arrival of modern humans has led to the suggestion that
an acculturation event may have spurred the transformation (Hublin et al., 1996). The possibility that Neanderthals
independently developed the Châtelperronian technology,
though, cannot yet be rejected (d’Errico et al., 1998). If the
Châtelperronian tool-culture was influenced by the invading modern humans, then it would not be surprising if the
differences between it and the Aurignacian were minimal
(d’Errico et al., 1998). Yet, this is far from the case. This has
suggested to some (d’Errico et al., 1998) that Neanderthals
independently created Châtelperronian utensils. However,
modern-human-inspired implements do not have to be
close replicas of those from the original Aurignacians. It is
also revealing that Neanderthals began fabricating more
advanced instruments around the time of the dispersal of
modern humans into Europe, after over 300,000 years of
relatively unchanged usage of Mousterian tools. Thus, it
seems more reasonable to expect that this quantum-leap in
technology was not coincidental but instead the result of
Neanderthals enlightened from contact with modern
humans.
Assuming that one or more acculturation events did
occur between the two groups, it appears to have been
largely unidirectional, with technology passing from
modern humans to Neanderthals (Mellars, 1992). In
addition to technology transfer, some locations provide
evidence suggesting the two species may have coexisted in
close proximity (Mellars, Gravina & Ramsey, 2007). A
Châtelperronian site in central France is controversially
claimed to be interstratified with Aurignacian material,
representing a direct indication of humans and Neanderthals living in close contact (Mellars et al., 2007).
(2) Analyses of fossil data
A number of anthropological findings have also provided
potential indications of hybridization events occurring
during recent human evolution. Discoveries of specimens
with specific characteristics thought to be unique to both
groups have led to increased support for the idea of
admixture in some locales. Perhaps the most notable
example is the 24,500 year old human fossil from the
Abrigo do Lagar Velho in western Portugal, which exhibits
distinct characteristics in its skull and limbs thought to be
indicative of both Neanderthals and modern humans
(Duarte et al., 1999). The conglomeration of features
included limb proportions more akin to Neanderthals than
early modern Europeans, but jaw shape and dentition
exclusive to humans. Duarte et al. (1999) proposed that the
Lagar Velho sample represents evidence for admixture
between Neanderthals and modern humans. Early modern
human fossils unearthed in Romania, the Czech Republic
and China are also said to possess a combination of features
Biological Reviews 84 (2009) 245–257 Ó 2009 The Authors Journal compilation Ó 2009 Cambridge Philosophical Society
Neanderthal/modern Human interactions
from both groups (Trinkaus et al., 2003; Soficaru, Dobos &
Trinkaus, 2006; Shang et al., 2007). The samples from
Romania and the Czech Republic show distinguishing
human features, date to approximately 35,000 years ago
and are therefore considered to be some of the oldest
modern human fossils from Europe. However, not all of
their morphological traits are distinctly modern human. A
few of the skulls’ features follow patterns indicative of
Neanderthal origin and thought to be rare or absent in most
modern humans, including larger dentition and more
robust bones. Similar patterns are reported in the 42–
39,000 year old fossil from Tianyuan Cave near Beijing,
China (Shang et al., 2007). If these patterns did indeed rise
from Neanderthal admixture, then it would be expected
that interbreeding between the two groups took place not
only in Europe, but also Asia and the Middle East.
Additional comparisons of contemporary European skulls
with Neanderthal and Middle Eastern human skulls found
that the European skull was actually more similar to the
Neanderthal skull than to the Middle Eastern, suggesting
two different ancestors for Europeans (Wolpoff et al., 2001).
However, these and other tests using morphological features
to reanalyse modern human origin theories have come
under methodological criticism (Bräuer, Collard & Stringer,
2004). Comparisons of a wide range of other Neanderthal
and modern human mandibles, on the other hand, yield
results antithetical to those from the skulls (Rak, Ginzberg &
Geffen, 2002). In fact, the degree of separation between
Neanderthals and modern humans based on mandibular
variation is even greater than that between modern humans
and Homo erectus. Although finding anatomical features
specific to both species in single individual fossils would
seem to suggest interbreeding, it has been argued that the
supposed Neanderthal-specific traits may be unreliable and
should not be immediately accepted as unequivocal
evidence for admixture (Tattersall & Schwartz, 1999). This
is due not only to difficulties in the assignment of certain
morphological features as being unique to either species,
but to the many gaps remaining in both the archaeological
and fossil records. Interestingly, a clinal distribution of
Neanderthal morphology is observed across Europe and
the Near East (Smith, 1991; Rak, 1993; Arensburg &
Belfer-Cohen, 1998; Voisin, 2006). Fossil samples from
Western Europe are more distinctively Neanderthal while
those from Central Europe and the Near East bear
a greater resemblance to modern humans, which would
be suggestive of gene flow between the two groups (Voisin,
2006).
