j.1399-0039.1999.530301.x

Key words:HLA; Berbers; Imazighen; Cretans; Greeks; Jews;Basques; Turks

Acknowledgments:This work was supported in part by grants fromthe Spanish Ministry of Education (PM-57–95)and PM-96–21, FIS (94–0367), the RamonAreces Fundacion and Comunidad de Madrid(06-70-97). We are grateful to Fernando Ucedafor help in the preparation of the manuscript andfigures.

Received 24 November 1998, revised,accepted for publication 8 January 1999

Copyright c Munksgaard 1999Tissue Antigens . ISSN 0001-2815

Tissue Antigens 1999: 53: 213–226Printed in Denmark . All rights reserved

213

A. Arnaiz-Villena The origin of Cretan populations asP. Iliakis determined by characterization of HLA allelesM. Gonzalez-HevillaJ. LongasE. Gomez-CasadoK. SfyridakiJ. TrapagaC. Silvera-RedondoC. MatsoukaJ. Martınez-Laso

Abstract: The Cretan HLA gene profile has been compared with those ofother Mediterranean populations in order to provide additional informationregarding the history of their origins. The allele frequencies, genetic dis-tances between populations, relatedness dendrograms and correspondenceanalyses were calculated. Our results indicate that the Indoeuropean Greeksmay be considered as a Mediterranean population of a more recent origin(after 2000 B.C.), while all other studied Mediterraneans (including Cretans)belong to an older substratum which was present in the area since pre-Neolithic times. A significant Turkish gene flow has not been detected inthe Greek or Cretan populations, although Greeks and Turks have two highfrequency HLA-DRB-DQB haplotypes in common. It is proposed that Im-azighen (Caucasoid Berbers living at present in the North African coast andSaharan areas) are the remains of pre-Neolithic Saharan populations whichcould emigrate northwards between about 8000–6000 B.C., when desert des-iccation began. They also could be part of the stock that gave rise to Su-merians, Cretans and Iberians; this is supported by both linguistic and HLAgenetic data.

The high HLA polymorphism has proven to be useful for singling

out individuals and populations. The discovery of new loci and the

presently available DNA typing and sequencing of new alleles have

dramatically increased the variety of HLA allelism (1). Certain al-

leles are frequent only in specific populations (i.e., A36, A43 in

African Americans) and the strong linkage disequilibrium between

HLA neighboring loci demonstrates that certain combinations of

contiguous alleles (HLA haplotypes) show a characteristic fre-

quency or are distinctive in certain living populations (2–5). HLA is

a unique tool for studying the origins of human groups, as the

characteristic HLA allele frequencies of founder populations have

not been completely lost with time in certain cases. Dendrograms

have been constructed according to the differences of HLA allele

frequencies and the population genetic distances (2). The ethnic

group clusters obtained, roughly Caucasoids, Mongoloids, and Neg-

Authors’ affiliations:

A. Arnaiz-Villena1*,P. Iliakis2*,M. Gonzalez-Hevilla1,J. Longas1,E. Gomez-Casado1,K. Sfyridaki2,J. Trapaga1,C. Silvera-Redondo1,C. Matsouka2,J. Martınez-Laso1

1Department of Immunologyand Molecular Biology, H.12 de Octubre, UniversidadComplutense, Madrid, Spain,

2Department of Hematology,Venizelion Hospital, Iraklion,Crete, Greece

*The contribution by AntonioArnaiz-Villena and PolyviosIliakis is equal and the orderof authorship is arbitrary

Correspondence to:Antonio Arnaiz-VillenaDepartamento de

Inmunologıa y BiologıaMolecular

H. 12 de OctubreUniversidad ComplutenseCarretera Andalucıa28041 MadridSpainE-mail:Antonio.Arnaiz/inm.h12o.eshttp://chopo.pntic.mec.es/biolmol

Arnaiz-Villena et al : HLA genes in Cretans and other Mediterraneans

roids, fit well with the classical, anthropologically defined ethnic

groups.

There have been frequent close cultural and circum-Mediterran-

ean contacts during the last 10,000 years (6–9). Since then, and after

the last Pleistocene glaciation, the fertile Saharan area has under-

gone drastic climatic changes, becoming hotter and drier (10, 11)

and it has been put forward that important northward migrations

from this area occurred intermittently after 10,000 B.C. (12).

Specifically, the emigration of these Saharan people is genetically

and historically supported in the case of the Iberian Peninsula (12–

14). However, the possibility that a certain northern (European) gene

flow also occurred towards the South (Africa) (15, 16) cannot be

overlooked. The widespread contacts of Mediterraneans may have

had an effect on a generalized gene flow among the different popu-

lations, but the most documented long-distance travelers (i.e., Cret-

ans, Mycenaeans, Phoenicians, Greeks and Romans), who set up

colonies all over the Mediterranean Sea, probably did not mix exten-

sively with autochthonous populations because they were mainly

involved in trading and war.

The strategic placement of the island of Crete in the Mediterran-

ean was of great commercial importance in the last millennia (see

map in Fig. 4). It is feasible that primitive Minoans come from the

North African stock since their language (linear A or Minoan) is

related to the paleo-North African group of languages (17, 18); it

also comprises Iberian, Basque, Berber (Imazighen) and Etruscan

among others which were spoken by paleo-North Africans in the

pre-Neolithic period (19, 20).

