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#1 Yervant1


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Posted 22 October 2015 - 10:27 AM


European Journal of Human Genetics
Oct 21 2015


Marc Haber1, Massimo Mezzavilla1,2, Yali Xue1, David Comas3, Paolo
Gasparini2, Pierre Zalloua4 and Chris Tyler-Smith1

1The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus,
Hinxton, Cambridgeshire, UK 2Institute for Maternal and Child Health
-IRCCS 'Burlo Garofolo'--Trieste, University of Trieste, Trieste, Italy
3Institut de Biologia Evolutiva (CSIC-UPF), Departament de Ciències
de la Salut i de la Vida, Universitat Pompeu Fabra, Barcelona, Spain
4The Lebanese American University, Chouran, Beirut, Lebanon

Correspondence: Dr C Tyler-Smith, The Wellcome Trust Sanger Institute,
Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK.

Tel: +44 1223 834244; Fax: +44 1223 494919; E-mail: cts@sanger.ac.uk

Received 17 February 2015; Revised 12 July 2015; Accepted 21 July
2015 Advance online publication 21 October 2015


The Armenians are a culturally isolated population who historically
inhabited a region in the Near East bounded by the Mediterranean and
Black seas and the Caucasus, but remain under-represented in genetic
studies and have a complex history including a major geographic
displacement during World War I. Here, we analyse genome-wide
variation in 173 Armenians and compare them with 78 other worldwide
populations. We find that Armenians form a distinctive cluster
linking the Near East, Europe, and the Caucasus. We show that Armenian
diversity can be explained by several mixtures of Eurasian populations
that occurred between ~3000 and ~2000 bce, a period characterized
by major population migrations after the domestication of the horse,
appearance of chariots, and the rise of advanced civilizations in the
Near East. However, genetic signals of population mixture cease after
~1200 bce when Bronze Age civilizations in the Eastern Mediterranean
world suddenly and violently collapsed. Armenians have since remained
isolated and genetic structure within the population developed ~500
years ago when Armenia was divided between the Ottomans and the
Safavid Empire in Iran. Finally, we show that Armenians have higher
genetic affinity to Neolithic Europeans than other present-day Near
Easterners, and that 29% of Armenian ancestry may originate from an
ancestral population that is best represented by Neolithic Europeans.

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Insights into the human past come from diverse areas including history,
archaeology, linguistics, and, increasingly, genetics. The observed
patterns of present-day genetic diversity can be compared with models
that include past population processes such as migration, divergence
and admixture, and the best model chosen. These models often require
representing ancestral populations and mostly consider present-day
populations as direct descendants of the ancient inhabitants of a
region. However, archaeological and genetic data reveal that human
history has often been shaped by regional or localized population
movements that can confound simple demographic models.1, 2 Ancient DNA
(aDNA) studies have also shown that the genetic landscape has been
continuously shifting,3, 4 possibly triggered by environmental and
cultural transitions. aDNA research is useful for understanding past
demographic events; however, samples are limited and obtaining aDNA
from warm climates remains a challenge. We have previously shown that
studying genetic isolates also provides insights into human genetic
variation and past demographic events.5 For example, by studying Jews,
Druze, and Christians from the Near East, we showed that the region
had more genetic affinity to Europe 2000 years ago than at present.5

In the present study, we investigate the Armenians, a population today
confined to the Caucasus but who occupied Eastern Turkey, reaching
as far as the Mediterranean coast, until the start of the twentieth
century (CE; Figure 1). Political turmoil in the region during World
War I resulted in the displacement of the Armenian population and
its restriction today to an area in the Caucasus between the Black
and the Caspian seas. Armenians are an ethno-linguistic-religious
group distinct from their surrounding populations. They have their own
church, the Armenian Apostolic Church, which was founded in the first
CE and became in 301 CE the first branch of Christianity to be adopted
as a state religion. They have also their own alphabet and language,
which is classified as an independent branch of the Indo-European
language family. The Armenian language is a subject of interest and
debate among linguists for its distinctive phonological developments
within Indo-European languages and for its affinity to Balkan
languages such as Greek and Albanian. The historical homeland of the
Armenians sits north of the Fertile Crescent, a region of substantial
importance to modern human evolution. Genetic and archaeological
data suggest that farmers expanding from this region during the
Neolithic populated Europe and interacted/admixed with pre-existing
hunter-gatherer populations.6 Furthermore, Armenia's location may have
been important for the spread of Indo-European languages, since it is
believed to encompass or be close to the Proto-Indo-European homeland
(Anatolia or Pontic Steppe) from which the Indo-Europeans and their
culture spread to Western Europe, Central Asia, and India.