III. INVESTIGATIONS USING MODERN
HUMAN DNA
Prior to the sequencing of Neanderthal DNA, research
focusing on DNA from contemporary human populations
yielded varying conclusions with respect to archaic
admixture. The vast majority of mitochondrial DNA
studies on modern humans reveal a single recent African
origin (Cann, Stoneking & Wilson, 1987; Vigilant et al.,
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1991; Ingman et al., 2000). These studies collectively came
to the conclusion that mtDNA lineages follow a single,
linear, and recent (<200,000 years ago) path from Africa
and did not experience any assimilation from archaic
populations, including Neanderthals (Cann et al., 1987;
Vigilant et al., 1991; Ingman et al., 2000). Similarly,
Y-chromosome research suggests a recent African origin
for contemporary humans less than 100,000 years ago,
without any genetic input from other Homo lineages
(Thomson et al., 2000; Underhill et al., 2000; Underhill &
Kivisild, 2007).
Although the mitochondrial and Y-chromosome evidence seems conclusive with regard to female and male
lineages surviving in current human populations, it lacks
information on the autosomal portion of the genome.
Although autosomal data are impeded by recombination,
it is estimated that regions of approximately 50,000 base
pairs may remain intact since the time of potential
Neanderthal and modern human admixture events (Wall,
2000). In fact, several recent autosomal studies of
contemporary human populations have yielded evidence
supporting the assimilation of archaic DNA into the
genome of modern humans (Eswaran, Harpending &
Rogers, 2005; Plagnol & Wall, 2006). An extensive series of
statistical simulations of autosomal loci uncovered that the
majority of these markers exhibited signs of introgression,
and that the data suggested a model that involved modern
humans originating from Africa and subsequently assimilating genetic material from archaic hominids (Eswaran
et al., 2005). Eswaran et al. (2005) stipulated that up to 80%
of human loci may have been influenced by archaic
admixture (Eswaran et al., 2005). In a separate study
searching for patterns of linkage disequilibrium reflecting
ancient admixture, it was found that at least 5% of the
modern human genome was introgressed from one or
more archaic species, including Neanderthals in Europe
and another, unknown ancient Homo group in Africa
(Plagnol & Wall, 2006). Most importantly, the statistical
model created by Plagnol & Wall (2006) identified a set of
modern human alleles of single nucleotide polymorphisms
(SNPs) with a high probability of having originated in an
archaic species. These SNP alleles may be useful as
markers to investigate Neanderthal genomic sequences to
confirm or negate the theoretical work of Plagnol & Wall
(2006). Utilising statistical analyses of DNA data from
multiple modern human populations, Fegundes et al.
(2007) suggest that the data support an African replacement model with little to no admixture from archaic Homo
lineages.
A pattern somewhat suggestive of an introgression event
emerges at the tau MAPT locus, a sequence related to
susceptibility to neurological diseases (Baker et al., 1999).
The MAPT region can be divided into two haplotypes,
H1 and H2. Haplotype H2, in particular, strongly
correlates with lower susceptibility to progressive supranuclear palsy and corticobasal degeneration (Houlden et al.,
2001). These two haplotypes diverged approximately
three million years ago (Stefansson et al., 2005), yet the
H2 haplotype is nearly entirely restricted to European
populations (Evans et al., 2004) and seems to have
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appeared in modern humans only 30,000 years ago
(Hardy et al., 2005). This date suggests that the H2
haplotype originated in a population other than from Homo
sapiens and was later incorporated into modern human
groups in Europe, perhaps by Neanderthals (Hardy et al.,
2005). Subsequent positive selection acting upon the H2
locus may have prevented it from being lost to genetic
drift. The singular high prevalence of H2 in Europe argues
for the integration event occurring subsequent to the
penetration of modern humans into the continent, 40,000–
45,000 years ago, corroborating the recent coalescent time
estimates (Stefansson et al., 2005).