The first Indoeuropean (pre-Mycaenian) Greeks who came from

the North appeared in the Balkan Peninsula by the second millen-

nium B.C.. Mycaenians rendered tributes to Crete and invaded the

island by about 1450 B.C., substituting Linear A language by Linear

B (or Greek) in the island. The Cretan Aegean Sea empire was

destroyed and was continued by the Mycaenians (21). The incidence

of Greek gene flow into the island is not documented, but Crete

remained isolated from continental Greece since it did not partici-

pate in either the Peloponnese or Persian wars (22). However, Cretan

civil wars were frequent and some of the factions established tem-

porary alliances with Egypt and North Africa (the Cyrenaica Prov-

ince; 23). Many cultural items (including writing characters) were

taken by the Greeks from the more ancient Minoan culture (18, 24,

25).

As the Crete Minoan culture may be one of the main basis of

Greek, and thus of Western Civilization (18, 24, 25), this work aimed

to study the relative contribution of different Mediterranean popula-

tions to the present day Cretan people gene pool. Also, this compari-

son may help to elucidate the true ancient relationships between

Cretans and Greeks (Mycaeans) and North Africans; these are still

214 Tissue Antigens 1999: 53: 213–226

controversial and poorly documented historically. Cretan genetic

data may also improve our understanding of Cretan people’s origins

and culture. Thus, we have studied the HLA genes Cretan profile,

since it has been shown that the very polymorphic HLA system

can be useful for comparisons among ethnic groups and for distin-

guishing populations.

Material and methods

Population samples

One-hundred and thirty-five unrelated Cretan individuals were used

for HLA genotyping and phylogenetical calculations. The samples

were taken from volunteers among blood donors who were born at

various places all over the island. Samples from Rethimnon, Irak-

lion, Sitia, Kastelli, Pitsidia, Ierapetra, Malia, Timbaki, etc. were

included; the grandparents (both of the parents of the mother and

father) of each volunteer had been born in Crete. The origin of all

other populations used for comparisons are detailed in Table 1. Both

Moroccan Berber (Imazighen) populations were named as such be-

cause about 40% of the Moroccan population speaks Berber (30%

in Algeria) (26); it has also been established that North Africans are

mostly Imazighen, those from urban areas speaking only Arab, and

others speaking Berber and Arab (26). Arabs from Arabian penin-

sula ascents are thus a small minority. In addition, Izaabel et al. (14)

have studied a Berber Moroccan country population from the Souss,

Agadir area. This population clusters with urban Algerians, Iberi-

ans and other Mediterraneans (see below); thus assigning our own

Berber population from El Jadida, which comes from a Berber

speaking area, as Berber is justified. It also provides genetic support

for the idea that most present day North Africans have a strong

Berber substrate.

HLA genotyping, DNA sequencing and statistics

Generic HLA class I (A and B) genotyping was done by polymerase

chain reaction using sequence-specific oligonucleotides (PCR-SSO),

a technique that has been previously described (27) with slight

modifications that yield a resolution equivalent to the standard

serology techniques (see Results and Discussion and Table 2). High

Resolution HLA class II (DRB1 and DQB1) was performed by using

a reverse dot-blot technique with the Automated Innolipa system

(Innogenetics N.V., Zwijndrecht, Belgium). HLA-DQA1 alleles were

characterized by using the 11th and 12th International Histocom-

patibility Workshops and local reagents and PCR-SSO (28, 29).

HLA-A, -B, -DRB1, -DQA1, and -DQB1 allele DNA sequencing was


Table 1Populations used for the present work

Figs. 3 and 4identificationnumbers Region and population n1 Reference (no.)

1 Berbers (El Jadida) 98 Unpublished data (Arnaiz-Villena et al.)

2 Berbers (Agadir) 98 14

3 Jews (Morocco) 94 56

4 Spaniards 176 41

5 Basques 80 41

6 French 179 3

7 Algerians (Oran) 47 57

8 Algerians (Algier) 102 58

9 Sardinians 91 3

10 Italians 284 3

11 Greeks (Attica) 96 33

12 Greeks (Attica /Aegean) 85 33

13 Cretans 135 Present study

14 Greeks (Cyprus) 101 33

15 Jews (Ashkenazi) 80 51

16 Jews (non-Ashkenazi) 80 51

17 Lebanese (NS)2 59 33

18 Lebanese (KZ)3 93 33

– San 77 3

– Japanese 493 3

1 n5number of individuals analysed for each population2 NS5Niha el Souff (town)3 KZ5Kafar Zubian (town)

only done when indirect DNA typing yielded ambiguous results

(30). Statistical analysis was performed with Arlequin v. 1.1 soft-

ware kindly provided by L. Excoffier and M. Slatkin (31). In sum-

mary, this program calculated HLA-A, -B, -DRB1, -DQA1 and -

DQB1 allele frequencies, Hardy-Weinberg equilibrium, the linkage

disequilibrium between two alleles at two different loci, their level of

significance (P) for 2¿2 comparisons and also their relative linkage

disequilibrium (RLD) (32). In addition, the most frequent complete

haplotypes were tentatively deduced from: 1) the 2, 3, and 4 HLA

loci haplotype frequencies (12); 2) the previously described haplo-

types in other populations (3); and 3) haplotypes if they appeared

in two or more individuals and the alternative haplotype was well

defined (3). In order to compare phenotype and haplotype HLA fre-

quencies with other populations, the reference tables of the 11th and

12th International HLA Workshops were used (2, 33) (see Table 1).

