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gcsp-2014-054

O P E N A C C E S S Review article

Arab gene geography: From
population diversities to
personalized medical genomics
Ghazi O. Tadmouri

1
, Konduru S. Sastry

2
, Lotfi Chouchane

2,
*

ABSTRACT

Genetic disorders are not equally distributed over the geography of the Arab region. While a number of

disorders have a wide geographical presence encompassing 10 or more Arab countries, almost half of

these disorders occur in a single Arab country or population. Nearly, one-third of the genetic disorders

in Arabs result from congenital malformations and chromosomal abnormalities, which are also

responsible for a significant proportion of neonatal and perinatal deaths in Arab populations.

Strikingly, about two-thirds of these diseases in Arab patients follow an autosomal recessive mode of

inheritance. High fertility rates together with increased consanguineous marriages, generally noticed in

Arab populations, tend to increase the rates of genetic and congenital abnormalities. Many of the

nearly 500 genes studied in Arab people revealed striking spectra of heterogeneity with many novel

and rare mutations causing large arrays of clinical outcomes. In this review we provided an overview of

Arab gene geography, and various genetic abnormalities in Arab populations, including disorders of

blood, metabolic, circulatory and neoplasm, and also discussed their associated molecules or genes

responsible for the cause of these disorders. Although studying Arab-specific genetic disorders

resulted in a high value knowledge base, approximately 35% of genetic diseases in Arabs do not have

a defined molecular etiology. This is a clear indication that comprehensive research is required in this

area to understand the molecular pathologies causing diseases in Arab populations.

Keywords: Arab populations, neolithic, population genetics, gene geography, genetic disorders, neoplasms

Cite this article as: Tadmouri GO, Sastry KS, Chouchane L. Arab gene geography: From population
diversities to personalized medical genomics, Global Cardiology Science and Practice 2014:54
http://dx.doi.org/10.5339/gcsp.2014.54

http://dx.doi.org/
10.5339/gcsp.2014.54

Submitted: 1 September 2014
Accepted: 11 December 2014
ª 2014 Tadmouri, Sastry &
Chouchane, licensee Bloomsbury
Qatar Foundation Journals. This is
an open access article distributed
under the terms of the Creative
Commons Attribution license CC BY
4.0, which permits unrestricted use,
distribution and reproduction in any
medium, provided the original work
is properly cited.

1
Faculty of Public Health, Jinan University,

Tripoli, Lebanon
2
Laboratory of Genetic Medicine and

Immunology, Weill Cornell Medical

College in Qatar, Qatar Foundation,

Doha, Qatar

*Email: loc2008@qatar-med.cornell.edu

A DEFINITION OF ‘ARAB POPULATIONS’

The term “Arabs” indicates a panethnicity of peoples of various ancestral origins, religious

backgrounds, and historic identities. It is possible to define the geographical area inhabited by Arabs

using one of the two following approaches:

(1) The linguistic approach is a relaxed definition and it includes all populations speaking the

Arabic language and living in a vast area extending from south of Iran in the east to Morocco in

the west including parts in the south-east of Asia Minor, East, and West Africa.

(2) The political definition of Arabs is more conservative as it only includes those populations

residing in 23 Arab States, namely: Algeria, Bahrain, Comoros, Djibouti, Egypt, Eritrea, Iraq,

Jordan, Kuwait, Lebanon, Libya, Mauritania, Morocco, Oman, Palestine, Qatar, Saudi Arabia,

Somalia, Sudan, Syria, Tunisia, United Arab Emirates (UAE), and Yemen.

In the subsequent parts of this paper, it is the political definition that would mainly be used to define

the term “Arab region” or simply “the region”. In all cases, the Arab geocultural unit is the largest in the

world after Russia and Anglo-America. The size of this unit exceeds 375 million people and spans more

than 14 million square kilometers.
1

PALEOLITHIC OUT-OF-AFRICA MIGRATIONS

Archeological excavations, historical records, and molecular analyses, mainly based on the study of

uniparental Y-chromosome and mitochondrial DNA (mtDNA), provided considerable information

regarding the early evolutionary history of modern humans in the vast geographical region embracing

Arab populations. The advent of genomic methodologies based on the simultaneous analysis of

hundreds of thousands of single nucleotide polymorphisms allowed the drawing of conclusions on the

genetic structures of Arab populations with a higher resolution.
2

DNA evidence indicates that modern humans originated in East Africa about 200-100 kiloyears (kyr)

ago then established regional populations throughout the continent.
3
Archeological artifacts excavated

from Taforalt in today’s Morocco indicate that human inhabitation of modern day’s Maghreb region

(i.e., modern day Morocco, Algeria, Tunisia and Libya) dates back to some 82 kyr ago.
4
At that time,

settlements in the region were characterized by developed cultural manifestations that could only be

present in Europe 40 millennia later.
5
According to the Recent Out-of-Africa model, members of one

branch of anatomically modern humans left Africa to the Near East some 70-45 kyr ago.
6,7

Phylogenies

constructed on the basis of mtDNA comparisons are indicative for two possible migration routes in this

episode of human history (see Figure 1):

(1) A major route laid across Bab-el-Mandeb straits in the Red Sea linking modern day Eritrea and

Djibouti in Africa to Yemen, hence, probably making the Arabian Peninsula as the initial

Figure 1. Out-of-Africa migration routes.

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Tadmouri, Sastry & Chouchane. Global Cardiology Science and Practice 2014:54

staging post in the first successful migration of anatomically modern humans out of Africa

70-60 kyr ago.
7-9

Y-chromosome diversity studies in modern Saudi males support this view as

14% of them exhibit a pool typical of African biogeographic ancestry.
10
High diversity in the

Y-haplogroup substructure in samples from the region extends the geography of this active

route to include southern Arabia, South Iran, and South Pakistan. This route has possibly

maintained its important role in influencing gene flow from Africa along the coastal

crescent-shaped corridor of the Gulf of Oman and could have facilitated human dispersals into

the region until nearly 2500 years ago.
11

(2) Another route followed the Nile from East Africa, heading northwards and crossing through the

Sinai Peninsula into the Levant and resulted in a noticeable gene flow during the Upper

Paleolithic and Mesolithic periods between 40-14 kyr ago.
12-14

Recent data from Alu/short

tandem repeat compound systems and genome-wide polymorphisms are in support with this

view with 4-15% of the Levantine groups harboring African ancestry while this influence barely

reaches 1-3% in Southern Europeans.
15-18

Human populations in the Near East then branched

in several directions, some heading north into Europe and others heading east into Asia.
19-22

Y-chromosome analysis supports this view and demonstrates the absence of any significant

genetic barrier in the Levant, where a remarkable genetic variation was attained and gene flow

followed the “isolation-by-distance” model. This is in contrast to a strong north-south genetic

barrier, for both male and female gene flow, in the western Mediterranean basin, defined by

the Gibraltar Strait.
23,24

Paleoanthropological evidence and mtDNA variation analysis indicate that both the Levantine

corridor and the Horn of Africa served, repeatedly, as migratory passageways between Africa and

Eurasia.
14,25

Some of the oldest known genetic mutations that could have followed this route include:

(1) the delta F508 (c.1521_1523delCTT) mutation of the CFTR gene, which is responsible today for a

majority of cases with cystic fibrosis in Europe,
26

and (2) the p.Glu6Val sickle cell mutation associated

with the Benin haplotype and frequently observed in the western coastal region of the Arabian

Peninsula, the Levant, Egypt, and in the Maghreb region.
27

Some studies also support the view that regions near, but external to northeast Africa, like the

Levant, the southern-Arabian Peninsula, or Mesopotamia could have served as incubators for the early

diversification of non-African lineages and the development of local cultural techniques.
10,28,29

Again,

the p.Glu6Val sickle cell mutation provides a supportive evidence for this view since the mutation

associated with the Arab/Asian haplotype seems to be restricted to the eastern coastal regions of the

Arabian Peninsula with milder presence in Mesopotamia and the Levant.
27

THE EARLY FARMERS

Around 12 kyr ago, Neolithic human populations adapted some developed agricultural technologies

that allowed them to cause a far-reaching shift in subsistence and lifestyle. Improvement of the climatic

conditions in the area along with the practice of agriculture helped in the establishment of major

historical settlements with sizeable densities that could have contributed enormously to the genetic

makeup of modern Arab populations. Yet, farming was almost always associated with settlements near

mosquito-infested soft and marshy soil causing large malarial outbreaks.
30-32

These outbreaks

imposed selective pressure on the human genome and amplified the frequencies of several genetic

disorders including sickle cell disease, b-thalassemia, and glucose-6-phosphate dehydrogenase

(G6PD) deficiency.
33-35

Infectious agents that favored humid conditions could have also played major

roles in the selective advantage to a variety of other genetic traits.
36,37

A major example in this category

includes the heterozygote advantage of cystic fibrosis carriers against tuberculosis.
38

On the other

hand, adapting to an active lifestyle along with calorie-restricted diets, common in communities at the

time, could have provided protective features that suppressed the expression of celiac disease, type 2

diabetes, and inflammatory bowel disease.
39

In this phase of human history, the Arabian Peninsula, Sub-Saharan Africa, the Levant and Iran saw

local population expansions from refugia that could have participated in the building of the primitive

Arabian population. Y-chromosome and mtDNA haplogroup data support this view.
9,40

For example,

approximately 62–69% of today’s males in Saudi Arabia share common structures with those in the

near east and this demonstrates a possibly important role for the Levant in shaping the Neolithic

dispersal of human settlements in the Gulf.
10
This genetic evidence is consistent with archeological

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Tadmouri, Sastry & Chouchane. Global Cardiology Science and Practice 2014:54

interpretations of the expansion of sedentary Natufian hamlets in the Levant during the wet phase

15–13 kyr.
41
Male lineage estimates for these prominent Levantine haplogroups indicate a north to

south influence with a history of almost 12 kyr in Saudi Arabia, 11 kyr in Yemen, mainly in the western

region, and only at nearly 7 kyr in Qatar and the UAE.
10
Detailed analyses hint to a major terrestrial

colonization for the eastern Arabian Peninsula, which was followed by subsequent population isolation

from the western Arabian Peninsula and demonstrating significant genetic affinities to near-eastern

populations.
42

Many of the earliest disease-causing genetic mutations might have followed these

steps.
43

In particular, the c.208-2A . G mutation in the human amnionless homolog (AMN) gene,

found in 15% of Imerslund-Gräsbeck syndrome cases, could have emerged in the region around

13.6 kyr. Today, this mutation is responsible for over 50% of the Imerslund-Gräsbeck syndrome cases

among Arabic, Turkish, and Sephardic Jewish families.
44

On the other hand, studies of mtDNA

variability confirm a notable sub-Saharan African female-driven flow in the Arabian Peninsula.
9,25,29

Iranian influence also existed, but this was weakened by the presence of barriers to gene flow posed by

the two major Iranian deserts and the Zagros mountain range.
45

Analysis of the pattern of Y-chromosome and mtDNA variations in North Africa provides evidence of

the relatively young population history of North Africa mainly influenced by a strong demic expansion

of Neolithic pastoralists from the Levant and possible admixture with original settlers.
7,46,47

Some of

these earliest civilizations in the Maghreb region include immigrant Berbers who originated from the

Sahara 10,000 years ago and left considerable gene imprints in the gene pool of the populations

inhabiting the area between modern day Mauritania and southern Egypt.
48,49

Nearly 2,000 years later,

Mesolithic Capsians became the next influential genetic stock in the region.
50

MAJOR EVENTS IN ANCIENT HISTORY

In the Arabian Peninsula, Semitic-speaking peoples of Arabian origin migrated into the valley of the

Tigris and Euphrates rivers in Mesopotamia some 7,000-5,500 years ago.
51,52

Analysis of Y

chromosome and mitochondrial DNA in Iraqi Marsh Arabs revealed a prevalent autochthonous Middle

Eastern component for both male and female gene pools, with weak Southwest Asian and African

contributions.
29

The detailed analysis of genome-wide variation patterns among Qataris indicate that

the Southwest Asian influence is derived from Greater Persia rather than from China while the African

stock has a sub-Saharan origin and not a Southern African Bantu origin.
53
Data from the neighboring

Bahraini and Emirati populations reveal an increasing North-to-South influence of the Southwest Asian

component with a high contribution of 23% and 24%, respectively.
54

This could also explain the

exceptionally high frequencies of the Asian sickle cell mutation in the region extending from Kuwait to

the United Arab Emirates.
27

Archeological evidence further indicates that another group of Semites left Arabia around 4,500

years ago during the Early Bronze Age and settled along the Levant and mixed in with the local

populations there. Some 3,500 years ago, the Phoenician civilization of Lebanon became a developed

enterprising maritime trading culture. Phoenician traders spread across the Mediterranean and

established major cities and colonies that harbored their pathologic or polymorphic gene

variations.
55-58

Among the pathologic gene variations that could have followed Phoenician footsteps

are (1) the IVS-I-110 (c.93-21G . A) beta-globin gene mutation, the most frequently encountered

beta-thalassemia mutation among Arabs, and (2) the p.G542X mutation in the CFTR gene, a frequently

observed cystic fibrosis mutation in the Mediterranean basin.
56,59

Results of the Genographic

Consortium from Y-chromosome variations indicate that as many as 1 in 17 men living today on the

coasts of North Africa and southern Europe may have a Phoenician direct male-lineage ancestry.
60