Perhaps even stronger evidence comes from a recent
report, which postulates that an allele of the microcephalin
gene that provides a selective advantage was obtained from
Neanderthals by way of an introgression event (Evans et al.,
2006). Microcephalin is a gene known to regulate brain size
during development of the cerebral cortex (Jackson et al.,
2002). A point mutation on base pair 74 of exon 2 is linked
to the disease primary microcephaly, which leads to
a decrease in cranial capacity from the average modern
human size of approximately 1,400 cm3 to about 400–650
cm3 (Jackson et al., 2002).
The microcephalin locus has been separated into two
haplogroups defined by a polymorphism on exon 8, which
is not involved in the onset of primary microcephaly. The
D haplogroup contains the derived allele of this site
relative to chimpanzee, while the non-D haplogroup
possesses the corresponding ancestral state (Evans et al.,
2005). Analyses of modern human DNA from an
ethnically diverse panel consisting of 16 Africans, 25
Europeans, 35 Asians, 6 Pacific Islanders and 7 Andeans
(the Coriell Panel), indicate that haplogroup D is present
in 70% of those analysed, despite having a coalescence age
of only 37,000 YBP (Evans et al., 2006). The less frequent,
non-D haplogroup, on the other hand, has a much older
coalescence age of approximately 990,000 YBP (Evans
et al., 2006). The age difference between the D and non-D
haplogroups suggests that haplogroup D may have been
introgressed from an ancient Homo lineage into the
modern human population by way of an admixture event,
at a time period when Neanderthals and modern humans
were co-habitating (Evans et al., 2006). In addition,
population analyses have shown that the non-D haplogroup is most common in sub-Saharan Africa, while the
D-haplogroup exhibits higher frequencies outside of
Africa (Evans et al., 2006). This implies that the
introgression likely took place subsequent to the modern
human dispersal out of Africa (Evans et al., 2006). Strong
positive selection acting on the derived allele makes it an
even more likely candidate site for an introgression event
(Evans et al., 2005). Strong selection in favour of a given
allele reduces the chance that the haplotype would
disappear due to genetic drift and would also explain its
prevalence despite its recent coalescence estimations
(Evans et al., 2005). Identification of haplogroup D in
the DNA of multiple Neanderthal specimens may provide
further support for the hypothesis that this version of the
microcephalin gene is the result of admixture between
modern humans and Neanderthals.
Kristian J. Herrera and others
IV. EVIDENCE FROM THE NEANDERTHAL
MITOCHONDRIAL GENOME
(1) The first mtDNA sequences from
Neanderthals
Due to its susceptibility to environmental damage, DNA in
fossils is typically present only in very small quantities and is
often highly fragmented or modified, compromising its
analysis (Pääbo, Higuchi & Wilson, 1989; Hoss et al., 1996).
Therefore, it was not until the advent of PCR (Mullis &
Faloona, 1987) that the sequencing of ancient DNA became
a possibility (Pääbo et al., 1989). Initial comparisons of
mitochondrial hypervariable region I (HVRI) DNA
extracted from a Neanderthal specimen in the Feldhofer
cave with a standardised modern human mtDNA sequence,
the Cambridge Reference Sequence (CRS) (Anderson et al.,
1981), indicated a high degree of divergence between
Neanderthals and modern humans (Krings et al., 1997). In
this study, Krings et al. (1997) reported an average of 27.2
]/[ 2.2 substitutions over 360 base pairs between the
Neanderthal and individuals from various modern human
populations; more than three times the average number of
substitutions detected between individuals from the same
contemporary human populations. This supports a most
recent common ancestor (MRCA) between modern
humans and Neanderthals living approximately 550,000–
690,000 YBP (Krings et al., 1997). Interestingly, this date is
250,000-390,000 years older than the estimated MRCA
based on some fossil and archaeological data (Foley & Lahr,
1997). However, this discrepancy may be expected, since
alleles from ancient polymorphisms could be partitioned in
a lineage-specific manner and separation of ancestral
populations will allow clade-specific mutations to accumulate in DNA prior to large-scale anatomical differences
becoming evident in the populations (Nei, 1987).