Phylogenetic trees (dendrograms) were constructed with the allelic

frequencies by using the neighbor-joining (NJ) method (34) with the

standard genetic distances (SGD) (35), by using the software DIS-

215Tissue Antigens 1999: 53: 213–226

PAN which contained the programs GNKDST and TREEVIEW (36,

37). Correspondence analysis in three dimensions and its bidimen-

sional representation were carried out by using the VISTA v. 5.02

computer program (38, http:/forrest.psych.unc.edu). Correspondence

analysis consists of a geometric technique that may be used for

displaying a global view of the relationships among populations

according to HLA (or other) allele frequencies. This methodology is

based on the allelic frequency variance among populations (simi-

larly to the classical components methodology) and on the display

of an statistical visualization of the differences.

Results

Characteristic HLA allele frequencies of the Cretan

population compared to other Mediterraneans

The expected and observed gene frequency values for HLA-A, -B,

-DRB1, -DQA1 and -DQB1 loci do not significantly differ and the


Table 2HLA-A, -B, -DRB1, -DQA1 and -DQB1 allele frequencies in the Cretan population

Allele Allele AlleleAlleles frequencies (%) Alleles frequencies (%) Alleles frequencies (%)

HLA-A HLA-DRB1 HLA-DQB1

A1 12.0 0101 6.6 02 20.0

A2 25.5 0102 1.4 0301 27.1

A3 7.5 0104 0.4 0302 9.2

A11 4.0 03011 7.4 03032 0.8

A23 8.0 0401 0.7 0304 0.4

A24 15.0 0402 5.1 0305 0.4

A25 3.0 0403 3.3 0401 0.4

A26 6.0 0404 1.1 0402 0.8

A29 4.0 0405 1.9 0501 13.0

A30 4.0 0701 11.1 0502 10.0

A31 1.0 08 1.1 05031 4.5

A32 3.5 1001 3.7 06011 1.9

A33 4.5 1101 11.1 06012 1.1

A28 0.5 1102 0.4 0602 3.7

A68 1.5 1103 2.2 0603 3.3

1104 10.0 0604 3.0

HLA-B 1201 0.7 0606/9 0.4

B7 7.0 12021 1.9 06051 0.4

B8 4.3 1301 3.3

B13 3.8 1302 3.7

B14 4.3 1303 1.1

B15 3.8 1305 0.4

B18 7.5 1401 4.4

B27 1.0 1501 3.7

B35 24.4 1502 4.4

B37 3.2 1601 7.8

B38 3.7

B39 1.6 HLA-DQA1

B40 2.2 01 16.6

B41 0.5 0102 17.8

B44 4.8 0103 5.2

B49 2.7 0201 12.6

B50 0.5 03 12.2

B51 10.2 0401 1.1

B52 3.2 0501 34.7

B53 3.2 0503 0.4

B55 3.7

B57 1.6

B58 2.1

Alleles DQA1*0101 and 0104 were all assigned as DQA1*01. Alleles DQA1*03011 and 0302 were all assigned as DQA1*03.

Alleles DQA1*05011, 05012 and 05013 were all assigned as DQA1*0501. Alleles DQB1*0201 and 0202 were all assigned as

DQB1*02. No null alleles are taken into account; exact 100% is not reached because only one decimal number is considered

216 Tissue Antigens 1999: 53: 213–226


population is in Hardy-Weinberg equilibrium. Table 2 shows the

HLA allele frequencies found in the Cretan population. They are

likely to be representative of most of the island population since the

samples were a scattered collection from all over (see Material and

methods). Class I antigens, HLA -A and -B, were detected by a

genotyping technology that only distinguished 21 alleles for locus

A and 41 alleles for locus B (27). A lower number of alleles was

studied in the last International HLA Workshop: 21 antigens for

locus A were defined and 35 antigens for locus B (33). However, we

typed class II genes by a high resolution methodology and most

existing HLA-DRB1 (n5155) and -DQB1 (n527) specificities were

analyzed (39). Therefore, two types of analyses were done to com-

pare Cretan HLA frequencies with other Mediterranean population

frequencies: 1) with pooled class I and DRB1 data; and 2) with

DRB1 data, which is probably a more informative and discriminat-

ing methodology. These two types of analyses were also performed

because some of the populations used for comparisons lacked HLA-

A and -B data [Berbers (from Souss, the Agadir area, and Morocco),

Algerians (Oran), Jews (Ashkenazi), Jews (Morocco), Jews (non-Ash-

kenazi), Lebanese (NS and KZ), or high resolution DQ typing

(Greeks (Attica), Greeks (Cyprus), Greeks (Attica-Aegean) see Table

1]. These partially HLA-typed populations should have been ig-

Fig. 1. Neighbor-joining dendrogram showing relatedness be- genotyping. Data from other populations were from references in Table 1.tween Cretans and other populations. Standard genetic distances were Bootstrap values from 1,000 replicates are shown.calculated by using HLA-A and -B (generic) and -DRB1 (high-resolution)

217Tissue Antigens 1999: 53: 213–226

nored, but they could be analyzed conjointly taking into account

only their DRB1 frequencies (Table 2, Figs. 2 and 3). On the other

hand, class I generic typing tends to homogenize the comparisons

based on DRB1 high resolution typing; one class I allele obtained

by generic DNA typing may contain several class I alleles, while

this is not the case for most DRB1 alleles. Only generic class I DNA

typing is presently available. This phenomenon is also observed in

the present work by comparing Figs. 1 and 2 and Fig. 3a, b (12, 14).