The

genetic pool was further enriched in Mesopotamia through Persians while Romans gained a 600

year-long period of settlements throughout most of the region that were subsequently replaced by the

Byzantines.
61

MAJOR EVENTS IN MEDIEVAL HISTORY

Soon after the rise of Islam 1,400 years ago, the Arab Caliphates unified the region flanking the

Mediterranean and amalgamated the dominant ethnic identity that persists today in the Near East, the

Levant, the Maghreb, and Andalusia in the Iberian Peninsula.
58,62,63

The Arabian Peninsula gained and

increasing role and linked distant populations of China and India to communities of the Mediterranean

and beyond. During this period, demographical dynamics were predominantly governed by cultural

change in endogenous populations rather than demic influences with significant gene flow.
64
This view

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Tadmouri, Sastry & Chouchane. Global Cardiology Science and Practice 2014:54

is strongly supported by Y-chromosome analysis of Muslim expansion in India and mtDNA

haplogroups in the Sinai Peninsula and North Africa.
24,65,66

During the 11
th
-13

th
centuries CE, the Levant witnessed major Crusader settlements that could have

caused remarkable genetic drifts and bottlenecks and introduced western European lineages.
58

In the

16
th
Century CE, the impact of the western European gene stock extended to the eastern Arabian

Peninsula where major parts, including today’s Bahrain, felt under the authority of the Portuguese for

nearly 150 years. This presence left clear impressions in the mutational spectrum of common disorders

in the eastern Arabian Peninsula as in the frequent observation of the western Mediterranean Codon 39

(c.118C . T) b-thalassemia mutation;
67-69

reviewed in Obeid and Tadmouri.
27

On the contrary, some

other disorders from the region have possibly spread out to geographically distant locations under this

Portuguese influence as demonstrated in the increasing evidence noted with regard to the world

distribution of Machado-Joseph disease.
70,71

During the 13
th
-19

th
centuries CE, Ottomans controlled

much of the lands surrounding the Mediterranean then expanded their influence to cover all the

Arabian Peninsula and further contributed to the enrichment of the genetic pool in the region.
72

After

the 19
th
century, areas of the Maghreb were colonized by France, Spain and Italy while the Levant,

Egypt, and the Arabian Peninsula where colonized by France and England.

Despite this long trail of historical admixtures, genetic isolates persisted in the Arab region. Some of

these isolates include the inhabitants of the Island of Jerba in Tunisia,
73

the Bedouins of Sinai,
65

the

dwellers of the Dead Sea region in Jordan,
74
the Druze of the Levant,

58
and the Kurdish population of

Northern Iraq.
75

THE GENETIC HETEROGENEITY OF ARABS

Arab populations display some of the highest rates of consanguineous marriages in the world

including a large proportion of first cousin marriages.
76
At a macrogenomic level, this norm permits the

reunion of ancestral chromosomal segments in a homozygous pattern referred to as the autozygome.
77

At a microgenomic level, however, populations in the region exhibit exceptionally high levels of

variance within those runs of homozygosity.
2
This variance seems to follow a sexually asymmetric

model with higher heterogeneity recorded among the female groups while paternal lineages are mostly

of autochthonous origin.
29,78

In either way, this variance leads phenotypically to a wide array of more

than 1,100 genetic disorders described in the region of which 44% are confined to a single population

or region, a diversity of affected body systems and of clinical outcomes, and a diversity of disease

incidence and geographical distributions (reviewed in Tadmouri
79
).

While the common practice of consanguinity seems to have also contributed to the preponderance

of more autosomal recessive (60%) than autosomal dominant (28%) disorders in the region,
76

it is

probably the large spectra of pathological gene mutations associated with many genetic disorders in

the region that emphasizes the genetic heterogeneity of Arab populations at its best. The following

disease families represent few examples of a continuously growing list of disorders related to a long list

of mutations many of which have possibly originated in the region.

BLOOD DISORDERS

b-Thalassemia

b-thalassemia syndromes are a group of hereditary disorders characterized by a genetic deficiency in

the synthesis of beta-globin chains. A meta-analysis of 6,652 b-thalassemia alleles from 17 Arab

populations indicated the presence of 73 out of the ,250 b-globin gene mutations occurring
worldwide. In contrast to many world populations, this heterogeneity seems to be a common

observation in many Arab populations irrespective of the size of pooled b-thalassemia alleles. This

case is clearly demonstrated in Algeria, Egypt, Morocco, Tunisia, and the United Arab Emirates

exhibiting the largest heterogeneity with more than 20 b-thalassemia mutation types described in each

population so far (reviewed in Obeid and Tadmouri
27
).

Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency

G6PD deficiency is an X-linked inherited disorder caused by a defect or deficiency in the production of

an important red blood cell enzyme called G6PD. G6PD deficiency may cause the sudden destruction of

premature red blood cells leading to hemolytic anemia since the body cannot compensate for the

destroyed cells. In Tunisia, the African G6PD*A
–
variant is the most prevalent among G6PD patients and

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Tadmouri, Sastry & Chouchane. Global Cardiology Science and Practice 2014:54

causes a severe phenotype hemolytic anemia following the ingestion of fava beans.
80

This mutation is

also followed by the G6PD*Mediterranean (c.563C . T; p.Ser188Phe) and the G6PD*Aures

(c.143T . C; p.lle48Thr) mutations. The later, was originally described in Algeria and then in Saudi

Arabia.
81,82

The analysis of mildly affected males, revealed the presence of the association of

c.1311C . T, a newly described silent mutation in the exon 12, with the c.93T . C polymorphism in the

intron 11 and two single intronic base deletions: IVS-V-17 (-C) and IVS-VIII-43 (-G).
80

In Sudan, the

G6PD*B variant represents the most common type of enzyme in all the population groups. However,

the mutant G6PD*A
þ
enzyme, but with normal activity, is prevalent among individuals of African

descent. Among the deficiency-causing variants G6PD*Mediterranean and G6PD*A
–
are the most

common.
83
The genetic heterogeneity of G6PD further continues in the Arabian Peninsula. In the United

Arab Emirates, G6PD*B
þ
is the major allele described among non-deficient subjects while the

G6PD*Mediterranean mutation is the most common cause of G6PD deficiency among Emirati

patients.
84

Other mutations detected include: the African G6PD*A
–
(c.202G . A) and the G6PD*Aures

mutations.
84

This spectrum of mutations seems to be common with neighboring Kuwait, where the

G6PD*Mediterranean and the African G6PD*A
–
genotypes are the most common followed less frequent

G6PD*Chatham and G6PD*Aures alleles.
85

The Saudi population is also no exception, the G6PD*A
2
,

G6PD*Mediterranean, and G6PD*B
þ
are the major variants producing a severe deficiency state among

affected individuals. These variants exhibit a significant difference in their frequencies, with the highest

recorded in areas that were endemic to malaria and have high frequencies of sickle cell disease and

b-thalassemia, namely, the Eastern and the Southern Regions.
86,87

In neighboring Jordan, molecular

screening of G6PD alleles revealed a higher incidence of the disease in Jordan Valley, known for its

historically higher rates of malaria, when compared to the Amman area and has also shown the

existence of six mutations: the c.563C . T G6PD*Mediterranean mutation (53%), the African G6PD*A
–

(c.376A . G þ 202G . A; p.Asn126Asp þ Val68Met) mutation, G6PD*Chatham (c.1003G . A;

p.Ala335Thr), G6PD*Valladolid (c.406C . T), G6PD*Aures (c.143T . C), and G6PD*Asahi

(c.202G . A).
88

Molecular screening of G6PD alleles in Iraqi Kurdish males indicated that the

G6PD*Mediterranean variant was the most common (88%), followed by the G6PD*Chatham variant

(c.1003G . A; 9%).
89

In a study of 21 unrelated individuals with G6PD*Mediterranean,
90

confirmed

that almost all patients from Saudi Arabia, Iraq, Iran, Jordan, Lebanon, and Palestine share the

c.563C . T mutation.

METABOLIC DISORDERS

Cystic fibrosis

Cystic fibrosis is a multi-system life threatening inherited disorder that primarily affects the lungs and

digestive system. The spectrum of cystic fibrosis mutations in Arab populations reveals a major

difference from worldwide observations. For examples, more than 70% of cystic fibrosis patients with

European ancestry show the delta F508 (c.1521_1523delCTT) mutation of the CFTR gene. In Arab

patients these figures are far from being homogenous. A comprehensive meta-analysis of 827 alleles

with cystic fibrosis and encompassing 15 Arab populations revealed a wide spectrum of 56 CFTR gene

mutations responsible for the disease in the region (unpublished observations). This heterogeneity

seems to continue at regional level as well. For instance, the cystic fibrosis population of the Arabian

Peninsula exhibit 17 CFTR mutations. In Saudi Arabians, the 3120 þ 1G . A (c.2988 þ 1G . A) CFTR

mutation is the most common, while in Kuwait it is replaced by the delta F508 mutation. In neighboring

Bahrain, three mutations other mutations seem to prevail, these are: 2043delG (c.1911delG), 548A . T

(c.416A . T), and 4041C . G (c.3909C . G). This battery of mutations is replaced in Qatar by the

commonly observed c.3700A . G (p.I1234V) mutation in the CFTR gene. The picture further changes in

Oman and the United Arab Emirates where the c.1647T . G (p.S549R) mutation is common and the

delta F508 occurs at relatively low frequencies, but exclusively in patients of Baluchi descent (reviewed

in Obeid and Tadmouri
27
).

Lipoid congenital adrenal hyperplasia

This is a severe genetic disorder of steroid hormone biosynthesis, in which the production of all adrenal

and gonadal steroids is significantly impaired by a severe defect in the conversion of cholesterol to

pregnenolone. Worldwide, lipoid congenital adrenal hyperplasia is caused by nearly 35 mutations in

the steroidogenic acute regulatory (StAR) protein gene. Collective results of 20 Arab patients from

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Tadmouri, Sastry & Chouchane. Global Cardiology Science and Practice 2014:54

Libya, Egypt, Palestine, Jordan, Kuwait, Qatar, Saudi Arabia, and Yemen indicate the presence of 12

mutations including five novel ones in the StAR gene (reviewed in Obeid and Tadmouri
27
).

DISORDERS OF THE CIRCULATORY SYSTEM

An extensive survey on genetic disorders in Arab people indicated that there are at least 27 disorders of

the circulatory system known to run in Arab families.
79

However, unlike blood disorders and common

metabolic abnormalities, appreciation of the genetic etiologies of diseases of the circulatory system

has only occurred in the last decade. This resulted in the presence of scanty information that hints to

specific genetic signatures characteristic of Arab patients with cardiovascular disorders.

Congenital heart disease (CHD)

CHD is a structural abnormality of the heart or intra-thoracic great vessels. It is the most common birth

defect worldwide representing one third of all congenital malformations presenting in the neonatal

period. Arabs are liable to have more children with congenital defects including CHD because of high

fertility rates.
76,91

The presence of small isolated communities in different parts of the Arab world with

the common practice of consanguinity is another evidence of high incidence of CHD (e.g., Armenians,

Bedouins, Druzes, Jews, Kurds, Nubians, Berbers, Tebo, and Twareq). A molecular study in Lebanese

CHD patients identified a differential duplication of a 44-bp intronic segment within the Rel-family

transcription factor gene, NFATC1, suggestive that this gene could be a potential ventricular septal

defect-susceptibility gene.
92

In a prospective study involving 60 Jordanian babies with cleft lip and/or

cleft palate, 47% had CHD. However, no chromosomal studies were performed in these patients.
93

Coronary artery disease (CAD)

A study of Arabs living in Kuwait, found a strong association between a C to G substitution substitution

in the 3-prime untranslated region (3’UTR) of the APOC3 gene with coronary artery disease. The

population in the study included adults from Kuwait, Jordan, Palestine, Lebanon, Syria, Egypt, and

Iraq.
94

In Saudi individuals, CAD was also found to be associated with the 3’UTR allele of the APOC3

gene,
95

but also other associations were found with the MTHFR c.677C . T variant, a platelet

glycoprotein receptor IIIa (PlA1/PlA1) genotype,
96,97

and the null-genotypes of GSTT1 and GSTM1.
98

support of a probable specificity of the genotypic etiology of coronary artery disease in Arabs, no

association was found with the lipoprotein lipase (LPL) polymorphisms (LPL-HindIII and LPL-PvuII);
99

the infrequent band of 3.2-kb of the apolipoprotein A-I/C-III;
100

the insertion/deletion sites in the

polymorphic region of intron 16 of the angiotensin I-converting enzyme (ACE) gene;
101

the p.W64R

polymorphism of the b3-adrenoceptor (b3-AR) gene;
102

PvuII polymorphism in the LPL gene;
103

and the

c.677C . T and c.1298A . C variants of the MTHFR gene.
104

Hypertrophic cardiomyopathy (HCM)

HCM is characterized by an abnormal thickening of the heart muscles, resulting from mutations in one

of several genes that result in defects in the protein component of the cardiac muscles. An apical

hypertrophic cardiomyopathy in father and daughter of a Lebanese Christian family has been reported.