The majority of subsequent mtDNA analyses (Ovchinnikov
et al., 2000; Gutierrez, Sanchez & Marin, 2002; Schmitz et al.,
2002; Serre et al., 2004; Beauval et al., 2005; Lalueza-Fox et al.,
2006) using a total of 11 Neanderthal specimens ranging from
the Iberian Peninsula to the Caucasus Mountains, corroborate the results of Krings et al. (1997). These Neanderthal
samples contain a net total of 40 base pair differences from
the modern human CRS over a sequence length of 363 base
pairs. Of these differences, 18 are non-polymorphic among
Neanderthals, six are identical in all but one or two
specimens, six are found only in the Feldhofer 1 sample
(Krings et al., 1997), and three are unique to the Mezmaiskaya
sample from the Caucasus mountains (Ovchinnikov et al.,
2000). Two additional sequences extracted from fossils in
Feldhofer and Vindija were obtained from the Hypervariable
Region II (HVRII) (Krings et al., 1999, 2000). These two
studies confirmed the results obtained by the HVRI
sequences, yielding data that corroborate that the number
of differences between Neanderthal and modern human
HVRII sequences is three times higher than the highest
number of differences between any two modern human
HVRII fragments (Krings et al., 1999, 2000). Collectively,
the above investigations on both HVRI and HVRII indicate
that this limited number of Neanderthal specimens possess
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mtDNA highly divergent and distant from extant humans,
arguing against maternally driven introgression in either
direction.
(2) Older, more diverse Neanderthal mtDNA
sequences
It is noteworthy that many of these early studies examined
samples that seemed to be constituents of a Neanderthal
population that was relatively low in genetic diversity
(Krings et al., 2000; Excoffier, 2006). The divergence
estimates calculated from these early studies were close to
those found within or between various modern human
populations (Krings et al., 2000). Such restrictions may have
limited the probability of finding sequences similar to
modern humans (Krings et al., 2000). Therefore, it was still
necessary to expand the collection of mtDNA sequences of
Neanderthals before any conclusions could be drawn. This
need was alleviated with the examination of mtDNA from
two older Neanderthal fossils, an approximately 50,000 year
old sample from Monti Lessini in Italy (Caramelli et al.,
2006) and an approximately 100,000 year old fossil from
Scladina in Belgium (Orlando et al., 2006). Together, the
mtDNA sequences from the older specimens suggest that
Neanderthals were much more genetically diverse than
previously hypothesized (Excoffier, 2006). When compared
with a 296 bp region from Neanderthal mtDNA HVRI
sequences from prior investigations (Krings et al., 1997;
Ovchinnikov et al., 2000; Serre et al., 2004), the 50,000 year
old Monti Lessini specimen yielded three unique nucleotide
differences, as well as two changes that were shared only
with the Mezmaiskaya sample (Excoffier, 2006). A comparison of the same mtDNA sequence from the Monti Lessini
sample with modern humans yielded only 23 substitutions,
suggesting that the Monti Lessini specimen is more closely
related to modern humans than the previously investigated
Neanderthals (Caramelli et al., 2006). The 100,000 year old
Scladina sequence, on the other hand, was more divergent
from both the other Neanderthal samples and modern
humans, exhibiting 14 differences from the Revised Cambridge
Reference Sequence (R-CRS) over only a 123 bp sequence,
including three never-before-identified substitutions
(Orlando et al., 2006). Within the same stretch of mtDNA,
the previously investigated sequences (Krings et al., 1997;
Ovchinnikov et al., 2000; Serre et al., 2004; Lalueza-Fox et al.,
2006) exhibit an average of only 11.6 ]/[ 0.49 substitutions
from the R-CRS, with only one site being variable. Relative to
the Scladina sample, the Neanderthal fossils that have been
dated to more recent times are more similar to modern
human sequences (Excoffier, 2006), possibly indicating that
modern human and Neanderthal mtDNA converged
through introgression during the arrival of modern humans
in Europe. However, the dating of the Monti Lessini sample to
50,000 years ago suggests that the most human-like sequence
was already present in Neanderthals prior to the arrival of
modern humans in Europe (Excoffier, 2006). It is possible that
the decrease in genetic diversity was the result of either
a putative selective sweep that may have acted upon
251
Neanderthals 100,000–40,000 YBP (Excoffier, 2006) or
a possible bottleneck occurring 60,000–70,000 YBP (van
Andel & Tzedakis, 1996). Either scenario could have
potentially reduced the diversity of the Neanderthal gene
pool, leaving only Neanderthals that fell within the limited
diversity exhibited by the more recent specimens.