Greeks and Japanese tend to cluster together (Fig. 1, in spite of their

large genetic distance) because outgroups among more homogenous

groups tend to be close in dendrograms.

HLA-DQ generic data (5 alleles) were useful to compare Turks,

Greeks and Cretans, since this was the only common HLA typing

data available for these three populations (33, 40).

Fig. 1 depicts a generic HLA class I and II neighbor-joining tree

and shows how the three Greek samples group together with Ja-

panese and Cretans on one side and Middle and Western Mediter-

raneans (both European and Africans) are grouped on the other

side of the tree. Bootstrap values are higher in Fig. 2 than in Fig. 1

because high-resolution DRB1 comparisons are more discriminative

and do not tend to homogenize populations. It is shown that Cretans

are closer to Middle and Western Mediterraneans (both African and


Fig. 2. Neighbor-joining dendrogram showing relatedness be- values from 1,000 replicates are shown. Figures with calculations done withtween Cretans and other populations. Standard genetic distances were DRB1 genes have been coloured to visually stress the degree of relatednesscalculated by using HLA-DRB1 (high-resolution) genotyping. Data from among populations (see also Figs. 3b and 4).other populations were taken from references detailed in Table 1. Bootstrap

European) than to Greeks. This effect is more evident in both Fig.

2 (DRB1 dendrogram) and in Table 3 (DRB1 genetic distances):

Greeks are almost outliers in neighbor-joining dendrograms and

Cretans are closer to all other Africans and Europeans, Eastern and

Western Mediterraneans than to Greeks. In fact, after the Cretans-

Basques genetic distance (32¿10ª2), a discontinuity with the next

closest value (72¿10ª2) may be observed and it corresponds to

the Greek-Cretan genetic distance. In addition, the following DRB1*

alleles are present in one or more of the three Greek groups ana-

lyzed, but absent in Cretans: 0103, 0304, 0305, 0306, 0307, 0309,

0408, 0409, 0411, 0413, 0415, 0416, 0417, 0420, 09012, 1106, 1108,

1110, 1112, 1113, 1118, 1120, 1121, 1122, 1125, 1304, 1306, 1310,

1311, 1316, 1317, 1318, 1321, 1324, 1326, 1327, 1402, 1403, 1404,

1407, 1408, 1413, 1415, 1416, 1423, 1506, 16021, 1604 and 1608.

218 Tissue Antigens 1999: 53: 213–226

HLA-A, -B, -DRB1 and -DQB1 linkage disequilibria and

correspondence analysis in Cretans

The study of Cretan HLA haplotypes (Tables 4 and 5) also shows

that the most common ones are predominantly found in other Medi-

terraneans; however, no high frequency haplotypes are found in

Cretans, in contrast to the results obtained in Basques or Sardinians

(41), which may also be relative genetic isolates; this may reflect the

existence of a higher admixture of Mediterranean populations in

Cretans (Table 5). Only one haplotype HLA-A2, -B13, -DRB1*1601

is specific for Cretans; this may come from Minoans (founder effect)

or may have been generated in the island after the admixture of

two different populations (42). However, the low frequency of the

haplotype and the fact that A2-B13 linkage disequilibrium is not


found (Table 4) make this assertion provisional until sample size is

increased.

Table 3 also suggests that Cretans are particularly close to

Fig. 3. Correspondence analysis showing a global view of the re- tation). a) (above) HLA-A, -B, -DRB1 allele frequencies data. b)lationship among Mediterranean populations according to HLA al- (below) HLA-DRB1 allele frequencies data.lele frequencies in three dimensions (two-dimensional represen-

219Tissue Antigens 1999: 53: 213–226

Middle East people, North Africans, Italians and French. Western

Mediterraneans from the northern and the southern part are also

close populations compared to Greeks, Japanese and San (Bush-


Standard genetic distances (SGD) between Cret-an and other populations (¿102) obtained byusing HLA-DRB1 allele frequencies (see Table 1for population identification)

HLA-DRB1 (SGD)

Non-Ashkenazi Jews 3.75

Algerians (Oran) 5.41

Ashkenazi Jews 7.36

Moroccan Jews 8.16

Italians 10.01

French 10.99

Algerians (Algiers) 13.43

Lebanese (NS) 17.11

Spaniards 19.56

Berebers (El Jadida) 22.46

Lebanese (KZ) 23.26

Sardinians 23.53

Berbers (Agadir) 24.01

Basques 32.31

Greeks (Attica) 72.85

Japanese 101.65

Greeks (Cyprus) 113.12

San 148.13

Table 3

men). In summary, the main conclusion is that Cretan and all other

Mediterraneans may have had a considerable gene flow among

them, probably since Paleolithic times; however, Western and East-

ern populations tend to be distinguished by forming two respective

groups which are more evidently shown in the DRB1 correspon-

dence analysis (Fig. 3b). Greeks are placed as outliers both in Fig.