In both, identical segments of the left ventricle were involved by the hypertrophic process with differing

degrees of severity.
105

In an analysis of data pertaining to all patients less than 50-years of age in Qatar,

six of 42 Qataris were diagnosed with HCM, making it the most encountered cardiomyopathy in this

group following dilated cardiomyopathy. HCM occurred in two peaks: one below 15-years of age, and

the other between 36 and 50-years of age. About 27% of the children (between 1- and 15-years) were

found to have HCM. The prevalence rate of HCM was calculated as 3.1 per 100,000 of the population.
106

Arterial tortuosity syndrome

Probably, the earliest account of the disease in the region dates back to year 2000 with the description

of 12 patients from eight different families in Saudi Arabia.
107

The first mutations associated with the

disease, however, were reported six years later in patients of Moroccan origin who had homozygosity

for the c.510G . A (p.W170X) and for a frameshift c.961delG (p.V321fsX391) mutation in the SLC2A10

gene.
108

In Qatar, two mutations, a novel p.R105C and a recurrent p.S81R, were recently described in the

SLC2A10 gene in seven patients from two unrelated families.
109

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Tadmouri, Sastry & Chouchane. Global Cardiology Science and Practice 2014:54

Other disorders

In two consanguineous Saudi families, long QT syndrome (LQTS) was described as segregating with a

novel homozygous splicing mutation in the KCNQ1 gene. The observation of the same mutation in both

families indicated that this could be a founder mutation.
110

On the contrary, Naxos disease, a rare

cardiomyopathy disorder, failed to exhibit linkage with the previously identified plakoglobin gene in

two Saudi patients
111

indicating that the disease might have a private signature in the region.

NEOPLASMS

Neoplasms are not typically regarded as population-specific disorders. However, several aspects of

these disorders differ by race and ethnicity. Among Arabs, several types of cancers show many distinct

features that are quite different from those seen in other populations worldwide. Very preliminary data

from the CTGA (Catalogue for Transmission Genetics in Arabs) Database for genetic disorders in Arab

populations indicate the presence of at least 55 cancer types in Arab people.
112

Breast, ovarian, lung,

and colorectal cancers are the main cancers that run in Arab families. Cancer susceptibility genes for

many of these cancers have been reported. Yet, other cancers with familial types such as prostate,

pancreatic, and testicular cancers did not reveal specific cancer-susceptibility genes at this time.

Breast and ovarian cancer

Broadly speaking, 90% of breast cancer cases are sporadic and the processes leading to gene

mutations in such cases are not well-understood. Defined genetic predisposition accounts for only

about 5–10% of inherited breast cancer types. In either familial or sporadic cases, multiple genetic

etiologies, related to mutations in oncogenes and tumor suppressor genes, characterize breast

carcinomas in Arab patients.
113

A large fraction of inherited cases of breast cancer are usually

associated with mutations of the BRCA1 and BRCA2 genes. Other genes have also been implicated,

such as: BRCATA, BRCA3, TP53, BRIP1, PTEN, and STK11 genes. In sporadic breast cancer, increased

susceptibility has been blamed on the mutation of low penetrance genes including TNFA, HSP70-2, and

TNFRII. These private signatures of the disease in the region have probably contributed to the peculiar

clinical characteristics of the disease in Arab women particularly the earlier mean age of onset, which is

at least a decade earlier than in women of other ethnicities, and the more aggressive course of the

disease.
114

According to a study by Rouba et al.
115
, the proportion of BRCA1 and BRCA2 mutations could be

higher in Arab women when compared to other populations.
115

In Morocco, five deleterious mutations

in the BRCA1 gene where encountered in families with breast/ovarian cancer, including the novel

compound deletional c.2805delA/2924delA mutation.
116

In Algerian women, four of 11 familial cases

were associated with BRCA1 alterations.
117

In neighboring Tunisia, the prevalence of breast cancer is

calculated to be between 16% and 38%.
118,119

There, four BRCA1 mutations have been identified

including a novel Tunisian-specific c.212 þ 2insG mutation and a frequently observed c.798_799delTT

Tunisian and North African founder mutation.
119,120

In Egypt, the p.Arg841Trp BRCA1 disease-associated

mutation was detected while a novel p.Glu1373X mutation in exon 12 of the BRCA1 gene was identified

in ovarian or breast cancer patients in Arab kindred from East Jerusalem.
121

An extensive analysis of

familial breast cancer in Lebanon revealed the presence of 38 BRCA1 sequence variants, many of which

are novel.
122

Adding to this heterogeneity, two other unclassified BRCA1 variants, p.Phe486Leu and

p.Asn550His, were detected in Saudi patients.
123

In the case of BRCA2 gene, the scene is far from being different. Four mutations in BRCA2 gene cause

breast/ovarian cancer in Moroccan families including three novel ones (c.3381delT/3609delT;

c.7110delA/7338delA, and c.7235insG/7463insG).
116
. The same study also identified a large number of

distinct polymorphisms and unclassified variants in BRCA2 as well as in BRCA1 that were described for

the first time.
116

In four unrelated Tunisian families, two novel c.1313dupT and c.7654dupT mutations in

exons 10 and 16 of the BRCA2 gene were reported.
124

In an Arab patient of Palestinian descent with

breast cancer, the c.2482delGACT novel BRCA2 truncating mutation was observed.
123

An extensive

analysis of familial breast cancer in Lebanon revealed the presence of 40 BRCA2 gene sequence

variants, many of which are novel.
122

In Saudi patients, an unclassified p.Asp1420Tyr BRCA2 variant

was detected.
123

This array of region-specific mutation seems to extend to Arab Diasporas as well. For

example, the c.5804del4 mutation in exon 11 of BRCA2 gene was seen in nearly half of the carriers of

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Tadmouri, Sastry & Chouchane. Global Cardiology Science and Practice 2014:54

deleterious mutations in Arab American women. This mutation has not been previously associated with

a particular Arab ethnicity and may represent a founder mutation of recent origin.
125

Another frequently mutated gene in Arab breast cancer patients is the TP53 gene. In fact, the

frequency of TP53 mutations among Saudi patients is one of the highest in the world. The list of

mutations include seven novel ones of which five are found in exon 4 of the TP53 gene. In brief, tumors

from Arab breast cancer patients have a high prevalence (29%) of TP53 mutations in exons 4 and 5,

whereas the smallest proportion of TP53 mutations (10%) is found in exon 7. Also, an excess of

G:C . A:T transitions (49%) at non-CpG sites was noted, suggesting exposure to particular

environmental carcinogens such as N-nitroso compounds.
126

In addition, several single nucleotide

polymorphisms in Arab patients seem to be specific to the indigenous populations and could be

associated with increased risk of breast cancer. Examples include: the p.Pro72Pro in the TP53 gene and

the c.309GG in the MDM2 gene in Saudi women, the c.-251A IL8 allele in Tunisian women, and the

c.1298A . C DNA polymorphism in the MTHFR gene in patients of Syrian ancestry.
127-129

In western societies, mutation of the TP3 gene is highly associated with epithelial ovarian cancers

(50–80%), however, only 32% Arab patients with this neoplasm exhibit TP3 gene mutations. Instead,

PIK3CA amplification, but not PIK3CA mutation, is the single most common genetic alteration in Arab

cases (60%) and is mutually exclusive with gene mutations in both PI3 Kinase and MAPK pathways

(PIK3CA, KRAS, and BRAF).
130-132

This finding is suggestive for a significant role of the dysregulated

PI3K/Akt pathway in the pathogenesis of ovarian cancers.
132

Colorectal carcinoma (CRC)

This type of neoplasm is a further example demonstrating a genetic heterogeneity in the region in

which not only different alleles of the same gene are involved, but also several genes seem to be of

importance for the emergence of this ailment. In Moroccan patients with attenuated polyposis, the

homozygous p.Tyr165Cys and c.1186_1187insGG mutations of the MYH gene were reported
133,134

whereas in neighboring Tunisia, a large deletion involving exon 6 of the MLH1, a DNA mismatch repair,

gene was observed in a family with six patients diagnosed with a colorectal or an endometrial cancer

and characterized by a severe phenotype and an early onset.
135

Another study in Tunisians

demonstrated a significant association between the p.E1317Q, p.D1822V, and p.I1307K variants of the

adenomatous polyposis coli (APC) gene with colorectal carcinoma risk.
136

The p.I1307K mutation

seems to have a long history in the region as demonstrated in the repeated observation of the allele

among many populations in the region. In 1999, the p.I1307K mutation was first described among

Ashkenazi and Yemenite Jews.
137

A study on the general population demonstrated a carrier frequency

of the allele in Yemenite Jews of approximately 5%.
138

A more extensive analysis showed the p.I1307K

mutation existed in Sephardi Jews of Syrian, Egyptian, Moroccan, Yemeni, and Palestinian origins, as

well as in Muslim and Christian individuals of Arab descent. This study also demonstrated that the

ancestor of modern p.I1307K alleles existed some 2.2-2.95 kya.
139

The portrait of colorectal carcinoma

further gets more interesting with the presence of a recent study that investigated the methylation

patterns in colorectal carcinoma from Egypt and Jordan and showed that differing gene methylation

patterns and mutation frequencies are also involved, hence, indicating dissimilar molecular

pathogenesis and probably reflecting different environmental exposures.
140

Prostate cancer

In Tunisians, a significantly increased prostate cancer risk was associated with the VEGF-634 (GC þ CC)

combined genotype while the VEGF-634C allele was associated with high histological grade. However,

the VEGF-1154A/-634G haplotype was negatively associated with prostate cancer risk and high tumor

grade.
141

No association was observed between the p.N700S TSP1 polymorphism and prostate cancer

risk or severity. Yet, subjects carrying one copy of the MMP9-1562T allele exhibited a threefold higher

risk of developing prostate cancer.
142

Other neoplasms

The CYP1A1*2C, GSTT1 null, and GSTP1 TT genotypes demonstrated significant association with diffuse

large B-cell lymphoma (DLBCL) in the Saudi population.
143

The CYP1A1 c.4887C . A genotypes CA, AA

and variant allele A were demonstrated to have significant differences and greater risk of developing

papillary thyroid cancer in Saudi patients compared to wild type genotype CC. Also, in thyroid cancer,

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Tadmouri, Sastry & Chouchane. Global Cardiology Science and Practice 2014:54

GSTT1 null showed higher risk while GSTM1 null showed protective effect.
144

Tunisian smokers carrying

this later allele had an approximately 2.2-fold high risk of bladder cancer.
145

Furthermore, individuals

carrying at least one copy of the methionine synthase (MS) c.2756A . G variant allele and

heterozygous for the c.1298A . C MTHFR polymorphism displayed a 2.33 and 1.8 times increased risk

of developing bladder cancer, respectively.
146

FINAL NOTE

A multitude of studies reviewed in this paper clearly indicate that the Arab region was an important

milieu for the early adaptations of modern human populations to the out-of-Africa environment. The

experiences learned in that period certainly have allowed human populations to establish further

settlements and cover many areas in the rest of the world. The tidal movements of historical

populations in and out of the Arab region allowed the area to become an important bridge for the flow

of genes between Africa, Asia, and Europe. This characteristic made the area a focal point of attraction

for many population geneticists seeking to fill the gap in the interpretation of benign or lethal genomic

variations in world populations.

While we could be fascinated with the extent of the genetic heterogeneity that characterizes Arab

population, understanding the genetic structure of populations and exploring their biogeographical

heterogeneities may also yield a better understanding of the genetic processes and, eventually,

disease etiologies in the region. In many instances, studying Arab families, with Arab-specific genetic

disorders, has resulted in a high value knowledge base and linked many genes to well-defined

phenotypes and helped a great deal in global genome annotation efforts.
147

Yet, many of the nearly

500 genes studied in Arab people revealed striking spectra of heterogeneities with many rare and novel

mutations causing large arrays of clinical outcomes, thus, considerably complicating proper counseling

and diagnosis for many disorders. Unfortunately, the materialization of large-scale personalized

medical genomics may not be expected in the near future especially because of the presence of

hundreds of genetic disorders in Arabs with no defined molecular determinants and because of the

restricted economies to sustain genomic research throughout the region.