Figure 1.

Map of the Near East and surrounding regions. The map shows the
location of the present-day Armenia and neighbouring countries. Blue
lozenges show the recruitment sites for the Armenian samples used
in this study. Political turmoil during World War I resulted in the
displacement of the East Turkey Armenian population (orange lozenge)
to present-day Armenia or to several other nearby countries such
as Lebanon.

Full figure and legend (121K)

Previous genetic studies of Armenians are scarce and genome-wide
analysis is limited to a few Armenian samples in broad surveys
without any detailed analysis. Armenians were found to have genetic
affinity to several other populations including the Jews, Druze,
and Lebanese Christians, in addition to showing genetic continuity
with the Caucasus.5, 7, 8

In this study, we analyse newly generated genome-wide data from
Armenians, as well as available data from 78 other worldwide
populations. We investigate genetic signatures of past events such as
the emergence of Armenians as an ethnic group, the cultural changes
in the Near East, and the expansions of ancient populations in
this region.

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Materials and methods

Subjects and the genetic data sets

Armenian samples were collected from Lebanon (n=39) and Armenia:
Chambarak (n=30), Dprabak (n=18), Gavar (n=12), Martuni (n=19),
Yegvard (n=11), and Yerevan (n=9). Armenian individuals recruited in
Lebanon traced their ancestry to East Turkey; they signed informed
consent approved by the IRB of the Lebanese American University and
were genotyped on Illumina 610 or 660â~@~IK bead arrays.

Armenian subjects recruited from present-day republic of Armenia signed
consents approved by the ethical committee of the Maternal and Child
Health Institute IRCCS-Burlo Garofolo Hospital (Trieste, Italy).

Samples were genotyped on Illumina HumanOmniExpress and described
previously by Mezzavilla et al.9

Genotype data can be downloaded as VCF files from the
European Variation Archive www.ebi.ac.uk/eva under
accession number PRJEB9822 or as plink files from

In addition, Armenian samples (n=35) were added along with 1509 samples
from the literature that represent 78 worldwide populations.5, 7, 8, 10

PLINK11 was used for data management and quality control. The required
genotyping success rate was set to 99%, sex-linked and mitochondrial
SNPs removed, SNPs with MAF <0.001 and H-W P-value <0.000001 also
removed, leaving 300â~@~I899 SNPs. Genotypes were phased with SHAPEIT12
using the 1000 Genomes Phase 1 haplotypes.13

Population structure

Principal components were computed with EIGENSOFT v 4.214 using 78
global populations, and the Armenian samples were projected onto the
plot. The Bayesian information criterion (BIC) was computed by mclust
(http://www.stat.washington.edu/mclust) over the first 10 principal
components of the projected Armenian samples on the global PCA. The
best model to classify the Armenians according to the BIC values was
with three components (clusters; Supplementary Figure S1).

The inference of population relations from haplotypes was assessed
using Chromopainter15 with 10â~@~I000â~@~I000 burn-in and runtime and
10â~@~I000 MCMC samples. A bifurcating tree of relationships among
these populations was built using fineSTRUCTURE15 (Supplementary
Figure S2).

We investigated convergence by running fineSTRUCTURE twice with
identical parameters but different random seeds and examined the
pairwise coincidence matrix visually using the fineSTRUCTURE GUI. The
two runs were identical, suggesting good convergence.

The effective population size of the Armenians was estimated from
linkage disequilibrium (LD) and the time of divergence between the two
major groups was calculated using NeON16 with default parameters. The
function uses Ne and the genetic distance (Fst) between populations
to estimate their time of divergence. Fst was calculated using the
software 4P.17 The generation time used was 28 years.

Admixture analysis

We used f3 statistics18 f3(A; B,C), where a significantly negative
statistic provides evidence that A is derived from an admixture of
populations related to B and C. We tested all possible f3 statistics
in our data set and calculated SE using blocks of 500 SNPs.19 To date
the time of admixture, we used ALDER20, which computes the weighted
LD statistic to make inferences about population admixture. The
reference populations consisted of 1300 samples and 53 populations
reduced from the original data set by removing populations that
are themselves highly admixed (Supplementary Table 1). We collected
results that were significant (z-score >|4|) and summarize the findings
in Table 1 after pooling populations into respective geographical
groups. Sardinians appear to have a distinctive admixture pattern from
other West Europeans and are therefore shown separately. Sardinians
have a European component but appear to have been less affected than
other Europeans by the post-Neolithic demographic changes in Europe.