3a and b; this is consistent with the fact that first Greeks (pre-

Mycaeans) arrived more recently (2000 B.C.) to the Mediterranean

coasts (18, 24, 25).

Historical background and discussion

Cretans and Greeks

Cretan upper Paleolithic human remains (20,000–10,000 B.P.) have

been found in caves like the one discovered at Mianou (18). The

Neolithic man already inhabited Magasa, a mountain settlement,

and the Neolithic people may have come to the island in galleys

with many oars, similar to those painted in pre-dynastic Egypt (be-

fore 2700 B.C.). Neolithic remains have also been found under the

220 Tissue Antigens 1999: 53: 213–226

Knossos palace and they may date from as long ago as 12,000 B.C.,

but no more recent Neolithic cultures have been found surrounding

the palace and it may be deduced that the ancient population that

reached Crete came from outside (probably North Africa) and bore

an advanced culture (18). Most cranial skeletons found in the Bronze

Age (after 3500 B.C.), in the Minoan epoch (about 2600 B.C.) are

dolichocephalous, similar to those found in North Africa, pre-dyn-

astic Egypt and Southern and South-western Europe (18).

Minoans built up Knossos, Phaistos, Aghia Triada and other

palaces in Crete and further developed their imported sophisticated

culture; they wrote and spoke Linear A (previously they used hiero-

glyphic characters, like the ones displayed on the Phaistos Disk);

they may have come from North Africa and were relatively isolated

from continental Greece. Later (700–300 B.C.), Crete was more in-

volved in North African affairs until the Cretans fell under the rule

of the Greek Egyptian governors (Ptolomies). However, Crete had

contributed 7,000 archers to Alexander the Great’s expedition to

Asia. After Ptolomain rule, Crete was taken and ruled by Romans

between 67 B.C. and 330 A.D.; the number of inhabitants was about

300,000 by then (22). Between 390–824 A.D., it belonged to the East-

ern Roman Empire (Byzantine) and between 824–961 A.D. it was

invaded by Arabs coming from Spain who built up the modern

capital, Iraklion. Byzantium controlled Crete again between 961 and

1204 A.D.; subsequently Crete was ruled by Venetians (1204–1669)

and Turks (1669–1898). Crete became an autonomous island sup-

ported by European nations and Greece (1898–1913) and became a

part of Greece in 1913, which had already been independent since

1827. In 1994, Crete had 500,000 inhabitants. Thus, it would be ex-

pected that gene flow into Crete primitive inhabitants had occurred

mostly from Italians and Turks, its most long-lasting and docu-

mented foreign rulers, but this has not been proven.

In addition, there is also a linguistic support for including

Cretans among the ancient Mediterraneans and to consider the

Greeks as being a more recent population (see Results and Fig.

4). Etruscan tablets have been found in the Aegean Lemnos Is-

land, which probably was under Cretan influence during the Mi-

noan period (21); Minoan Linear A and Etruscan languages are

both ancient Mediterranean languages, which together with an-

cient Iberian, Berber (Imazighen), Coptic (ancient Egyptian) and

Sumerian have been recently related to and/or translated from the

Basque-Spanish equivalencies (20, 43, 44). However, there are

many examples where genetic and linguistic population studies

do not correlate (45). Therefore, all Indoeuropean Greek groups

coming into the Balkan peninsula around and after 2000 B.C.

may not be considered as old Mediterraneans; this is based on

linguistic, historical and genetic data. All other Mediterraneans

(or their ancestors) may come from Saharans (Fig. 4): Iberians,


paleo-North Africans (present day Berbers or Imazighen), Egyp-

tians, Etruscans, Cretans, Phoenicians (Lebanese), Jews and Su-

merians among others (very likely Arabs) were living in the

Mediterranean environment, probably since about 20,000 B.P. (17,

18, 20, 24, 46). Many of these people may have been displaced

from a fertile and heavily populated Sahara, when it became hot-

Table 4HLA-A-B, B-DRB1 and DRB1-DQB1 two-loci haplotypes with significant linkage disequilibrium in the Cretanpopulation