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Genetic heterogeneity of Arab pop-HLA gene-2018 (1)

RESEARCH ARTICLE

The genetic heterogeneity of Arab

populations as inferred from HLA genes

Abdelhafidh Hajjej
1*, Wassim Y. Almawi2¤, Antonio Arnaiz-Villena3, Lasmar Hattab4,

Slama Hmida
1

1 Department of Immunogenetics, National Blood Transfusion Center, Tunis, Tunisia, 2 Department of

Medicine, Harvard Medical School, Boston, MA, United States of America, 3 Department of Immunology,

University Complutense, School of Medicine, Madrid Regional Blood Center, Madrid, Spain, 4 Department of

Medical Analysis, Hospital of Gabes (Ghannouch), Gabes, Tunisia

¤ Current address: School of Pharmacy, Lebanese American University, Byblos, Lebanon
* abdelhafidhhajjej@gmail.com

Abstract

This is the first genetic anthropology study on Arabs in MENA (Middle East and North Africa)

region. The present meta-analysis included 100 populations from 36 Arab and non-Arab com-

munities, comprising 16,006 individuals, and evaluates the genetic profile of Arabs using HLA

class I (A, B) and class II (DRB1, DQB1) genes. A total of 56 Arab populations comprising

10,283 individuals were selected from several databases, and were compared with 44 Mediter-

ranean, Asian, and sub-Saharan populations. The most frequent alleles in Arabs are A*01,
A*02, B*35, B*51, DRB1*03:01, DRB1*07:01, DQB1*02:01, and DQB1*03:01, while
DRB1*03:01-DQB1*02:01 and DRB1*07:01-DQB1*02:02 are the most frequent class II hap-
lotypes. Dendrograms, correspondence analyses, genetic distances, and haplotype analysis

indicate that Arabs could be stratified into four groups. The first consists of North Africans

(Algerians, Tunisians, Moroccans, and Libyans), and the first Arabian Peninsula cluster (Sau-

dis, Kuwaitis, and Yemenis), who appear to be related to Western Mediterraneans, including

Iberians; this might be explained for a massive migration into these areas when Sahara under-

went a relatively rapid desiccation, starting about 10,000 years BC. The second includes Levan-

tine Arabs (Palestinians, Jordanians, Lebanese, and Syrians), along with Iraqi and Egyptians,

who are related to Eastern Mediterraneans. The third comprises Sudanese and Comorians,

who tend to cluster with Sub-Saharans. The fourth comprises the second Arabian Peninsula

cluster, made up of Omanis, Emiratis, and Bahrainis. It is noteworthy that the two large minori-

ties (Berbers and Kurds) are indigenous (autochthonous), and are not genetically different from

“host” and neighboring populations. In conclusion, this study confirmed high genetic heteroge-

neity among present-day Arabs, and especially those of the Arabian Peninsula.

Introduction

The human leukocyte antigens (HLA) system plays a key role in self-nonself recognition, and
is divided into class I (HLA-A, -B, and -C) and class II (HLA-DP, -DQ, and -DR) loci, and com-
prises 220 genes in a 3.6 Mb region found on the short arm of chromosome 6. HLA system is
highly polymorphic, and in excess of 17,000 alleles were detected. For example, there are 4,828

PLOS ONE | https://doi.org/10.1371/journal.pone.0192269 March 9, 2018 1 / 24

a1111111111

OPEN ACCESS

Citation: Hajjej A, Almawi WY, Arnaiz-Villena A,

Hattab L, Hmida S (2018) The genetic

heterogeneity of Arab populations as inferred from

HLA genes. PLoS ONE 13(3): e0192269. https://

doi.org/10.1371/journal.pone.0192269

Editor: Amr H Sawalha, University of Michigan,

UNITED STATES

Received: November 6, 2017

Accepted: January 19, 2018

Published: March 9, 2018

Creative Commons Attribution License, which

permits unrestricted use, distribution, and

reproduction in any medium, provided the original

author and source are credited.

Data Availability Statement: All relevant data are

within the paper and its Supporting Information

files.

Funding: The authors received no specific funding

for this work.

Competing interests: The authors have declared

that no competing interests exist.

https://doi.org/10.1371/journal.pone.0192269

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https://doi.org/10.1371/journal.pone.0192269

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B, 3,968 A, and 3,579 C class I alleles, compared with 2,103 DRB1, and 1,142 DQB1 class II
alleles. Several HLA alleles were associated with various auto-immune and infectious diseases
[1]. HLA class I and class II loci are characterized by high (80–90%) heterozygosity, and thus
constitute reliable genetic markers for phylogenetic study, and thus are useful for anthropolog-

ical studies.

Population studies confirmed varied frequencies of HLA alleles and haplotypes according
to ethnicity and geographic origin. Given the codominant nature of the expression of HLA
markers, this enables distinguishing between heterozygotes from homozygotes, hence allowing

assignment of genotypes and allele frequencies [2]. Linkage disequilibrium (LD) analysis

between HLA alleles identified the number of generations in-between two closely related pop-
ulations from the time of their separation. Diversity in haplotype distribution, allele frequency,

and LD analysis reflect the extent of variation between closely related populations. Allele fre-

quency-based genetic distance analysis allows for construction of phylogenetic tree (Dendro-

grams), so as to infer relative estimate of the time that elapsed since the populations existed as

single cohesive units [3–6].

Arabs are a major panethnic group, and their union, Arab League, is a cultural and ethnic

union of 22 member states. As of 2013, nationals of the Arab League countries are 357 mil-

lions, who populate an area of 13 million km
2
, straddling Africa and Asia [7]. Ethnic, religious,

and linguistic diversity (triple heterogeneity) characterize Arabs. Most Arabs follow Islam, and

Christianity is the second largest religion, with over 15 million Christians. There are also

smaller but significant religious minorities (as Druze, Jews), and a number of non-Arab ethnic

minorities (as Berbers, Kurds) [7, 8].

The history of Arabs extends from circa 1200 BC when Southern Arabian Peninsula

was ruled by three successive civilizations: Mineans, who established their capital Karna

(1200–650 BC), Sabeans in Marib (1000 BC—570 AD), and the Himyarite (2nd-6th centu-

ries AD) in Dhafar (Oman) [9–11]. These civilizations were built by authentic Yemeni

tribes. The kingdom of Kinda was established in Central Arabia in 4th-early 6th century

AD, while Dilmun civilization was founded in Eastern Arabia. In 3rd century AD, East

African Kingdom of Aksum extended into Yemen and Western Saudi Arabia [12]. In

addition, the Lakhmids (Yemeni origin), established a dynasty which ruled part of pres-

ent-day Iraq and Syria in 300–602 AD [10, 13, 14]. The Arab Christian Ghassanids

(220–638 AD), originating from Southern Arabia, migrated in 3rd century to Jordan,

where they established their kingdom that extended from Syria to Yathrib (Saudi Arabia)

[12.13]. Islam was introduced in 610 AD to Arabian Peninsula. Shortly thereafter, Arabian

tribes were united as a single Islamic state in the Arabian Peninsula, which was spear-

headed by the Islamic prophet Muhammad. This Islamic state progressively grew in area,

and in types and numbers of populations, and extended from Andalusia (Spain) to the

west, to Indus in the east [14].

Subsequent spread of Islam involved swift invasion of Persia (637-651AD), Iraq, Levant,

and Egypt (639 AD), which extended into North Africa (640–709), and to Spain, Portugal, and

France (Poitiers) in 8
th

century AD. Eastwards, Arab expansion to Central Asia, Bukhara

(Uzbekistan), Afghanistan (637–709), and the Indus border (664–712) followed. Northwards,

Arab invaders were in contact with the Byzantine Empire, and the Caspian and Caucasus to

the north [15, 16]. With the Islamic expansion from 7th century, social and political groups

were gradually Arabized. The spreading of Arab-Muslim culture was at the expense of local

languages (as Berber, Kurdish), especially in Middle East and North Africa, resulting in the

Arabized population speaking variants of Arabic, mixed with original languages (dialect). The
extent of gene Arab exchange with these autochthonous groups is undetermined but is thought

to be lower than religious/cultural influence.

Genetic heterogeneity of Arabs

PLOS ONE | https://doi.org/10.1371/journal.pone.0192269 March 9, 2018 2 / 24

https://en.wikipedia.org/wiki/Panethnicity

https://en.wikipedia.org/wiki/Africa

https://en.wikipedia.org/wiki/Christianity

https://en.wikipedia.org/wiki/Druze

http://www.newworldencyclopedia.org/entry/Yemen

http://www.newworldencyclopedia.org/entry/Saudi_Arabia

https://en.wikipedia.org/wiki/Islamic_prophet

https://en.wikipedia.org/wiki/Muhammad

https://en.wikipedia.org/wiki/Spain

https://en.wikipedia.org/wiki/Indus

https://en.wikipedia.org/wiki/Uzbekistan

https://doi.org/10.1371/journal.pone.0192269

Given the large number of conquests, Arabs were in contact with different ethnicities resid-

ing on a vast area stretching from Mauritania (West Africa) to the western China border (East

Asia). This suggests that cultural and perhaps genetic relationships were established with these

ethnic groups. This work aims to study the HLA distribution in North African and Oriental
Arab populations, and compare them to neighboring populations (Sub-Saharans Africans,

Europeans, and Asians).

Populations and methods

Search strategy

Datasets of HLA allele frequencies were collected from a systematic review performed per Pre-
ferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) criteria [Only

the criteria from 1–10, 17, and 26 are applicable to this type of study (S1 Checklist)] [17].

PubMed, ScienceDirect, AlleleFrequencies.net, and ResearchGate databases were searched for

all papers on HLA polymorphism, and HLA disease associations in Arabs. This systematic lit-
erature search covering published papers up to May 31, 2017 was conducted by two investiga-

tors (H.A and H.L); the search terms used were: ‘HLA Arabs’, or ‘Human Leukocyte Antigen
Arabs’. A search per country followed: ‘HLA Tunisians’, ‘HLA Saudis’, and so on. This was
repeated for remaining countries, which resulted in excess of 50 keywords used. A database

from International Histocompatibility Workshops was also used. Some authors were also con-

tacted by e-mail, or through ResearchGate, requesting information and missing data. While

most datasets were taken from studies with an explicit anthropological focus, control groups

from case-control disease studies were also used. There was no language restriction used for

this search.

Inclusion and exclusion criteria

All included studies met the following criteria. HLA allele frequencies must be obtained by
molecular typing, and that subjects should be typed for at least one of the following: HLA-A,
HLA-B, HLA-DRB1, and HLA-DQB1. Publications were excluded in case of serological data;
sample size less than 35 individuals, typed individuals (or controls) were either related and not

randomly selected, presentation of duplicate data sets. Studies were also excluded if they pre-

sented incomplete/partial allele frequencies, or there were significant ambiguities in the typing.

Data extraction

Studies were independently selected by two authors (H.A and H.L). An external referee was

invited in case of disagreements not resolved by both reviewers. Data extracted from selected

papers included publication year, study type (anthropology, association), sample size, HLA-A, -B,
-C, -DRB1, and -DQB1 allele frequencies, haplotype frequencies, region, country, and typed loci.

Statistical analysis

A three-dimensional correspondence analysis and bi-dimensional representation were per-

formed using VISTA V5.02 software [18]. Phylogenetic trees were constructed based on allele

frequencies using the Neighbor-Joining (NJ) method [19], and standard genetic distances

(SGD) [20], using DISPAN software containing GNKDST and TREEVIEW software [21, 22].

Genetic heterogeneity of Arabs

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Results

Study flow

The use of more than fifty key words allowed identification of 5,456 papers and HLA datasets,
of which 315 were deemed relevant to the study. Of these, 42 articles and 11 HLA datasets con-
taining information on 56 Arab populations, and meeting the study criteria, were included.

The study flow is illustrated in Fig 1. In addition, 20 articles and 18 HLA datasets which meet
the criteria of this study, containing complete information on 44 other populations were

selected, but without going through systematic review. The populations used in the compari-

son were chosen mainly from neighboring Arab countries. This study relied on a database con-

sisting of 100 populations (of which data of 11 populations were extracted from association

studies) from 36 countries Arab and worldwide countries, and belonging to Asia, Europe, and

Africa. The distribution of populations by region is illustrated in Fig 2A. These populations

represent allele frequency data for 16,006 individuals (160.06 individuals/population), and

from 63 references.

Selected populations

Arab populations. The 42 articles and 11 HLA datasets (http://www.allelefrequencies.net)
selected provided information on 56 populations (Table 1), comprising 10,283 individuals

[23–67]. The 56 different ethnic and religious populations were selected from 18 Arab coun-

tries. There were no reliable HLA data for the remaining countries (Somalia, Djibouti, Mauri-
tania, and Qatar) (Fig 2B). The studied populations are divided into 29 African (26 North

Africans and 3 Sub-Saharans), and 27 Asian populations (13 Levantines, and 14 Arabian Pen-

insula). With the exception of 8 populations [28, 38, 47, 48, 50, 52, 53, 55], where HLA data
were extracted from association studies, the 50-remaining studies were extracted from anthro-

pological ones.

Neighboring populations. Forty-four worldwide populations [23, 34, 39, 66, 68–85] com-

prising 5,723 individuals, were selected from 18 countries in three continents, using the same

criteria previously described (Table 2). These comprised 22 European, 11 non-Arab Asian,

and 11 Sub-Saharan African populations. Of the 11 Asian populations, there were two Arab

minorities living in Iran (Khuzestan and Famoori).

Data of only three populations [74, 75, 84] were extracted from association studies. These

populations were typed for at least HLA-A, -B, -DRB1, or DQB1.

HLA allele frequencies features of Arab populations

Table 3 shows the most frequent HLA-A and -B alleles in Arab populations. A�02 was the
most prevalent allele, and its frequency exceeded 25% in some populations, such as Saudis

(30.4%) [23], Tunisian Berbers of Zrawa (29.3%) [24], Moroccans (26.2%) [25], and Suda-

nese (25.9%) [23]. A�01, �03, �24, �30, and �68 alleles were also common in most Arab popu-
lations. For example, the highest frequency of A�01 was seen in Tunisians (15%) [26] and
Moroccans (14.8%) [25], while A�03 was prevalent among Iraqi Kurds (15.1%) [23], and
A�30 was prevalent among Sudanese (17.6%) [23]. In addition, A�24 was common among
Lebanese-Armenians (17.3%) [27], while A�68 was prevalent in Saudis (10.5%) [28]. In con-
trast, A�25, �28, �34, �36, �43, �66, �69, �74, and �80 are rare among Arabs. It is noteworthy
that A�34, described as rare allele among Arabs, is found at a high frequency (22.2%) in
Tunisian Berbers from Zrawa [24], the highest reported for any population worldwide.

