mini Review article (500 words)

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 * [email protected]

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

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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

Copyright: © 2018 Hajjej et al. This is an open access article distributed under the terms of the

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.

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

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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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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).

https://doi.org/10.1371/journal.pone.0192269.g002

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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Genetic heterogeneity of Arabs

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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

https://doi.org/10.1371/journal.pone.0192269.t003

Genetic heterogeneity of Arabs

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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.

https://doi.org/10.1371/journal.pone.0192269.g004

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.

https://doi.org/10.1371/journal.pone.0192269.g005

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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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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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

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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].

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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

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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

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

(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

Formal analysis: Abdelhafidh Hajjej, Slama Hmida.

Investigation: Abdelhafidh Hajjej.

Methodology: Wassim Y. Almawi, Slama Hmida.

Software: Abdelhafidh Hajjej, Lasmar Hattab.

Supervision: Slama Hmida.

Validation: Abdelhafidh Hajjej, Wassim Y. Almawi, Antonio Arnaiz-Villena, Lasmar Hattab,

Slama Hmida.

Writing – original draft: Abdelhafidh Hajjej.

Writing – review & editing: Wassim Y. Almawi, Antonio Arnaiz-Villena.

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Genetics, health, urban Dubai-2018.pdf

• Abstract
• Introduction
• Diabetes in the Emirates
• Diabetes and fate
• The body and the city
• Conclusion
• Ethical approval
• Acknowledgments
• Disclosure statement
• References