Haplotype HF LD RLD Haplotype HF LD RLD

A-B

A26-B35 2.9 2.23 0.54 B40–0405 0.7 0.76 0.49

A23-B35 2.6 1.61 0.32 B49–1501 0.7 0.72 0.38

A24-B18 2.2 1.72 0.36 B52–15021 0.7 1.78 1.00

A1-B8 1.8 1.64 0.51 B55–1302 0.7 0.61 0.26

A3-B51 1.5 1.11 0.21 B58–03011 0.7 0.61 0.46

A30-B51 1.5 1.23 0.40

A32-B51 1.5 1.34 0.54 DRB1-DQB1

A2-B52 1.4 0.91 0.47 0701–02 10.4 8.18 0.92

A30-B13 1.1 1.04 0.35 1104–0301 9.6 6.98 0.95

A25-B55 0.7 0.73 0.31 1101–0301 8.9 6.18 0.80

A26-B40 0.7 0.72 0.47 03011–02 7.4 5.01 1.00

A29-B53 0.7 0.72 0.31 1601–0502 7.4 6.68 0.95

A32-B7 0.7 0.61 0.25 0101–0501 6.3 5.58 1.00

A33-B8 0.7 0.61 0.19 0402–0302 5.2 4.78 1.00

A33-B14 0.7 0.61 0.22 1001–0501 3.7 3.28 1.00

A33-B38 0.7 0.72 0.31 1401–05031 3.7 3.58 0.82

A33-B58 0.7 0.72 0.48 1301–0603 3.3 3.28 1.00

1302–0604 2.9 2.88 1.00

B-DRB1 1501–0602 2.6 2.48 0.69

B35–0101 4.8 3.77 0.67 0403–0302 1.8 1.54 0.51

B52–1502 2.5 1.78 0.70 1103–0301 1.8 1.21 0.77

B8–03011 2.2 2.08 0.64 12021–0301 1.8 1.32 1.00

B18–1104 2.0 1.32 0.28 0102–0501 1.5 1.34 1.00

B44–0701 1.6 1.11 0.38 0405–02 1.5 1.12 0.75

B51–0402 1.5 1.11 0.23 0404–0302 1.1 1.04 1.00

B7–1501 1.1 0.92 0.26 1502–06011 1.1 1.08 0.74

B13–1601 1.1 0.91 0.38 0701–03032 0.7 0.62 1.00

B14–0102 1.1 1.18 0.74 1502–06012 0.7 0.74 0.65

B57–0701 1.0 0.61 0.62 1404–05031 0.7 0.75 0.82

B14–0405 0.7 0.73 0.38

B15–1302 0.7 0.61 0.26

B37–1001 0.7 0.61 0.31

HF, haplotype frequency (¿100); LD, linkage disequilibrium (¿100); RLD, relative linkage disequilibrium. 15¿10ª2±P±5¿10ª3;25¿10ª3±P±5¿10ª4; 35¿10ª4±P±5¿10ª5; 45¿10ª5±P±5¿10ª6; 55¿10ª6±P±5¿10ª7; 65¿10ª7±P±5¿10ª9;75¿10ª9±P±5¿10ª10; 85¿10ª10±P±5¿10ª11

221Tissue Antigens 1999: 53: 213–226

ter and drier after 10,000 B.C. (10, 11). Thus, Greeks may not be

at the root of Western civilization, which may stem from the

more ancient cultural heritage of Cretans, Middle Easterners,

Egyptians and Sumerians; this cultural heritage is best expressed

by a similar language and religious beliefs (18, 20), although each

of these groups developed a distinctive culture, regardless of


Table 5Most frequent HLA-A, -B, -DRB1, -DQA1 and -DQB1 extended haplotypes in the Cretan population

HaplotypeHaplotypes frequency (%) Possible origin

A26-B35-DRB1*1601-DQA1*0102-DQB1*05021 1.5 Mediterranean

A24-B35-DRB1*0101-DQA1*0101-DQB1*05012 1.1 Paneuropean


A1-B8-DRB1*03011-DQA1*0501-DQB1*024 1.1 European

A2-B13-DRB1*1601-DQA1*0102-DQB1*05025 0.8 Specific (Minoans?)



A2-B7-DRB1*1501-DQA1*0102-DQB1*06028 0.4 European-Basque-North African

1 This haplotype has been found in Albanians (1.4%), Romanians (2.8%) and Sardinians (3.9%) (3). 2 This haplotype has been found

in Austrian (2.4%), British (3.1%), Cornish (2.5%), Czech (2.8%), French (1.5%), Germans (1.3%), Italians (3.2%), Romanians (4.1%),

Sardinians (2.7%), Spaniards (1.9%) and Hungarians (3.6%) (3). 3 It shows the highest frequency in Italians (7.2%), Armenians

(4.4%), and is found at a lower frequency in Indians (3.2%), Portuguese (2.0%), Spaniards (1.7%) and French (1.1%) (3). 4 Also found

in Basques (2.4%), Spaniards (3.4%), British (2.9%) and Danes (3.4%) with similar frequencies. Germans (4.8%), Austrians (5.3%),

Yugoslavians (7.7%) show slightly higher frequencies (3,12). 5 Only present in Cretans. 6 Show the highest frequency in Armenians

(3.1%) and is also high in frequency or present in other Mediterranean Caucasoid populations as Sardinians (2.7%), Spaniards

(2.6%), French (1.4%), Greeks (1.1%) and Italians (0.7%) (12,41). 7 It is a Mediterranean haplotype present mainly in Arabic Peninsula

and Middle East (41, 42). 8 Common to French-Basques (3.6%), Cornish (3.6%), Austrian (2.6%), Britons (2.3%), Spaniards (1.9%),

Spanish-Basques (1.8%) and Algerians (0.9%) and to other Mediterraneans (3, 41, 58)

whether they had migrated from Sahara or not. Indeed, Sumeri-

ans were always considered as foreigners in Mesopotamia and in

addition, Egyptian dynasties started with an immigration (47).

Fig. 4. Mediterranean area showing classic populations (squares); of a more ancient ‘‘Villanovan’’ (Villanova, near Bologna) and pre-Villanov-circled numbers correspond to present day populations for which an cultures (second millennium B.C.) (59). Semitic people were nomadicHLA genes have been studied. Arrows represent population people, comprising Jews, Arabs, Phoenicians and Acadians who were prob-movements before 3000 B.C. (52). Etruscans had their highest develop- ably present when Sumerians arrived to Mesopotamia (52).ment in the first millennium B.C.; however, their culture was a continuity

222 Tissue Antigens 1999: 53: 213–226

Taking into account that both Europeans and Africans spoke

(and some still speak) similar Saharan languages, the division be-

tween African and Non-African languages (48) should be revised.