Results of HLA-B locus are presented in Table 3. B�35 was the most frequent B� allele in
Palestinians (20.3%) [29] and Lebanese-Armenians (19.8%) [27]. B�35 was found at varied

Genetic heterogeneity of Arabs

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http://www.allelefrequencies.net/

https://doi.org/10.1371/journal.pone.0192269

frequencies in Iraqi Kurds (15.6%) [23], Omanis (15.3%) [30], Jordanians (14.9%) [31], and

Arab Emirati (11.1%) [23] populations. B�51 was the second most frequent allele, and high fre-
quencies were recorded for Saudis (19.3%) [23], Omanis (17.5%) [30], and Arab Emirati

(15.6%) [23] populations. B�50 was also a frequent B� allele in most Arabs, including Saudis
(18.8%) [23], and Libyans (16.1%) [31], along with B�08, and B�44 among the Tunisian Berbers
of Zrawa (32.8%) [24], the latter being the highest frequency worldwide. Similarly, the fre-

quency of B�27 is the highest among Jordanians (27.1%) [31]. In contrast, B�37, �42, �46, �47,
�48, �54, �59, �67, and �78 alleles are extremely rare or virtually in all Arab populations.

The most common DRB1 and DQB1 alleles among Arabs are shown in Table 4.
DRB1�07:01 was the most frequent allele among Tunisians from Ghannouch (28.6%) [33], Jor-

danians (26.9%) [31], and Saudis (26.6%) [23], while Egyptians (8.3%) and Sudanese had the

lowest frequencies of DRB1�07:01. DRB1�03:01 was the second most frequent DRB1� allele in
some Arabs, such as Tunisians of Tunis (21.9%) [34] and Moroccans of Metelsa (20.2%) [23],

Fig 1. Flow diagram of the study selection process.

https://doi.org/10.1371/journal.pone.0192269.g001

Fig 2. The distribution of studied populations by region (A) and country (B).

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Genetic heterogeneity of Arabs

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but rare in Jordanians (2.4%) [31]. DRB1�11:01 was also frequent among some Arabs, such as
Lebanese (36.8%) [35], but rare among Saudis (4.8%) and Moroccans of Chayoua (2.5%) [23].

Furthermore, DRB1�13:01, �13:02, and �15:01 alleles are relatively frequent among Arabs. High
frequency of DRB1�13:01 were recorded for Sudanese (23.3%), while DRB1�13:02 was virtually
absent in Bahraini [35] and Sudanese [23]. All DRB1�09, �12, and �14 subtypes are extremely
rare among Arabs. In addition, DRB1�16 subtypes are rare in all Arab populations except for
Bahrain, where DRB1�16:01 is found at a high frequency (13.9%) [35].Haut du formulaire.

DQB1�02:0X and �03:01 alleles are the most frequent DQB1� in Arabs. The highest frequen-
cies of DQB1�02:0X were reported for Tunisians (Ghannouch; 40.01%) [33], Yemenites-Jews
(39.1%) [36], Moroccans (Agadir-Souss; 37.8%) [37] and Saudis (37.3%) [23], while the lowest

frequency was found in Egyptians (6%) [38]. On the other hand, DQB1�03:01 is very common
among Lebanese (45%) [39] and Algerians (Oran; 35.1%) [23], but not Saudis (7.6%) [23].

DQB1�03:02 and �05:01 are also frequent in most Arabs, such as Tunisians (Ghannouch;
20.7%) [33], Jordanians (17.8%) [31], Palestinians (17.6%) [29] and Lebanese (16.8%) [35].

DQB1�05:01 is frequent among Bahrainis (29.2%) [35], Tunisians (Berbers of Jerba; 22.7%)
[40], and Lebanese (20.5%) [35]. Among DQB1�06 subtypes, DQB1�06:02 and �06:03 were the
most frequent in most Arab populations, but absent in Bahrainis where DQB1�06:01 is very
frequent (13.20%) [35]. Furthermore, all DQB1�04 subtypes are rare among Arabs, particularly

Table 1. List of Arab populations used in the present work.

N
o

Populations Symbols Size References N
o

Populations Symbols Size References

1 Algiers Alg 102 [67] 29 Comorians Com 117 [43]

2 Algerians-B Alg-B 97 [23] 30 Jordanians Jor 146 [31]

3 Algerians-A Alg-A 132 [48] 31 Jordanians-A Jor-A 1254 [46]

4 Algerians-Oran Ora 100 [23] 32 Syrians Syr 200 [47]

5 Gabesians Gab 77 [59] 33 Syrians-A Syr-A 225 [58]

6 Gabesians-A Gab-A 96 [40] 34 Lebanese Leb 95 [35]

7 Ghannouchians Gha 82 [33] 35 Lebanese-A Leb-A 1123 [45]

8 Berbers-Jerba Ber-J 55 [40] 36 Lebanese-B Leb-B 191 [44]

9 Berbers-Matmata Ber-M 81 [40] 37 Lebanese-Armen Leb-Ar 368 [27]

10 Berbers-Zrawa Ber-Z 70 [24] 38 Lebanese-KZ Leb-Kz 93 [39]

11 Tunisians Tun 376 [61] 39 Lebanese-NS Leb-Ns 59 [39]

12 Tunisians-A Tun-A 80 [60] 40 Lebanese-Yohmor Leb-Y 75 [39]

13 Tunisians-B Tun-B 101 [34] 41 Palestinians Pal 165 [29]

14 Tunisians-C Tun-C 100 [63] 42 Palestinians-A Pal-A 109 [36]

15 Tunisians-M Tun-M 123 [26] 43 Saudis Sau 105 [28]

16 Southern Tunisians Tun-S 250 [62] 44 Saudis-A Sau-A 213 [23]

17 Libyans Lib 118 [32] 45 Saudis-B Sau-B 158 [49]

18 Libyans-Jews Lib-J 119 [36] 46 Saudis-C Sau-C 499 [23]

19 Berbers-Metelsa Ber-Me 99 [64] 47 Saudis-D Sau-D 383 [50]

20 Moroccans Mor 96 [25] 48 Omanis-A Oma-A 259 [30] [51]

21 Moroccans-A Mor-A 110 [42] 49 Kuwaitis Kuw 212 [52]

22 Moroccans-Agadir Mor-Ag 98 [37] 50 Kuwaitis-A Kuw-A 114 [53]

23 Moroccans-Chaouya Mor-Ch 98 [65] 51 Bahrainis Bah 72 [35]

24 Moroccans-Jews Mor-J 94 [66] 52 Emiratis Emi 373 [23]

25 Egyptians Egy 101 [39] 53 Iraq kurds Ira-K 209 [54]

26 Egyptians-A Egy-A 121 [38] 54 Yemenite-Jews Yem-J 76 [36]

27 Sudanese Sud 200 [23] 55 Yemen-sana’a Yem 50 [55]

28 Sudanese-Nuba Sud-N 46 [23] 56 Omanis Oma 118 [56] [57]

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DQB1�04:01 which is virtually absent, except in Egyptians (10.17%) [38]. The most common
DQB1�04 subtype in Arabs is DQB1�04:02.

Allelic comparison between Tunisians and other populations

Allelic comparisons were done at Neighbor-Joining, correspondence analysis, and standard

genetic distances. Analyses were performed with Class I and Class II markers, and at generic

and high-resolution levels to make the most of available data, and seeing that some of the pop-

ulations included in these comparisons lack high-resolution data.

Neighbor-joining dendrograms. Comparison at the generic level was made using genetic

distances based on DRB1� and DQB1� allelic frequencies. Four groups can be interpreted from
Fig 3. The first group comprises North African Arabs (Tunisians, Algerians, Moroccans, Liby-

ans), Western Mediterranean Europeans (Iberians, French), Arabian Peninsula Arabs (Saudis,

Kuwaitis, Yemenis), and Arab minority of Iran (Khuzestani). The second group is formed by

Eastern Mediterranean Europeans (Greeks, Cretans, Albanians, Turks, Macedonians), Italians,

Levant Arabs (Palestinians, Lebanese, Syrians), Iraqi-Kurds, Tunisian Berbers (Djerba), and

Iranians. The third group comprises Sub-Saharan Africans (Fulani, Mossi, Rimaibe, Bubi,

Mandenka, and Senegalese). Omanis, Bahrainis, Egyptians, and Sudanese form a heteroge-

neous group containing Asians and Sub-Saharan Africans. Similar results but with notable dif-

ferences, were observed in dendrograms built with standards genetic distances (SGD) based

on generic DRB1(S1 Fig) and generic B loci (S2 Fig).
Correspondence analysis. High-resolution DRB1 correspondence analysis (Fig 4) dem-

onstrated the clustering of the studied populations into three groups. The first containing

North Africans (Tunisians, Algerians, Moroccans, and Libyans), Iberians (Basques, Spaniards,

Table 2. Worldwide populations included in the meta-analysis.

N
o

Populations Symbols Size References N
o

Populations Symbols Size References

1 Spaniards Spa 176 [41] 23 Mossi Mos 42 [39]

2 Portuguese Por 118 [39] 24 Mandenka Mad 200 [39]

3 Murcians Mur 173 [80] 25 Amhara Amh 98 [39]

4 Italians Ita 284 [68] 26 Bubi Bub 101 [39]

5 Basques-A Bas-A 82 [41] 27 Congolese Con 85 [72]

6 Basques-Arratia Bas-Ar 83 [77] 28 Fulani Ful 38 [39]

7 Basques-B Bas-B 99 [70] 29 Gabonese Gab 167 [85]

8 French Fre 179 [68] 30 Nigerians Nig 258 [23]

9 French-Rennes Fre-R 200 [34] 31 Oromo Oro 83 [39]

10 Balearic Bal 90 [71] 32 Rimaibe Rim 39 [39]

11 Corsica Cor 100 [71] 33 Senegalese Sen 177 [39]

12 Sardinians Sar 91 [68] 34 Famoori Arabs Fam 84 [73]

13 Ashkenazi-Jews Ash-J 132 [66] 35 India-Northeast Ind-N 188 [83]

14 Greeks-A Gre-A 96 [39] 36 Indians-Delhi Ind-D 112 [84]

15 Greeks-B Gre-B 101 [39] 37 Iranian-Jews Ira-J 91 [73]

16 Greeks-C Gre-C 98 [39] 38 Iranians Ira 120 [74]

17 Greeks-D Gre-D 242 [23] 39 Iranians-A Ira-A 100 [75]

18 Macedonians Mac 172 [78] 40 Iranians-Azeri Ira-Az 100 [81]

19 Turks Tur 250 [23] 41 Iranians-Kurd Ira-k 100 [81]

20 Turks-A Tur-A 228 [79] 42 Khuzestani Arabs Khu 50 [73]

21 Albanians Alb 160 [76] 43 Pakistanis-Pathan Pak-P 100 [82]

22 Cretans Cre 135 [69] 44 Pakistanis-Sindh Pak-S 101 [82]

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Genetic heterogeneity of Arabs

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Portuguese, Murcians), French, Saudis, Yeminis-Jews, and Khuzestani Arabs. The second con-

tains Eastern Mediterraneans (Greeks, Cretans, Lebanese, Palestinians, and Macedonians),

Berbers of Djerba, Italians, Iraqi-Kurds, Iranians, Egyptians, Ashkenazi-Jews, and Moroccan-

Jews. The last cluster consists of Sub-Saharan populations. It should be noted that Jordanians,

Bahrainis, and Sudanese were outside these main groups. Similarly, correspondence analysis

using class I (A and B) identified three main clusters (Fig 5). The first cluster contained all
Sub-Saharan Africans along with Sudanese. The second cluster contains Eastern Mediterra-

nean populations (Albanians, Greeks, Cretans, Lebanese, Palestinians, and Macedonians), Ital-

ians, Iraqi-Kurds, Ashkenazi-Jews, and Jordanians-A. The last cluster includes North Africans

(Tunisians, Algerians, Moroccans, and Libyans), Iberians (Basques, Spaniards), French, and

Saudis.

Correspondence analysis based on generic DRB1 data, and using only Arab populations
shows that Arabs can cluster into four groups (Fig 6). The first contains the North Africans

(Tunisians, Algerians, Moroccans, and Libyans), Saudis, Yemenis, Kuwaitis, and Khuzestanis

(Iranian Arabs). The second cluster includes the Arabs of Levant (Palestinians, Jordanians,

Lebanese, Syrians), Egyptians, Iraqi Kurds, and Moroccans Jews. The third group consists of

Table 3. Most frequent HLA-A� and–B� alleles in Arab populations.