(3) Issues involving the mtDNA sequences
The present collection of mtDNA sequences does not argue
for introgression of mtDNA from Neanderthals into
modern humans or vice versa (Excoffier, 2006). However,
these regions of the mtDNA may be selectively neutral, and
genetic drift may hamper the detection of introgressed
DNA in a limited number of individuals (Nordborg, 1998).
In fact, several studies have examined the probabilities of
introgression events in modern human mtDNA being lost to
genetic drift in extant human mtDNA (Nordborg, 1998;
Currat & Excoffier, 2004; Serre et al., 2004). Both Nordborg
(1998) and Serre et al. (2004) agree with a maximum
possible mtDNA contribution from Neanderthals of 25%.
Conversely, the statistical model of Currat & Excoffier
(2004) proposes a more complex depiction of modern
human expansions into Europe, and predicts that the
maximum rate of admixture had to be less than 0.1%;
a rate corresponding with no more than 120 specific
matings over the entire course of the Neanderthal and
modern human coexistence.
V. EVIDENCE FROM THE NEANDERTHAL
NUCLEAR GENOME
(1) The earliest large-scale sequencing efforts
The 16.7 kB haplotype of the mtDNA genome only
represents the maternal lineages. Any sexual bias in mating
patterns and/or genetic drift might mask the detection of
Neanderthal and modern human admixture events as
a result of Neanderthal mitochondrial lineages being lost
from the modern human gene pool over time. Since
mtDNA haplotypes genetically behave as a single locus,
they are particularly susceptible to evolutionary drop-outs.
Therefore, it has become increasingly apparent that
autosomal nuclear DNA analyses are also necessary to
ascertain potential introgression events (Dalton, 2006;
Hebsgaard et al., 2007). Fortunately, a recent breakthrough
in DNA sequencing technology has allowed researchers to
isolate and sequence higher quantities of ancient DNA
(Margulies et al., 2005). The new method enables highthroughput sequencing of the highly fragmented DNA that
results from degradation over time.
Following an extensive search for the Neanderthal fossils
with the most highly preserved, unfragmented DNA, two
separate efforts (Noonan et al., 2006; Green et al., 2006) led
to the assessment and release of large quantities of
Neanderthal DNA sequences. The study by Noonan et al.
(2006) yielded approximately 65,000 base pairs of Neanderthal nuclear DNA, while Green et al. (2006) released
Biological Reviews 84 (2009) 245–257 Ó 2009 The Authors Journal compilation Ó 2009 Cambridge Philosophical Society
252
roughly one million base pairs of Neanderthal nuclear
DNA. Interestingly, however, the two reports produced
conflicting results with regard to the question of modernhuman-Neanderthal admixture (Wall & Kim, 2007). The
dataset released by Noonan et al. (2006) shows few data
supporting admixture between Neanderthals and modern
humans. Using the NCBI Reference Genome, Noonan et al.
(2006) yielded a MRCA date for Neanderthals and modern
humans of 706,000 YBP (confidence interval 468,000–
1,015,000 years ago). In addition, Noonan et al. (2006)
found that 3% of the SNPs present in the Neanderthal
sequences exhibit the derived state with respect to the
chimpanzee genome. From this, Noonan et al. (2006)
estimate 0% (confidence interval 0–20%) admixture
between Neanderthals and modern humans. Conversely,
Green et al. (2006) calculated a MRCA date for modern
humans and Neanderthals of only 516,000 years ago
(confidence interval 465,000–569,000 YBP). To establish
a frame of reference for this date, Green et al. (2006)
generated sequences from a contemporary modern human
using the same sequencing methods used for the Neanderthal, and subsequently calculated the MRCA between those
sequences and the NCBI Reference genome. Interestingly,
their calculated date of 459,000 YBP (confidence interval
419,000–498,000) overlaps considerably with that of the
Neanderthal sequences. Furthermore, the study performed
by Green et al. (2006) demonstrated that Neanderthals
possessed the derived allele (in reference to the chimpanzee
ancestral allele) for 30% of all human SNPs within the
dataset. Such a high number of SNPs exhibiting the derived
state implies either that the majority of the polymorphisms
were in place as common-ancestral polymorphisms prior to
the split of Neanderthals and modern humans or were
introgressed at a much later time, suggesting that there was
a considerable amount of gene flow between the two
lineages.