Middle-East Populations

Jews (Ashkenazi, non-Ashkenazi and Moroccan) and Lebanese

people cluster together with Cretans in the correspondence analysis

for DRB1 frequencies (Fig. 3b) and show very low genetic distances

to Cretans (Table 3). This distinction is less evident in the corre-

spondence analysis using also HLA-A and -B loci (Fig. 3a), which

tends to homogenize most of the Mediterraneans, but also leaves

Greeks as outliers.

Several consequences may be drawn:

1) These genetic data (together with others previously published

(49, 50, 51) show that Central European, Russian, Moroccan

and Mediterranean Jews remained relatively isolated from the

surrounding populations after the last Diaspora (before 135

A.D.) and that all of them came from Israel and Juda (North-

ern and Southern Israel, respectively). Prior to the second mil-

lennium B.C., Phoenicians, together with Jews, were con-

sidered to be the Western branch of ancient nomadic Semitic

people. The Eastern Semitic branch was composed of Acadi-

ans, Amorites and Arameans (52). The latter branch adopted

the Sumerian culture and Arameans invaded lower Mesopota-

mia taking the name of Caldeans. The Aramaic language be-

came widespread and dominant and was spoken by Middle

East people, including Mesopotamia in New Testament times.

Aramaic was only substituted by the Arab language after

Muhammad (seventh century A.D.).

2) At present, a part of the Lebanese people is a mixture of

ancient populations described in the Old and New Testaments

(52); however, it shows a remarkable genetic relatedness with

Cretans and Jews (Table 3, Fig. 3b). This shows that the so-

called Semitic people may be distinguished mostly by lan-

guage differences and that they may be included together

with the ancient Mediterranean groups. Present day Arab

speaking Lebanese are genetically related to Jewish and Cret-

an people in the DRB1 correspondence analysis (Fig. 3b) and

to French, Italians, Algerians (who are mostly paleo-North

Africans or Berbers) (26), Spaniards and Berbers (Table 3).

Again, all pre-Neolithic Mediterraneans are shown to be gen-

etically related, particularly when compared to more recent

Mediterraneans, i.e., Greeks.

North Africans and Iberians

Iberians are closely related to North Africans (Berbers from El Jadi-

da [Morocco], Berbers from Souss (Agadir, Morocco) and Algerians

from Oran and Algiers, see Fig. 4). Western Mediterraneans, from

both Africa and Europe tend to cluster together in our genetic

223Tissue Antigens 1999: 53: 213–226

analyses compared to Eastern Mediterraneans, who also are more

inter-related. This is particularly evident in the correspondence

analysis (Fig. 3b). This may be explained if northward Saharan

migrations occurred between 10,000 and 4000 B.C. (12); it may be

assumed that Saharans spoke a similar language with local differ-

ences, like present day Berber speaking people do in places close to

the Mediterranean coasts (Moroccan Rif, Algerian Kabylia) and

other more distant ones located in the southern Sahara Desert (Tua-

regs in Algiers, Niger and Mali) (53). Even if the HLA profile was

similar in primitive Saharans, the local founder effect of the people

who emigrated and who finally established in Iberia, other Mediter-

ranean places, Egypt or Sumer would have been diluted and

changed because of the subsequent admixture with the already

existing people or with later invaders; however, a common genetic

substrate (relatedness) may still be noticed in Mediterraneans (Fig.

3a, b), which supports a common (Saharan) origin. This is also

confirmed by linguistic similarities between present day Basque

and Berber languages and ancient Iberian, Etruscan, Minoan (Lin-

ear A), Coptic (ancient Egyptian) and Sumerian (20).

The Maghreb Berber language is presently spoken by about 20

million people distributed throughout Egypt (Siwa oasis), Libya,

Algeria, Tunisia, Morocco, Western Sahara, Mauritania, Mali, Niger

and Chad (26). These people have different local names (Trarza in

Western Sahara; Chleuh, Braber and Rifens in Morocco; Kabilians

and Mzabs in Algeria; Awyila and Sukna in Libya; Siwans in Egypt

and Tuaregs, Iforas, Ahaggar, Ajjer, Ayr and Iullemeden in the

southern Sahara (53); they speak the Tamazight language, which

joins all these groups (Imazighen). This language is highly influ-

enced by the Arabic language and understanding among different

tribes is difficult; Tamazight has evolved rapidly locally because of

a strong Arabic influence. Imazighen have been left out at one side

of history (26, 53), but they are probably descendants from the

primitive Saharans, which could be the origin of part of the Sumeri-

ans, Egyptians, Minoans, Iberians and Etruscans and thus repre-

sent the roots of Western civilization (54) (see Fig. 4). Saharan paleo-

archeology and other old cultural aspects have been forgotten but

many Paleolithic and Neolithic tools (including a possible autoch-

thonous chariot) and paintings are strewn throughout the Sahara

Desert (55).