HLA-A A�01 A�02 A�03 A�24 A�30 A�68
Population % Population % Population % Population % Population % Population %

Tun-M 15.0 Sau-D 30.4 Ira-k 15.1 Leb-Ar 17.3 Sud 17.6 Sau 10.5

Mor 14.8 Ber-Z 29.3 Leb-Ar 14.0 Gha 15.2 Mor-C 13.0 Tun-M 09.4

Jor-A 14.7 Mor 26.2 Pal 10.7 Ira-k 13.9 Tun-A 11.8 Mor 09.3

Ira-k 13.2 sud 25.9 Lib 10.3 Sau-B 13.3 Jor 11.5 Alg-K 08.6

Pal 12.5 Emi 25.2 Mor-A 10.0 Jor-A 10.7 Alg-K 10.2 sud 08.5

Leb-A 12.2 Oma 24.9 Alg-K 09.3 Pal 10.1 Sau-B 10.2 Emi 08.4

Sau-A 12.2 Alg 24.6 Jor-A 09.1 Alg 09.4 Pal 08.4 Lib 08.2

Alg 11.9 Lib 23.5 Emi 09.1 Lib 09.3 Oma-A 07.5 Jor 07.6

Lib 11.5 Jor-A 22.0 Sau-A 08.9 Mor 07.3 Leb-A 06.7 Oma-A 07.1

Oma 07.2 pal 20.5 Gab 07.7 Oma 06.3 Lib 06.4 Leb-A 05.1

Sud 06.5 Leb-A 18.7 Sud 07.1 Sud 06.1 Emi 05.0 Ira-k 03.8

Emi 06.2 Ira-k 17.0 Oma 06.4 Emi 05.2 Ira-k 03.8 Pal 03.6

HLA-B B�07 B�08 B�35 B�44 B�50 B�51
Population % Population % Population % Population % Population % Population %

Jor 27.1 Oma 11.0 Pal 20.3 Ber-Z 32.8 Sau-D 18.8 Sau-C 19.3

Sau-A 11.7 sau-B 10.1 Leb-Ar 19.8 Ira-k 10.3 Lib 16.1 Oma 17.5

Mor 09.0 Emi 08.6 Ira-k 15.6 Mor-C 10.2 Ber-Z 15.7 Emi 156

Lib 07.7 Gha 08.5 Oma-A 15.3 pal 09.6 Tun-S 14.2 Ira-K 15.6

Tun-A 07.5 Ira-k 07.2 Jor-A 14.9 Alg 08.8 Mor-C 12.5 Gha 12.2

Alg-k 07.1 Lib 06.4 Emir 11.1 Leb-Ar 08.4 Emi 09.4 Leb-Ar 12.1

Leb-Ar 04.5 Mor-C 06.2 Alg 10.3 Lib 07.6 Jor-A 06.4 Lib 11.1

Ira-k 04.1 Jor 04.7 Lib 10.1 Jor-A 05.6 Pal 05.8 Jor-A 10.3

Oma-A 03.1 Sud 04.0 Tun-M 09.8 Sau-D 03.5 Leb-Ar 05.2 Sud 07.8

Sud 02.8 Alg 03.5 Sau 08.6 Sud 02.3 Alg 05.1 Mor 07.4

Emi 02.4 Leb-Ar 03.0 Mor-C 06.9 Emi 02.3 Oma-A 04.2 Pal 06.4

Pal 01.8 Pal 02.7 sud 06.1 Oma-A 02.1 Sud 02.5 Alg-k 04.7

Only one population per country is illustrated; the frequencies are ranked from highest to lowest for each allele; to identify the population and country see Table 1

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Table 4. Most frequent HLA-DRB1� and–DQB1� alleles in Arab populations.

HLA-DRB1� 03:01 07:01 11:01 13:01 13:02 15:01
Population % Population % Population % Population % Population % Population %

Tun-B 21.9 Gha 28.6 Leb 36.8 Sud 23.3 Mor-Me 11.1 Alg-B 13.4

Mor-Me 20.2 Jor 26.9 Bah 16.0 Sau-A 10.6 Lib 09.3 Mor-c 12.6

Sau-B 16.5 Sau-B 26.6 Egy-A 13.2 Ber-M 08.0 Sau-A 08.9 Ber-Z 11.4

Ora 15.1 Yem-J 22.1 Gab-A 11.2 Leb-B 06.8 Egy-A 07.4 Jor 09.0

Bah 13.9 Mor-Ag 20.5 Pal 10.0 Alg-B 05.6 Tun-C 06.7 Sau-A 08.9

Sud 13.8 Lib-Y 19.6 Ora 08.6 Lib 05.5 Leb-N 05.0 Bah 07.6

Lib 13.6 Lib 17.0 Sud 08.3 Yem-J 05.4 Ora 04.5 Leb 04.7

Yem-J 12.0 Alg-B 15.9 Jor 08.3 Egy-A 04.6 Yem-J 04.0 Lib 04.2

Leb-B 09.6 Pal 12.7 Lib 05.1 Mor-Me 03.5 Pal 03.9 Pal 03.6

Pal 07.6 Bah 09.0 Sau-A 04.8 Jor 02.1 Jor 00.3 Sud 03.3

Egy-A 07.0 Egy-A 08.3 Yem-J 03.4 Bah 02.1 Sud 00.0 Egy-A 02.5

Jor 02.4 Sud 07.8 Mor-C 02.5 Pal 00.9 Bah 00.0 Yem-J 02.0

HLA-DQB1� 02:0X 03:01 03:02 05:01 06:02 06:03
Population % Population % Population % Population % Population % Population %

Gha 40.1 Leb-NS 45.0 Gha 20.7 Bah 29.2 Mor-C 12.9 Egy-A 10.2

Yem-J 39.1 Ora 35.1 Jor 17.8 Ber-J 22.7 Alg 12.8 Jor 08.3

Mor-Ag 37.8 Lib-J 29.6 Pal 17.6 Leb 20.5 Egy-A 12.7 Ber-J 07.8

Sau-B 37.3 Ber-J 27.4 Leb 16.8 Alg 13.9 Tun-A 12.6 Lib-J 07.4

Jor 35.9 Pal 26.7 Yem-J 14.2 Mor-C 12.3 Jor 10.7 Yem-J 06.1

Lib-J 33.3 Yem-J 19.1 Lib-J 13.0 Pal 11.8 Sau-B 05.1 Ora 04.3

Bah 25.7 Bah 16.0 Alg 12.3 Sau-B 10.1 Pal 04.2 Sau-B 04.1

ora 24.5 Mor-C 15.4 Mor-C 12.3 Jor 09.3 Leb-Y 03.7 Leb-Y 03.3

Pal 20.9 Egy 11.9 Bah 09.7 Egy-A 08.5 Yem-J 02.0 Mor-C 01.8

Leb-Y 20.0 Jor 10.0 Sau-B 08.9 Yem-J 06.1 Lib-J 00.8 Pal 01.2

Only one population per country is illustrated; the frequencies are ranked from highest to lowest for each allele; to identify the population and country see Table 1

https://doi.org/10.1371/journal.pone.0192269.t004

Fig 3. Neighbor-Joining dendrograms, based on Standard genetic distances (SGD), showing relatedness between

Arabs and other populations using generic HLA-DRB1� and -DQB1� allele frequencies data. Populations’ data were
taken from references detailed in Tables 1 and 2. Bootstrap values from 1.000 replicates are shown.

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Genetic heterogeneity of Arabs

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Bahrainis, Omanis, Emiratis and Famoori (Iranian Arab). The fourth is composed of Suda-

nese, Sudanese from Nuba, and Comorians.

Genetic distances. Table 5 illustrates standard genetic distances (SGD) between Arabs

and other populations, using generic DRB1� allele frequencies. North Africans and Iberians
are the closest to Saudis. Moroccans (Agadir, 0.0024), Basques-Ar (0.0057), and Tunisians-S.

Fig 4. Correspondence analysis (bi-dimensional representation), based on the standard genetic distances, showing

the relationship between Arabs and other populations according to high resolution HLA-DRB1� allele frequencies
data. Only individuals with defined DRB1� subtypes are considered. Populations data were taken from references
detailed in Tables 1 and 2.

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Fig 5. Correspondence analysis (bi-dimensional representation), based on the standard genetic distances, showing

a global view of the relationship among Arabs and other populations according to generic HLA�-A and–B� allele
frequencies data. Populations data were taken from references detailed in Tables 1 and 2.

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Genetic heterogeneity of Arabs

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Syrians are genetically close to Eastern Mediterranean, as Cretans (-0.0001) and Lebanese

Armenians (0.0050), while Tunisians are closed to Western Mediterraneans as North Africans

and Iberians, and Saudis. The populations most related to Tunisians are the other Tunisian

populations (Gabesians, -0.0139), Moroccans (Agadir; -0.0080), and Algerians (-0.0055). Sub-

Saharans such as Congolese (0.0519) and Nigerians (0.0828), and Greeks (0.0836) showed the

closest genetic distances to Comorians. It is noteworthy that Arab minority in Khuzestan

(Iran) displayed close relatedness with North Africans [as Gabesians from Tunisia (-0.0086)

and Orans from Algeria], and Saudis (0.0231).

HLA Class I and Class II haplotype
HLA-A-B haplotypes. HLA A-B haplotypic data are extremely rare in Arabs. The most

frequent A-B haplotypes in Arabs are shown in Table 6. A�02:01-B�50:01 (9.0%) and
A�02:01-B�44:02/03 (7.5%) were the haplotypes with the highest frequencies in Berbers of
Zrawa. Diversity in A-B haplotype frequencies are found among Arabs, hence demonstrat-
ing comparable frequencies of A-B haplotype in Arab populations, which did not exceed
5.3% in Gabesians (Tunisia). For example, while A�34:02-B�08:01 and A�29:01-B�45:01
characterize Tunisians, A�01-B�57(02.9%), A�30-B�18 (01.50%), and A�33:01-B�14:01
(02.50%) characterize Algerians. Several haplotypes identified in Arabs were also seen in

other Mediterraneans. For example, A�32:01-B�40:02 was seen in Greeks (2%) [39] and
Spaniards (0.5%) [41], while A�02:01-B�50:01 was seen in Italians (2%) [68], Portuguese
(3%) [39], and Moroccan Jews (3%) [66]. A�24:02-B�08:01 (4.75%) and A�30:02-B�53:01
(3.48%) were only identified in Saudis.

HLA-DRB1-DQB1 haplotypes. The most frequent DRB1-DQB1 haplotypes with signifi-
cant LD in Arabs are listed in Table 7. In general, class II haplotype frequencies are markedly

higher than those of class I haplotypes. DRB1�03:01-DQB1�02:01 haplotype was the most fre-
quent DRB1-DQB1 haplotype in Arabs (Table 7), and its frequency ranging from 3.2% in Leba-
nese to 16.60% in Tunisians. DRB1�03:01-DQB1�02:01 is a common class II haplotype in the

Fig 6. Correspondence analysis (bi-dimensional representation), based on the standard genetic distances, showing

the relationship between different Arab populations according to generic HLA-DRB1� allele frequencies data.
Populations data were taken from references detailed in Tables 1 and 2.

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Genetic heterogeneity of Arabs

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https://doi.org/10.1371/journal.pone.0192269.g006

https://doi.org/10.1371/journal.pone.0192269

Table 5. The closest populations to Arabs using standard genetic distances (SGD) based on HLA-DRB1� alleles.

Saudis-B Emiratis Omanis-A Sudanese

Population SGD Population SGD Population SGD Population SGD

Moroccans-Ag 0.0024 Omanis-A 0.0411 Emirates 0.0411 Nigerians 0.0497

Basques-Ar 0.0057 Bahrain 0.0429 Sardinians 0.0939 Egyptians-A 0.0556

Tunisians-S 0.0124 Sardinians 0.0593 Bahrain 0.1327 Congolese 0.0594

Saudis-C 0.0160 Kuwaitis 0.0688 Kuwait 0.2014 Egyptians 0.0620

Ghanouchians 0.0203 Tunisians-B 0.1169 Famoori Arabs 0.2377 Mandenka 0.0908

Saudis 0.0258 Khuzestanis 0.1213 Macedonians 0.2461 Moroccans 0.0984

Tunisians 0.0272 Tunisians-A 0.1276 Tunisians-B 0.3071 Senegalese 0.1044

Kuwaitis-A 0.0312 Algerians-Oran 0.1371 Khuzestanis 0.3192 Bubi 0.1078

Khuzestanis 0.0349 Algerians-A 0.1407 Greeks-B 0.3197 Palestinians-A 0.1111

Spaniards 0.0354 Algerians-B 0.1612 Tunisians-A 0.3261 Pakistanis-S 0.1122

Saudis-D 0.0374 Algiers 0.1639 Kuwaitis-A 0.3544 Tunisians-A 0.1133

Gabesians 0.0377 Saudis-C 0.1746 Algerians-Oran 0.3600 Libyans 0.1197

Gabesians-A 0.0394 Macedonians 0.1756 Algerians-A 0.3639 Sudanese-Nuba 0.1234

Jordanians 0.0428 Gabesians 0.1820 Greeks-D 0.3657 Algerians-B 0.1315

Algerians-B 0.0433 Saudis-D 0.1820 Algerians-B 0.3867 Berbers-Matmata 0.1317

Basques-B 0.0449 Moroccans-Agadir 0.1830 Greeks-C 0.3927 Algerians-A 0.1407

Saudis-A 0.0450 Kuwaitis-A 0.1837 Turks 0.3944 Berbers-Zrawa 0.1409

Algerians-A 0.0497 Famoori Arabs 0.1894 Saudis-C 0.3984 Gabesians 0.1413

Tunisians-C 0.0533 Moroccans-A 0.1900 Algiers 0.4027 Jordanians-A 0.1434

Yemenite-J 0.0536 Gabesians-A 0.1908 Albanians 0.4034 Gabesians-A 0.1442

Khuzestanis Tunisians Syrians-A Comorians

Population SGD Population SGD Population SGD Population SGD

Gabesians -0.0086 Gabesians -0.0139 Cretans -0.0001 Congolese 0.0519

Orans -0.0074 Gabesians-A -0.0081 Lebanese-Ar 0.0050 Nigerians 0.0828

Gabesians-A -0.0025 Moroccans-Agadir -0.0080 Syrians 0.0076 Greeks-A 0.0836

Algerians-A -0.0015 Southern Tunisians -0.0062 Iranians-Kurd 0.0100 Gabonese 0.0904