(2) Issues relating to the genomic studies
The discrepancies between the sequencing results of
Noonan et al. (2006) and Green et al. (2006) have led to
a reanalysis of both datasets using the methodology of
Noonan et al. (2006) (Wall & Kim, 2007). Wall & Kim (2007)
found that the Noonan et al. (2006) study supported
a Neanderthal and modern European population split
occurring approximately 325,000 YBP with limited admixture between the two groups. However, reanalysis of the
Green et al. (2006) data suggests a Neanderthal-European
human population divergence around 35,000 YBP and up
to 95% introgression. These numbers are in direct
contradiction with nearly every human-Neanderthal comparison to date (Wall & Kim, 2007). The high amount of
introgression estimated from the Green et al. (2006) data
seems to indicate that one or more errors occurred in the
process of generating the Green et al. (2006) sequences such
as modern human DNA contamination, alignment errors,
and/or sequencing misreads (Wall & Kim, 2007).
Under the assumption that longer autosomal DNA
fragments are more likely to represent modern human
Kristian J. Herrera and others
contaminants, Wall & Kim (2007) estimated the divergence
times of three groups of sequences from the Green et al.
(2006) dataset based on size. They observed that while short
sequences agreed with the divergence time obtained by
Noonan et al. (2006), the long sequences from the Green et
al. (2006) data yielded a much younger date. Furthermore,
in each of these three groups, they found that the
percentage of modern human SNPs for which the derived
state appears in Neanderthals is highest in the longer
fragments (Wall & Kim, 2007). Wall & Kim (2007) also
noted that the sequences generated by Noonan et al. (2006)
contained a higher rate of substitutions that are more likely
to be caused by post-mortem damage (C/T and G/A)
(Hofreiter et al., 2001) than those of Green et al. (2006). Such
errors may have affected calculations of divergence and
admixture rates (Wall & Kim, 2007). The authors indicate
that the most likely scenario is that approximately 73% of
the sequences produced by Green et al. (2006) were derived
from modern human DNA contaminants.
(3) Searches for genes
In addition to random, large-scale sequencing of Neanderthal autosomal DNA, there have also been efforts to
examine specific genes such as Forkhead Box P2 (FOXP2)
(Krause et al., 2007b). FOXP2 is one of the most highly
conserved genes in the mammalian genome (Enard et al.,
2002) and is essential for the proper development of speech
(MacDermot et al., 2005). A defective form of the gene,
related to a missense mutation at position 328 of exon 7,
is known to cause developmental verbal dyspraxia
(MacDermot et al., 2005). Since the divergence of humans
and chimpanzees, two independent single base pair
substitutions have accumulated in the FOXP2 gene, both
of which are located in exon 7, at positions 911 and 977
(Enard et al., 2002). Using population data from the flanking
sequences surrounding exon 7, a coalescence simulation
concluded that a selective sweep ending approximately
200,000 years ago may have acted upon the gene (Enard
et al., 2002). Retrieval of the FOXP2 diagnostic sites in two
distinct Neanderthal samples demonstrated that both
specimens contain the derived allele. The presence of the
derived state implies that either these two substitutions
occurred prior to the split of Neanderthals and humans, or
that the derived FOXP2 allele was introgressed from
Neanderthals to modern humans or vice versa (Krause
et al., 2007b). The coalescence age of the gene to
approximately 200,000 years ago in modern humans makes
it logical to consider that FOXP2 was introgressed from
modern humans into Neanderthals, as opposed to the other
way round, which would necessitate an older coalescence
date (Coop et al., 2008). In addition, recent reanalysis of the
FOXP2 data suggests that low rates of gene flow between
modern humans and Neanderthals was a likely scenario
(Coop et al., 2008).