Turks, Cretans and Greeks

Continental and Aegean Greeks and Cretans were under Turkish

rule (see above) for several centuries (almost five). Gene flow from

Turks to Greeks and Cretans may have occurred; however, the de-

gree of that gene flow is uncertain. Language and cultural barriers

have always existed. Around the 10th century A.D., Turk tribes


started moving towards Azerbajan, Iran and Anatolia from the Al-

tai mountains and Aral lake areas (52). Byzantium fell in 1453 and

the Turkish Empire extended through part of Europe and the

Southern Mediterranean. The Turks started living within the limits

of what is presently Turkey only after World War I.

The island of Cyprus has Turkish and Greek communities and

Fig. 1 and 2 show that the Cyprus Greek community is very similar

in HLA genetic composition to the Greeks of Attica and the Aegean.

Thus, it seems that previously existing ancient populations in the

Greek part of Cyprus (other than the Greek one) are not detected in

the sample according to HLA data.

The only modern HLA data available for comparing Turks with

Cretans and Greeks is the HLA-DQB1 generic typing (5 alleles) (33,

40). Cretans show the following standard genetic distances (¿10ª2)

to: Attica Greeks (0.1); Spaniards (0.2); Algerians (0.3); French (0.4);

Ashkenazi Jews (0.7); Sardinians (2); Lebanese (2.5); non-Ashkenazi

and Moroccan Jews (3); Berbers (7); Basques (19); Turks (21); Ja-

panese (28). It is observed that Greeks and Cretans have a low re-

latedness with Turks, suggesting that the degree of gene flow and

admixture has also been low during the nearly five centuries of

Turkish rule over Greece and Crete. However, studies with a more

polymorphic HLA and non-HLA markers are necessary to further

document this issue. In fact, the DRB1*11-DQB1*03 haplotype has

the highest phenotypic frequency (generic DNA typing) in Attican

Greeks (30.1%) and it is also one of the most frequent in Turks

(16%); in addition, DRB1*04-DQB1*03 is one of the most frequent

haplotypes in Turks (16%), while it is also frequent in Attican

Greeks (7.2%) (40).

Conclusions

The HLA genetic, historical and linguistic data discussed above

support the following cultural and historical events which have

been previously documented (52).

Western culture, sedentarism, cities and an alphabet appeared in

places surrounding the Mediterranean Sea, including Mesopotamia

(see map in Fig. 4). Documented agricultural settlements have been

found in Mesopotamia between 8000 and 5000 B.C.; Sumerians ar-

rived about by 6000 B.C.; during the same period there was a popu-

lation of hunters-fishers between the Nile River Delta and the first

fall and the first agricultural settlements in Egypt occurred in 5500

B.C. (47). Between 5000 and 3000 B.C. important water engineering

224 Tissue Antigens 1999: 53: 213–226

works and channels were constructed in Sumer and Sumerians in-

vented writing and constructed a sophisticated urban civilization.

In Egypt, a pre-dynastic El Badari culture (similar to that found in

Southern Iberia (9) had developed.

The Nile River Delta was also engineered for cultivation; a poss-

ible ‘‘Dynastic People’’ came from abroad and Upper and Lower

Egypt were unified under King Menes (47). These advancements

occurred in other parts of the Mediterranean area, but it was in

Lower Mesopotamia where the first urban cities of human history

were built between 3500 and 3000 B.C. It was in the latter site where

the Sumerians invented cuneiform writing and water engineering.

Egypt was the site of another civilization that probably appeared

at a slightly later time. Neither Sumerians nor Egyptians spoke

semitic languages (rather, a similar one from which Berber and

Basque may now be speaking relics, see above); however, Semites

(Acadians, Amorites and Arameans) were living among Egyptians

and Sumerians, and probably had been established there before the

time when the Egyptians and Sumerians arrived (52). In any case,

the Semites inherited Sumerian culture and at the beginning of the

second millennium B.C., Babylonia was ruling in the area, particu-

larly under the Amoritic Hammurabi. Arameans soon invaded

Lower Mesopotamia and they named themselves Chaldeans. Be-

tween the 9th and 7th centuries B.C., Upper Mesopotamian Acadi-

ans (Assyrians) ruled over all the region. In the western part (pres-

ent day Lebanon and Israel), Phoenicians and Hebrews developed

the first alphabets during the 2nd millennium B.C. The Phoenician

alphabet soon became widespread and with time would become the

Greek alphabet; in the meantime, the Aramaic language, with a

similar alphabet, spread all over the Middle East.

The first cultivated Cretan people came to the island with a pre-

Minoan or Minoan culture before 3500 B.C., probably from North

Africa; they built up an Aegean Sea empire (or wider) and Greek

Myceneans newcomers (2000 B.C.) paid tribute to Minoans. Mycene-

ans probably invaded and destroyed Minoans by 1450 B.C., but they

absorbed their culture and writing system and built their own Ae-

gean Sea empire.

A part of Iberians came from North Africa, mostly after 10,000

B.C.. The ancient North Africans are represented by present day

Berbers or Imazighen, who compose most of the population of the

Maghreb countries, but are strongly Arabized; some of them still

live in the Saharan Desert, as nomadic people, while others have

settled in small towns (mainly farmers) or the larger cities. They

may be part of the stock that gave rise to most classic ancient

Mediterranean civilizations (Fig. 4).


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