Moroccans-Ag 0.0106 Algerians-A -0.0055 Lebanese-A 0.0149 Iranians-A 0.0947

Tunisians-S 0.0140 Moroccans-A 0.0010 Lebanese-Y 0.0151 Egyptians-A 0.1090

Tunisians 0.0161 Algerians-B 0.0019 Iranians 0.0159 Iranians 0.1184

Tunisians-C 0.0195 Berbers-Zrawa 0.0027 Lebanese-B 0.0161 Italians 0.1222

Yemenite-J 0.0217 Libyans 0.0028 Iranians-Azeri 0.0185 Iranians-Azeri 0.1394

Tunisians-M 0.0225 Algerians-Oran 0.0033 Turks 0.0192 Iranians-Kurd 0.1418

Saudis-C 0.0231 Tunisians-M 0.0038 Iraq kurdistan 0.0198 Albanians 0.1426

Spaniards 0.0291 Saudis-C 0.0061 Ashkenazi-Jews 0.0222 Turks 0.1428

Saudis 0.0324 Tunisians-C 0.0083 Iranians-A 0.0223 Syrians 0.1470

Saudis-B 0.0349 Algiers 0.0103 Palestinians-A 0.0228 Cretans 0.1483

Algerians-B 0.0353 Berbers-Matmata 0.0106 Italians 0.0241 Egyptians 0.1483

Tunisians-B 0.0422 Moroccans-Chaouya 0.0111 Turks-A 0.0288 Greeks-C 0.1487

Indians-Delhi 0.0454 Spaniards 0.0126 Lebanese 0.0320 Palestinians-A 0.1559

Algiers 0.0461 Moroccans 0.0144 Jordanians-A 0.0355 Iraq Kurdistan 0.1564

Basques-Ar 0.0471 Saudis-D 0.0159 Lebanese-KZ 0.0368 Greeks-D 0.1594

Libyans 0.0485 Khuzestani Arabs 0.0161 Greeks-A 0.0407 Syrians-A 0.1617

(0.0124) had the closest genetic distances from Saudis, while Emiratis were closely related to Omanis (0.0411), Bahrainis (0.0429), Sardinians (0.0593), and Kuwaitis

(0.0688). On the other hand, Sudanese are related to Sub-Saharans, including Nigerians (0.0497), Congolese (0.0594), and Egyptians (0.556).

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Genetic heterogeneity of Arabs

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Mediterranean basin, and is frequent among Basques (17.5%) [41], Moroccans (17.3%) [25],

Algerians (11.3%) [67], and Cretans (7.4%) [69]. In addition, DRB1�07:01-DQB1�02:02 is also
frequent in Arabs, such as Moroccans (16.70%), and is reportedly common in Spaniards

(17.3%) [41], and Moroccans (12.6%) [25], but rare in Southern Tunisians (2.10%) (Gabe-

sians). In addition, DRB1�07:01-DQB1�02:01 is also a common DRB1-DQB1 haplotype, and its
frequency exceeds 4% in several Arab populations.