Krause et al. (2007b) also generated information with
regard to paternally inherited Y-chromosome data in
Neanderthals. These Y-chromosome sequences were utilised as controls to assess the level of modern human DNA
Biological Reviews 84 (2009) 245–257 Ó 2009 The Authors Journal compilation Ó 2009 Cambridge Philosophical Society
Neanderthal/modern Human interactions
contamination in the FOXP2 sequences. The dating of the
modern human Y-chromosomal MRCA to 90,000 YBP
(Thomson et al., 2000) allowed Krause et al. (2007b) to test
the level of modern human contamination since this date is
well below that of the expected Neanderthal and modern
human MRCA. In turn, it was expected that the
Neanderthal Y-chromosome divergence from modern
humans would be far greater than that between any two
modern humans. This would only hold true, however, if
introgression between the two groups was limited or nonexistent and not detectable. The results of Krause et al.
(2007b) indicate that all five sequenced Y-SNPs contained
the ancestral allele in both of the Neanderthals that were
further analysed for the FOXP2 gene. Although these
conclusions are only based on a limited number of
individuals and a single haplotype, these data do not argue
for introgression (Krause et al., 2007b).
It is worth mentioning that Krause et al. (2007b)
employed the Y2 (M42) marker to assess the level of
contamination from extant humans in Neanderthal samples. If the fossils were ancestral for M42, Krause et al.
(2007b) assumed that the sample was genuinely Neanderthal. However, testing of M42 alone without assessing the
basal M91/M13 markers does not rule out the possibility of
individuals from the two other sister clades of haplogroup A
(A1 and A3) contributing to contamination. In addition, if
the M91/M13 markers are derived for a given Neanderthal
specimen, it may represent an ancestral polymorphism or
an introgression event. Although the A haplogroup is
currently restricted to Sub-Saharan Africa, it has been
detected in the Levant (Underhill et al., 2000; Richards et al.,
2003; Luis et al., 2004), Syria (Richards et al., 2003) and
Sardinia (Underhill et al., 2000) at low frequencies, where
Neanderthals and modern humans once co-existed. Furthermore, the present distribution of this haplotype mainly
in Africa does not preclude a much wider distribution at the
time of Neanderthal/modern human interaction. Therefore, these issues should be considered when assessing
admixture events.
VI. CONCLUSIONS
(1) At present, incontrovertible evidence for or against
Neanderthal and modern human admixture has yet to be
identified. Reports from varying sources seem to provide
contradictory results. In support of admixture are the
genetic studies of Hardy et al. (2005), Green et al. (2006),
Evans et al. (2006) and Plagnol & Wall (2006), as well
a number of anthropological findings (Duarte et al., 1999;
Trinkaus et al., 2003; Soficaru et al., 2006; Shang et al.,
2007).
(2) However, most of these reports have been criticised for
various reasons, and it is clear that further work is required.
For instance, the sequences produced by Green et al. (2006)
may suffer from modern human DNA contamination (Wall &
Kim, 2007). Similarly, many anthropologists disagree
(e.g. Tattersall & Schwartz, 1999) with resounding statements such as those by Duarte et al. (1999) regarding the
253
identification of hybrids or modern humans with Neanderthallike traits.
(3) The modern human haplotypes that possess signals of
introgression, including the microcephalin D-haplogroup
(Evans et al., 2006) and the H2 haplotype of the MAPT
locus (Hardy et al., 2005) as well as the set of Neanderthalspecific SNPs identified by Plagnol & Wall (2006) are in
need of empirical testing and verification in multiple
Neanderthal samples. Widespread distribution in Neanderthals of either the microcephalin D-haplogroup or the
MAPT H2 haplotype would be highly indicative of
successful interbreeding between modern humans and
Neanderthals.
(4) On the other hand, repeated mtDNA studies and the
work by Noonan et al. (2006) seem to suggest that little or no
gene flow took place between Neanderthals and modern
humans. Studies of mtDNA from both Neanderthal DNA
and modern humans come to this conclusion.
(5) With the recent assessment of modern human
genomes from two individuals (Levy et al., 2007; Wheeler
et al., 2008) one can foresee that the entire sequencing of
multiple individuals from bio-geographically targeted,
extant human populations might also help answer the
question of whether Neanderthals and modern humans
admixed. It is expected that future research in ancient
genetics as well as the forthcoming completion of
a Neanderthal genome and sequencing data from multiple
Neanderthal specimens will continue to shed light on these
species.
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