Consequently, Sardinians retain high affinity to Neolithic European
farmers such as the Tyrolean Iceman21 and samples from the Early
Neolithic Körös culture.22

Table 1 - Source populations and admixture time for Armenians.

Full table

For tests of genetic affinity to Neolithic Europeans, we merged our
samples with the genome of the Tyrolean Iceman.21 We downloaded the
BAM file mapped to hg18 and called all variants using GATK.23 liftOver
(http://genome.ucsc.edu) was used to convert the coordinates to hg19;
the final data set consisted of 91â~@~I115 SNPs.

For tests of genetic affinity to Mesolithic Europeans, we merged our
data set with the genome of the La Braña sample.24 We downloaded
the BAM file mapped to hg19 and called the variants using GATK. The
final data set consisted of 103â~@~I627 SNPs.

We applied TreeMix19, rooting the tree with a Denisovan genome, and
estimated SEs using blocks of 500 SNPs. We generated 100 bootstrap
replicates by resampling blocks of 500 SNPs to assess the stability of
the tree topology. We used outgroup f3 statistics3, 18 in the form of
f3(Yoruba; Iceman, X) and f3(Yoruba; La Braña, X) to assess the shared
genetic history of the ancient Europeans with the modern populations.

In the absence of admixture with Yoruba, deviation from 0 will be a
function of the shared genetic history of the ancient Europeans and
the non-African population.

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Armenians' relationship to world populations

To study the Armenians' genetic relationship to worldwide populations,
we computed principal components using 78 populations (Supplementary
Table 1) and projected the Armenians onto the plot in a procedure
called 'PCA projection'14 (Figure 2a), which ensures that the PCA
patterns are not affected by the large number of Armenians used in the
analysis. We observe that Armenians form a distinctive cluster bounded
by Europeans, Near Easterners, and the Caucasus populations. More
specifically, Armenians are close to (1) Spaniards, Italians, and
Romanians from Europe; (2) Lebanese, Jews, Druze, and Cypriots from
the Near East; and (3) Georgians and Abkhazians from the Caucasus
(Figure 2b). The position of the Armenians within the global genetic
diversity appears to mirror the geographical location of Turkey.

Previous genetic studies have generally used Turks as representatives
of ancient populations from Turkey. Our results show that Turks are
genetically shifted towards Central Asians, a pattern consistent with
a history of mixture with populations from this region.

Figure 2.

Principal component analysis of >240â~@~I000 SNPs showing the top
two components. (a) The position of Armenians in a global genetic
diversity sample based on 78 populations from 11 geographical regions.

Armenians (173 individuals) were projected to the plot and
therefore did not contribute to the observed global structure. (B)
A magnification shows that the Armenians (red) demonstrate genetic
continuity with the Near East, Europe, and the Caucasus.

Full figure and legend (176K)

These diversity patterns observed in the PCA motivated formal testing
of admixture in Armenians and other regional populations.

Admixture in the Near East

To formally test for population mixture in Armenians, we performed
a 3-population test25 in the form of f3(Armenian; A, B), where
a significantly negative value of the f3 statistic implies that
Armenians descend from a mixture of the populations represented by
A and B, chosen from the 78 global populations. We found signals of
mixture from several African and Eurasian populations (Table 1, Figure
3). The most significantly negative f3 statistics are from a mixture
of populations related to Sardinians and Central Asians, followed by
several mixtures of populations from the Caucasus, Arabian Peninsula,
the Levant, Europe, and Africa. We sought to date these mixture of
events using exponential decay of admixture-induced LD. The oldest
mixture events appear to be between populations related to sub-Saharan
Africans and West Europeans occurring ~3800 bce, followed closely
by a mixture of Sardinian and Caucasus-related populations. Later,
several mixture events occurred from 3000 to 1200 bce involving
diverse Eurasian populations (Table 1, Figure 3).

Figure 3.

Genetically inferred source populations for Armenians, admixture times
and genetic structure. Admixture events were estimated using decay
of linkage disequilibrium with regional populations as sources for
Armenians. Each horizontal coloured line indicates an admixture event
and its width reflects the estimated date of admixture and SE. The plot
also shows the estimated date of establishment of genetic structure
within Armenians (1494-1545 CE). Major historical events and cultural
developments in the Near East are shown at the bottom.

Full figure and legend (138K)

We compared the patterns of admixture in Armenians with those of
other regional populations and detected signals of recent admixture
in most other populations. For example, we find 7.9% (±0.4) East
Asian ancestry in Turks from admixture occurring 800 (±170) years
ago. We also detect sub-Saharan African gene flow 850 (±85) years
ago in Syrians, Palestinians and Jordanians.