Table 6. Most frequent (%) HLA Class I (A-B) two-locus haplotypes with significant linkage disequilibrium (P<0.05) in Arabs. A-B haplotype Tun Saudi-B Alg Mor-Ch Mor-a Ber-Z Lib Gab 01:01–50:01 - - - 04.10 - - - - 01–57 - - 02.90 - - - - - 02:01–07:02 - - - - - - 02.97 - 02:01–44:02/03 03.86 - - 02.10a 02.95c 07.50b - 05.26 02:01–50:01 03.30 - - - 01.99d 09.01 - - 02:01–51:01 - 04.66 - 03.40 01.62f - - - 23:01–50:01 - 04.90 - - - - 02.97 - 24:02–08:01 - 04.75 - - - - - - 29:01–45:01 01.79 - - - - - - 02.10 29:02–44:03 - - - 02.70 - - - - 30–18 - - 01.50 - 02.60 03.00 - - 30:02–53:01 - 03.48 - - - - - - 32:01–40:02 00.80 - - - - 05.66 - - 33:01–14:01 - - 02.50 - 01.86e 01.41 - - 34:02–08:01 02.12 - - - - 06.11 - 02.10 a02:01–44:02. b02:01–44. c02-44. d02-50. e33-14. f02-51. https://doi.org/10.1371/journal.pone.0192269.t006 Table 7. Most frequent (%) HLA Class II (DRB1-DQB1) two-locus haplotypes with significant linkage disequilibrium (P<0.05) in Arabs. HLA-DRB1-DQB1 Tun Sau-B Mor-Ch Bah Leb Alg Lib-J Yem-J Ber-Z Ber-J 01:02–05:01 02.40 02.85 - - - 08.00 02.10 0.70 09.85 04.50 07:01–02:02 14.80 12.32 16.70 - - - 24.70a 22.10a 16.03 - 03:01–02:01 16.60 13.56 12.30 12.02 03.21 11.30 05.60a 12.00a 11.26 - 10:01–05:01 03.80 03.80 - 01.35 04.90 00.30 00.80 04.00 01.41 03.30 07:01–02:01 - - - 09.38 04.20 09.90 - - - 11.00 15:01–06:02 07.80 03.80 08.90 - - 09.90 - - 11.26 02.00 04:02–03:02 02.60 - 06.20 - - 04.20 03.00 07.50 05.15 - 13:01–06:03 02.40 - - - - 03.30 07.70 05.40 05.63 01.80 16:01–05:01 - - - 13.18 03.79 - - - - - 04:01–03:02 - - - 02.78 14.16 - - - - - 11:01–03:01 07.20b 02.22 - 11.98 31.42 04.70 09.30 03.40 07.00b 03.20 aDQB1�02 b11:01/04-03:01 https://doi.org/10.1371/journal.pone.0192269.t007 Genetic heterogeneity of Arabs PLOS ONE | https://doi.org/10.1371/journal.pone.0192269 March 9, 2018 13 / 24 https://doi.org/10.1371/journal.pone.0192269.t006 https://doi.org/10.1371/journal.pone.0192269.t007 https://doi.org/10.1371/journal.pone.0192269 In addition, DRB1�16:01-DQB1�05:01 and DRB1�04:01-DQB1�03:02, rare in neighboring populations and Mediterraneans, were identified only in Lebanese and Bahraini Arabs. The high frequency of DRB1�11:01-DQB1�03:01 haplotype (31.42%) among Lebanese is notewor- thy, since it is the highest in all populations studied, but rare in Saudi (2.2%). Furthermore, DRB1�11:01/04-DQB1�03:01, identified in Arabs, is also frequent in Cretans (18.5%) [69] and Basques (3.1%)[41], while DRB1�01:02-DQB1�05:01 was seen in Spaniards (6.30%) [41]. Var- ied frequency of DRB1�13:01-DQB1�06:03 was also reported for Spaniards (13.23%) [86], Cre- tans (3.3%) [69], and Germans (10.8%) [87]. Likewise, DRB1�15:01-DQB1�06:02 was observed in Cretans (2.6%) [65], German population (25.2%) [87], and Southern Ireland (14.90%) [23]. HLA class I and class II extended haplotypes. Table 8 shows the most frequent extended haplotypes in Arab populations, and their likely origins. The systematic review did not reveal haplotypes shared by Arab populations because of partial presentation of haplotypic data, dis- parity in the level of typing resolution, variability of the studied loci, and lack of data. In addi- tion, Arab populations share their frequent extended haplotypes with several European, especially Mediterranean, and Asian populations (Table 8). Furthermore, the possible origins of the most frequent extended haplotypes among Arabs are mainly European, Asian or Autochthonous. Table 8. The most frequent (%) HLA extended haplotypes in Arabs. HLA Extended haplotypes Arab Populations [references] Possible origin A�02:01-B�50:01-DRB1�07:01-DQB1�02:02a Southern Tunisians (3.2%)[62], Berbers of Zrawa (8.12%) [24] Euro-Asiatic A�02:01–B�44– DRB1�04:02–DQB1�03:02b Berbers of Zrawa (6.5%)[24] Tunisians (0.6%) [61] Western European A�24:02-B�08:01-C�07:02-DRB1�03:01c Saudis (3.16%) [49] Euro-Asiatic A�23:01-B�50:01-C�06:02-DRB1�07:01 Saudis (3.16%) [49] Autochthonous A�33-C�8-B�14-DRB1�01:02-DQA1�01:01-DQB1�05:01d Algerians (1.5%) [88] Mediterranean A�30-C�5-B�18-DRB1�03:01-DQA1�05:01-DQB1�02:01e Algerians (1.5%) [88] Iberian-paleo-North African A�02:01-C�06:02-B�50:01-DRB1�07:01-DQA1�02:01-DQB1�02:02f Moroccans (2.9%) [65] Euro-Asiatic A�01:01-C�06:02-B�50:01-DRB1�03:01-DQA1�05:01-DQB1�02:01g Moroccans (2.9%) [65] Mediterranean A�30-B�07-DRB1�03-DQA1�05:01-DQB1�02:01h Jordanians (1.38%) [31] Euro-Asiatic A�1-B�8-DRB1�03-DQA1�05:01-DQB1�02:01i Jordanians (1.03%) [31] Pan-European A�02:01-B�50:01-DRB1�07:01j Libyans (4.24%) [32] Tunisians (1.8%) [60], and Ghannouch (2.5%) [33]. North African A�11:01-B�52:01-DRB1�15:02k Libyans (2.54%) [32]; Yemen Jews (0.93%) [23] Mediterranean A�69-B�49-DRB1�04:03-DQB1�03:02 Palestinians (2.4%) [29] Autochthonous A�24-B�18-DRB1�11:04-DQB1�03:01l Palestinians (1.8%) [29] Central-South-Eurasian a present in Spaniards (1.2%) [41], Turks (1.3%) [79], Italians (0.5%) [68], and Moroccan Jews (2%) [66]. b also found in British (2.6%), Cornish (7.9%), Danes (2%) [39], Italians (0.9%) [68], Spaniards (0.6%) [41], Spanish Basques (1.9%), Pasiegos (3.3%), Cabuemigos (2.2%) [77], and Portuguese (3.1%) [39]. c present at low frequencies in the Euro-Asian minorities of Germany [23]. d found in Armenians (0.031), Sardinians (0.027), French (0.014), Greeks (0.011), and Italians (0.007) [68]. e also found in Sardinians (11.4%), and French-Basques (4.7%) [68]. f present also in Mongolians [68], Turks [79]. g found in Spaniards, Italians, and north Africans [65]. h present in Cornish (0.084), British (3.3%), and Danes (3.8%) [68]. i present in Basques (5%), Spaniards (3.4%) [41], Macedonians (4.9%) [78], Yugoslavians (7.7%), British (2.9%), and Germans (4.8%) [68]. j found in Poland Jews (1.15%); Ashkenazi Jews (0.92%) [23]. k present in Ashkenazi Jews (1.05%) [23]. l found in Armenians (2.1%) and Italians (0.7%) [23]. https://doi.org/10.1371/journal.pone.0192269.t008 Genetic heterogeneity of Arabs PLOS ONE | https://doi.org/10.1371/journal.pone.0192269 March 9, 2018 14 / 24 http://www.allelefrequencies.net/pop6001c.asp?pop_id=3374 http://www.allelefrequencies.net/pop6001c.asp?pop_id=3388 https://doi.org/10.1371/journal.pone.0192269.t008 https://doi.org/10.1371/journal.pone.0192269 Discussion This meta-analysis is the first genetic anthropology study in MENA region, and included 100 populations from 36 Arab and neighbouring countries, and comprising in excess of 16,000 individuals. A main outcome of the study is the lack of striking differences in the distribution of HLA alleles and haplotypes between North Africans and Arabian Peninsula populations. On the contrary, key differences were noted between Levant Arabs (Lebanese, Palestinians, Syr- ians), and other Arab populations, highlighted by high frequencies of A�24, B�35, DRB1�11:01, DQB1�03:01, and DRB1�11:01-DQB1�03:01 haplotype in Levantine Arabs compared to other Arab populations. Class I haplotype frequencies are lower than Class II haplotypes, because of weak LD between A and B loci, due to long physical distance between them, compared to DRB1 and DQB1 loci. The identification of shared haplotypes between Arabs and other Medi- terranean and Asian populations is attributed to the higher admixture of Mediterraneans and Asians in Arab populations. Iberians, North Africans, and Arabian Peninsula inhabitants The relatedness between North Africans and Iberians was previously discussed [29, 59–62, 69, 78, 79, 86, 88]. Using correspondence analysis, NJ trees and genetic distances, our results show that North Africans are genetically close to Iberians, which is supported by historical events. First, this relatedness is attributed to the Berber migration from the African Sahara northwards in 10000–4000 BC, because of hyper-arid conditions [69]. It may also be explained by the simi- lar history between Iberians and North Africans, both of whom were invaded by Phoenicians, Romans, Germans, Muslim Arabs [89]; the respective invading armies had a mixed genetic complexity; indeed, most of them were mercenaries recruited in recent conquests like in the case of Phoenicians [90] and Muslim who invaded Iberia had troops that were mostly Berbers. The invasion of Iberia by Muslims in the 8th century AD may have had a role in the related- ness between North Africans and Iberians for two reasons: first, most Muslim invaders recruits were North African Berbers, and the second is explained by the 8 centuries period of settle- ment of the Muslims in Iberia, although more ancient and continuous gene exchange since prehistoric times between Iberia and North Africa may have been induced the main exchange [86]; massive mixed marriages and breeding across religious Iberian groups under Muslim rule is not documented. The analyses performed showed that current North Africans are closely related to Tunisian (Zrawa and Matmata) and Moroccan (Sousse-Agadir and Eljadida) Berbers, suggesting that North Africans have a genetic Berber profile. On the contrary, North Africans displayed a greater distance from the Arabs of Levant (Palestinians, Syrians, Lebanese, and Jordanians), indicating low genetic contribution of Phoenician and Levant Arab invasion of North Africa. These observations based on HLA markers prompted the conclusion that all Berbers of North Africa constitute a homogeneous genetic unit, except for small isolates, such as the Berbers of Djerba, who display a Berber genetic profile. Saudi populations used in this study originated from Eastern Saudi Arabia, especially from Riyadh province. There is no reliable HLA data on Eastern Saudi Arabia that shed light on pre- Islamic history; some ancient people may have originated from old Persians, but quantification is difficult and undetermined [91]. The genetic heterogeneity between Eastern and Western Saudi Arabia is very possible, and should be taken into account in further interpretation. All analyses performed here, using HLA-A,-B, -DRB1, and DQB1 markers support the notion that Saudis along with the Kuwaitis and Yemenis are closely related to North Africans. The most plausible explanation for West Arabia and Yemen clustering with Iberian/North Africans is a possible important massive migration that occurred when Sahara underwent Genetic heterogeneity of Arabs PLOS ONE | https://doi.org/10.1371/journal.pone.0192269 March 9, 2018 15 / 24 https://doi.org/10.1371/journal.pone.0192269 desiccation in all directions [92, 93]. Cultural and language relatedness of many Mediterranean languages, including old Iberian and Basque [92], with Berber language are concordant with our genetic findings and Saharan origin hypothesis; also a part of Arabian Peninsula inhabitants (including Yemen) may had been reached by Saharan people. In fact, Malika Hachid who has been studying Saharan and North African Archaeology, culture and rock painting/writing of pre- historic Sahara, even suggests that first known writing alphabet was originated in Sahara. Proto- Berber writing rock characters have been used (very similar to present day used Berber scripts). This Proto-Berber language could have appeared 5,000 years BC [94, 95]. Explanation to HLA Kuwait genetic similarity to this group seems more difficult to achieve but interaction between Arabian Peninsula and Mesopotamia through this strategic Kuwait area is documented since 6,500 years BC (Ubard Period) [96]. Arabs of Levant Using genetic distances, correspondence analysis and NJ trees, we showed earlier [61, 62] and in this study that Palestinians, Syrians, Lebanese and Jordanians are closely related to each other and to Eastern Mediterranean Europeans (Turks, Cretans, Greeks), Egyptians and Irani- ans, and confirmed by HLA class I (A, B) and class II markers (DRB1 and DQB1) analysis. However, Levant Arabs are distant from North African Arabs (Tunisians, Algerians, Moroc- cans and Libyans) and Iberians (Basques, Spaniards). The strong relatedness between Levant Arab populations is explained by their common ancestry, the ancient Canaanites, who came either from Africa or Arabian Peninsula via Egypt in 3300 BC [97], and settled in Levant low- lands after collapse of Ghassulian civilization in 3800–3350 BC [98]. The relatedness is also attributed to the close geographical proximity, which constituted one territory before 19th cen- tury British and French colonization. The close relatedness of Levant Arabs to Egyptians, as confirmed genetic distances using HLA markers, may be due to three reasons. First, Egypt is a neighbor to Levant Arab countries, and historically part of the Levant. Second, the Egyptians invaded the Levant several times throughout history; the most significant was 1468 BC invasion, where they settled for 12 centu- ries [99]. Third, the Canaanites, the likely ancestors of Levant Arabs, may have originated from Africa through Egypt, where they settled for a long period, suggesting likely admixture between Canaanites and Egyptians. Historically, Levant is a wider region that included countries along the Eastern Mediterra- nean with its islands, and extended from Greece to Cyrenaica [100]. Broadly, Levant was his- torically characterized by high migratory flow between its sub-regions in all directions. For example, present-day Levant comprising Palestine, Lebanon, Syria, and Jordan has undergone successive invasions by populations originating from the great Levant, including Egyptians (1468 BC), Horites, Amorites, Hitites (Turks), Greeks (1200 BC), Assyrians (1090 BC) [99], and more recently the Ottomans. This has favored admixture, reduced distances and homoge- nized Great Levant populations, thus explaining the close relatedness of Levant Arabs to East- ern Mediterranean populations. On the other hand, Levant Arabs are distant from Saudis, Kuwaitis, and Yeminis, an indication that the contribution of the Arabian Peninsula popula- tions to Levantine gene pool is low, probably due to the absence of the demographic aspect of 7th century invasion. Sudanese and Comorians Sudanese are close to sub-Saharan Africans (Nigerians, Congolese, and Senegalese), and North Africans, in particular Egyptians, suggesting that the genetic profile of Sudanese is the admix- ture between North Africans (especially Egyptians) and sub-Saharan Africans throughout Genetic heterogeneity of Arabs PLOS ONE | https://doi.org/10.1371/journal.pone.0192269 March 9, 2018 16 / 24 https://en.wikipedia.org/wiki/Greece https://en.wikipedia.org/wiki/Cyrenaica https://doi.org/10.1371/journal.pone.0192269 history. The close relatedness of Sudanese to sub-Saharan Africans suggests a reduced genetic effect of Arabs on Sudanese. Also, the Comorians (Comoros islands officially joined League of Arab Countries in 1993) are close to sub-Saharan Africans (Congolese, Nigerians, and Gabo- nese) [43], Egyptians, Iranians, and Eastern Mediterranean. This suggests high admixture between populations belonging to three continents in the Comoro Islands, and can be explained by their geographical position as a corridor for international trade. Bahrainis, Emiratis, and Omanis Bahrainis, Emiratis, and Omanis are geographically similar populations, which explains their genetic relationship as demonstrated in this study. These three populations tend to form a het- erogeneous group with Pakistanis, Indians, Iranian Arabs (Famoori), Sardinians (the later probably close to Iberians/North Africans but behaving as out layer group in analyses because of they are a genetic island isolate), Egyptians, and some sub-Saharan Africans, such as Congo- lese. These populations appear close to certain Eastern Mediterranean populations including Greeks, Macedonians, and those further, in particular North Africans, hence explaining their intermediate grouping, and distinction from two main clusters. Collectively, this suggests high admixture in these populations brought about by their commercially important position. Sar- dinia is a relative genetic isolate “founded” by Iberian Norax/Nora (first documented Sardin- ian capital close to Cagliari) and Iberians/North Africans may be genetically related to Sardinians (A�30-B�18-Cw�5 basic HLA haplotype is very high in Sardinia, Iberia, and North Africa) [93]. Minorities of Arab World Ethnic minorities. The Kurds and Berbers are the two major ethnic minorities in Arab world. Berbers are indigenous North African ethnic group found over a vast area stretching from Atlantic Ocean to Siwa Oasis in Egypt, and from Mediterranean Sea to Niger River. Berbers number about 20 million people, and constitute 40–45% of Moroccans, 20–25% of Algerians, and 2–7% in both Libya and Tunisia. The Kurds live in the northern regions of Iraq (15–20%) and Syria (10%). They constitute an Indo-European ethnic group, and speak Kurdish. Less important minorities include Armenians, Nubians, Assyrians, and Turkmen [99]. Berbers populations used in this work are closely linked to each other, as well as to present- day North Africans, and to Western Mediterranean populations, especially Iberians. Indeed, the Moroccan Berbers are not genetically different from the current Moroccans, nor those of neighboring populations, like Algerians and Tunisians. This also applies to Tunisian Berbers, except those of the island of Djerba, who appear to be related to Eastern Mediterranean popu- lations, including Levant Arabs. This suggests that North African Berbers are in perfect har- mony with their environments, and that differences between them are cultural rather than genetic due to 7th century Arabization of the region. Clustering and genetic distances analyses demonstrated that Iraqi and Iranian Kurds are not genetically different from Iranians or neighboring populations, including Levant Arab, and are close to Turks and other Eastern Mediterranean populations. This suggests that Kurds originate from the region, and are in genetic harmony with neighboring populations, despite the clear cultural differences. This suggests that Kurds, Syrians, Jordanians, Palestinians, Iraqis, Lebanese, and Iranians probably share the same genetic profile, with few differences. Accordingly, our findings confirm the results of an earlier study of Arnaiz-Villena on Iraqi Kurds [54]. Religious minorities. Sunni Muslims constitute the majority (80%) of Arab populations, followed by Shi’a Muslims (10%) who are present in parts of Iraq, Lebanon, Saudi Arabia, Kuwait, Yemen, and Bahrain. Non-Muslims make up about 10% of all Arabs, and Christianity Genetic heterogeneity of Arabs PLOS ONE | https://doi.org/10.1371/journal.pone.0192269 March 9, 2018 17 / 24 https://doi.org/10.1371/journal.pone.0192269 (6%) is the second largest religion among Arabs, with about 20 million Christians living in Lebanon, Egypt, Iraq, Syria, and Jordan. Other minor religions (4%) such as Judaism, Druze and others are practiced on a much smaller scale [99]. HLA data on Sunni and Shiite Arabs are not available, same as comparison of Muslims to Christians. The only available data are those concerning Arab Jews. In this study, data are available for three Jewish populations, including two from North Africa (Moroccan and Lib- yan Jews) and one from the Arabian Peninsula (Yemenite Jews). While genetic distances sepa- rating these three groups of Jews are small (S1 Table), genetic heterogeneity between these Jewish populations was noted. For example, Yemenite Jews are related to Western Mediterra- nean populations, including North Africans and Iberians, while Libyan Jews are related to Eastern Mediterraneans, including Levantine Arabs. The relatedness of Moroccan Jews depends to other communities on the studied HLA loci; they associate with Eastern Mediterra- neans using DRB1, but group with Eastern Mediterraneans when the other markers are used. Conclusion This study supports the notion that Arabs are divided into four groups. The first consisting of North Africans (Algerians, Tunisians, Moroccans, and Libyans), Saudis, Kuwaitis, and Yemenis, with relatedness to Western Mediterraneans, including Iberians. The second includes Levantine Arabs (Palestinians, Jordanians, Lebanese, and Syrians), Iraqi, and Egyptians, who appear to be related to the Eastern Mediterranean and Iranians, who in turn belonged to ’Great Levant’ historically described. The third consists of Sudanese and Comorians who associate with Sub-Saharan Africans. Finally, the fourth group of Arabs comprises Omanis, Emiratis, and Bahrainis. This group associates with heterogeneous pop- ulations (Mediterranean, Asian and sub-Saharan). Lastly, the two main indigenous minori- ties, Berbers and Kurds, are not genetically different from the ‘host’ and neighboring populations. Supporting information S1 Checklist. PRISMA 2009 checklist. (DOC) S1 Fig. Neighbor-Joining dendrograms, based on standard genetic distances (SGD), show- ing relatedness between Arabs and other populations using generic HLA-DRB1� allele fre- quencies data. Populations’ data were taken from references detailed in Tables 1 and 2. Bootstrap values from 1.000 replicates are shown. (TIF) S2 Fig. Neighbor-Joining dendrograms, based on standard genetic distances (SGD), show- ing relatedness between Arabs and other populations using generic HLA-B� allele frequen- cies data. Populations’ data were taken from references detailed in Tables 1 and 2. Bootstrap values from 1.000 replicates are shown. (TIF) S1 Table. Genetic distances between three groups of Arab Jews based on HLA-DRB1 and -DQB1 alleles frequencies. (DOC) Author Contributions Conceptualization: Abdelhafidh Hajjej, Lasmar Hattab, Slama Hmida. Genetic heterogeneity of Arabs PLOS ONE | https://doi.org/10.1371/journal.pone.0192269 March 9, 2018 18 / 24 http://www.plosone.org/article/fetchSingleRepresentation.action?uri=info:doi/10.1371/journal.pone.0192269.s001 http://www.plosone.org/article/fetchSingleRepresentation.action?uri=info:doi/10.1371/journal.pone.0192269.s002 http://www.plosone.org/article/fetchSingleRepresentation.action?uri=info:doi/10.1371/journal.pone.0192269.s003 http://www.plosone.org/article/fetchSingleRepresentation.action?uri=info:doi/10.1371/journal.pone.0192269.s004 https://doi.org/10.1371/journal.pone.0192269 Formal analysis: Abdelhafidh Hajjej, Slama Hmida. 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