Structure of the Armenian population

To investigate the presence of genetic structure within the Armenian
population, we performed model-based clustering on the values of
the Armenian samples from the global PCA. The BIC computed by MCLUST
suggests the best model to classify the Armenians is Î"kA (diagonal
distribution, variable volume, and equal shape) with three components
(clusters). We observe the following: (1) Armenians in the diaspora
that trace their origin to historical Western Armenia (modern-day
East Turkey) form one group (Supplementary Figure S1, Cluster 1). (2)
Armenians in modern-day Armenia (historical Eastern Armenia) are
split into two major groups: 33% form Cluster 1 and 57% form Cluster
2 (Supplementary Figure S1). This structure could be the result of
the Western Armenians' migration to the East after the events of
1915 CE that displaced the entire Western Armenian population. (3)
A few Armenians recruited from Chambarak and Maykop (Republic of
Adygea, Russia) form an outlier to the two major Armenian clusters
(Supplementary Figure S1, Cluster 3).

We investigated Armenian structure further using a procedure called
'chromosome painting',15 which reconstructs the haplotype of every
individual (receiver) in a data set using the haplotypes of other
individuals (donors) in the data set. We then constructed a tree that
infers population relationships and similarities (Supplementary Figure
S2). We found, similarly to our previous clustering results, a fine
genetic structure that splits Armenians into two major groups that are
more similar to each other than to any other global population. The
node containing most Armenians is deep compared with many other
nodes containing several diverse regional populations. This probably
reflects a prolonged isolation of the Armenians from their surrounding
populations as suggested by the LD-based admixture tests.

We estimate from the LD patterns that divergence between the two
major Armenian groups started 450-575 years ago (Figure 3).

Relationship to ancient Europeans

We merged our data set with the genome of the Tyrolean Iceman, a
5300-year-old individual discovered on the Italian part of the Otztal
Alps. We used TreeMix19 to construct a tree of genetic relationships
using representative regional populations plus Armenians and Turks from
the Near East. TreeMix uses a model that allows for both population
splits and gene flow to better capture historical relationships
between populations. We obtained a tree that recapitulates the known
relationships among population groups.

Furthermore, the tree shows that the Iceman shared drift with
Sardinians, as previously reported.21 We then ran TreeMix allowing
it to infer only one migration event, and revealed gene flow from the
Iceman to Armenians, accounting for about 29% of their ancestry. The
graph structure appeared robust in 100 bootstrap replicates with the
first migration (highest weight and lowest P-value), always leading
from the Iceman to Armenians (Figure 4).

Figure 4.

Inferred population tree with one mixture event. The graph was
inferred by TreeMix allowing one migration event. The migration arrow
is coloured according to its weight; the weight is correlated with the
ancestry fraction and shows that 29% of Armenian ancestry is derived
from a population related to ancient Europeans. The graph is stable
in 100 bootstrap replicates.

Full figure and legend (51K)

This structure was further investigated using outgroup f3 statistics.3,
18 The expected value of f3(Yoruba; Iceman, X) in the absence of
admixture with Yoruba will be a function of the shared genetic
history of the Iceman and X (non-African populations). Most shared
ancestry of the Iceman is with Sardinians and other Europeans
(Supplementary Figure S3). This is followed by shared ancestry with
some Near Eastern populations: Cypriots, Sephardic Jews, Armenians,
and Lebanese Christians. Other Near Easterners such as Turks, Syrians,
and Palestinians show less shared ancestry with the Iceman.

To investigate if the affinity of the Near East genetic isolates
to Europeans preceded the arrival of the early farmers to Europe
(represented by the Iceman), we repeated the outgroup f3 statistics and
replaced the Iceman with a 7000-year-old European hunter-gatherer from
Spain (La Braña).24 West European hunter-gatherers have previously
been shown to have contributed ancestry to all Europeans but not to
Near Easterners.6 Consistent with this, we found reduced affinity and
no noticeable structure in the Near Easterners in their relation to
La Braña (Supplementary Figure S4; compared with the Iceman).

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The origins of the Armenians and their cultural uniqueness are poorly
understood. Here, we investigate the information that can be obtained
by genetic analysis of present-day Armenians and comparisons with
other present-day and ancient samples.

The position of the Armenians within global genetic diversity appears
to mirror the geographical location of Turkey, which forms a bridge
connecting Europe, the Near East, and the Caucasus. Turkey's location
and history have placed it at the centre of several modern human
expansions in Eurasia: it has been inhabited continuously since
at least the early Upper Palaeolithic,26 and has the oldest known
monumental complex built by hunter-gatherers in the tenth millennium
bce.27 It is believed to have been the origin and/or route for
migrating Near Eastern farmers towards Europe during the Neolithic,28
and has probably also played a major role in the dispersal of the
Indo-European languages.29

We investigated Armenians further by inferring their admixture
history. The Armenians show signatures of an origin from a mixture
of diverse populations occurring from 3000 to 2000 bce. This period
spans the Bronze Age, characterized by extensive use of metals in
farming tools, chariots, and weapons, accompanied by development of
the earliest writing systems and the establishment of trade routes and
commerce. Many civilizations such as in ancient Egypt, Mesopotamia,
and the Indus valley grew to prominence. Major population expansions
followed, triggered by advances in transportation technology and the
pursuit of resources. Our admixture tests show that Armenian genomes
carry signals of an extensive population mixture during this period.

We note that these mixture dates also coincide with the legendary
establishment of Armenia in 2492 bce. Admixture signals decrease
to insignificant levels after 1200 bce, a time when Bronze
Age civilizations in the Eastern Mediterranean world suddenly
collapsed, with major cities being destroyed or abandoned and most
trade routes disrupted. This appears to have caused Armenians'
isolation from their surroundings, subsequently sustained by the
cultural/linguistic/religious distinctiveness that persists until
today. The genetic landscape in most of the Middle East appears to
have been continuously changing since then. For example, we detect
East Asian ancestry in Turks from admixture occurring 800 (±170)
years ago coinciding with the arrival of the Seljuk Turks to Anatolia
from their homelands near the Aral sea. We also detect sub-Saharan
African gene flow 850 (±85) years ago in Syrians, Palestinians,
and Jordanians consistent with previous reports of recent gene flow
from Africans to Levantine populations after the Arab expansions.5, 30

The admixture pattern in Armenians appears similar to patterns we
have observed in some other genetic isolates in the region, such as
Sephardic Jews and Lebanese Christians, who show limited admixture
with culturally different neighbouring populations in the last two
millennia.5 Our tests suggest that Armenians had no significant
mixture with other populations in their recent history and have thus
been genetically isolated since the end of the Bronze Age, 3000 years
ago. In recent times, we detect genetic structure within the Armenian
population that developed ~500 years ago. The date coincides with the
start of the Ottoman-Persian wars and the split of Armenia into West
and East between the Ottoman Empire in Turkey and the Safavid Empire
in Iran.

One of the most-studied demographic processes in population genetics
is the Neolithic expansion of Near Eastern farmers into Europe
beginning ~8000 years ago. Armenians' location at the northern tip
of the Near East suggests a possible relationship to the expanding
Neolithic farmers. We find in Armenians and other genetic isolates
in the Near East high shared ancestry with ancient European farmers,
with ancestry proportions being similar to present-day Europeans
but not to present-day Near Easterners. These results suggest that
genetic isolates in the Near East - Cypriots (an island population),
Near Eastern Jews and Christians (religious isolates), and Armenians
(Ethno-linguistic isolate) - probably retain the features of an ancient
genetic landscape in the Near East that had more affinity to Europe
than the present populations do. Our tests show that most of the Near
East genetic isolates' ancestry that is shared with Europeans can be
attributed to expansion after the Neolithic period.

Armenians' adoption of a distinctive culture early in their history
resulted in their genetic isolation from their surroundings. Their
genetic resemblance today to other genetic isolates in the Near East,
but not to most other Near Easterners, suggests that recent admixture
has changed the genetic landscape in most populations in the region.

Armenians' genetic diversity reveals that the ancient Near East
had higher affinity to Neolithic Europe than it does now, and that
Bronze Age demographic processes had a major impact on the genetics
of populations in this region.

The importance of populations like the Armenians is not limited to
the study of past demographic processes; isolated populations are
emerging as a powerful tool for many different genetic investigations
such as rare variant associations with complex phenotypes and the
characterization of gene-environment interactions.31 Armenians'
emergence from founders in the Bronze Age, accompanied by a long period
of subsequent isolation, may have enriched rare disease alleles and
therefore merits future medical exploration.

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Conflict of interest

The authors declare no conflict of interest.

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We thank the sample donors for making this study possible. We thank
Qasim Ayub, Levon Yepiskoposyan, and Peter Hrechdakian for their
comments and suggestions on the manuscript. We also thank Collin
Renfrew and Merritt Ruhlen for their comments at early stages of this
study. This work was supported by Wellcome Trust grant 098051.


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