"This time, Arthur Kemp has used the writings of Spanish geneticist Antonio Arnaiz-Villena to support his theory that Greeks mixed with Sub-Saharan slaves. This is what world-leading geneticists Neil Risch from Stanford U., Alberto Piazza from the University of Torino and L. L. Cavalli-Sforza also from Stanford had to say on the interpretations of Arnaiz-Villena based on the HLA-DRB1 marker [1]:

Even a cursory look at the paper's diagrams and trees immediately indicates that the authors make some extraordinary claims. They used a single genetic marker, HLA DRB1, for their analysis to construct a genealogical tree and map of 28 populations from Europe, the Middle East, Africa and Japan. Using results from the analysis of a single marker, particularly one likely to have undergone selection, for the purpose of reconstructing genealogies is unreliable and unacceptable practice in population genetics.

The limitations are made evident by the authors' extraordinary observations that Greeks are very similar to Ethiopians and east Africans but very distant from other south Europeans; and that the Japanese are nearly identical to west and south Africans. It is surprising that the authors were not puzzled by these anomalous results, which contradict history, geography, anthropology and all prior population-genetic studies of these groups. Surely the ordinary process of refereeing would have saved the field from this dispute."

Dropped genetics paper lacked scientific merit
Nature 415, 115 (10 January 2002) © Macmillan Publishers Ltd.

Sir - Even though the controversial withdrawal of a paper on the genetic relatedness of Palestinians and Jews by the journal Human Immunology (see Nature 414, 382; 2001) is a minor episode compared with the tragedies caused by ethnic/religious conflicts over past decades, the issues involved are worth revisiting.

The stated purpose of the paper by Antonio Arnaiz-Villena et al. was to "examine the genetic relationships between the Palestinians and their neighbours (particularly the Jews) in order to: (1) discover the Palestinian origins, and (2) explain the historic basis of the present ... conflict between Palestinians and other Muslim countries with Israelite Jews".

They conclude: "Jews and Palestinians share a very similar HLA genetic pool that supports a common ancient Canaanite origin. Therefore, the origin of the long-lasting Jewish-Palestinian hostility is the fight for land in ancient times."

It is difficult to believe that knowledge of genes may help to explain the present conflict. Although population genetics can address issues of relatedness of populations, mating patterns, migrations and so on, obviously it cannot provide evidence about reasons for conflicts between people.

Our primary concern, however, is that the authors might be perceived to have been discriminated against for political, as opposed to legitimate scientific, reasons.

Even a cursory look at the paper's diagrams and trees immediately indicates that the authors make some extraordinary claims. They used a single genetic marker, HLA DRB1, for their analysis to construct a genealogical tree and map of 28 populations from Europe, the Middle East, Africa and Japan. Using results from the analysis of a single marker, particularly one likely to have undergone selection, for the purpose of reconstructing genealogies is unreliable and unacceptable practice in population genetics.
The limitations are made evident by the authors' extraordinary observations that Greeks are very similar to Ethiopians and east Africans but very distant from other south Europeans; and that the Japanese are nearly identical to west and south Africans. It is surprising that the authors were not puzzled by these anomalous results, which contradict history, geography, anthropology and all prior population-genetic studies of these groups. Surely the ordinary process of refereeing would have saved the field from this dispute.

We believe that the paper should have been refused for publication on the simple grounds that it lacked scientific merit.

Neil Risch
Department of Genetics, Stanford University School of
Medicine, Stanford, California 94305, USA

Alberto Piazza
Department of Genetics, Biology and Biochemistry,
University of Torino, Via Santena 19, 10126 Torino, Italy

L. Luca Cavalli-Sforza
Department of Genetics, Stanford University School of
Medicine, Stanford, California 94305, USA

The highly polymorphic HLA system has been validated as useful for distinguishing and/or relating populations (and individuals) in many papers and in all the subsequent international workshops since the First International HLA Anthropology Workshop (Evian, 1970).

HLA gene frequencies correlates with geographically related populations; the existence or absence of gene flow among neighbours may be assessed with the study of HLA frequencies and the corresponding genetic distances. (sources: Genetic relationships among various human populations indicated by MHC polymorphisms. In: Tsuji K, Aizawa M, Sasazuki T, eds. HLA 1991. Vol 1. Oxford: Oxford University Press, 1992: 627-32; and Clayton J, Lonjou C. Allele and Haplotype frequencies for HLA led in various ethnic groups In: Charron D, ed. Genetic diversily of HLA, functional and medical implications. Vol 1. Paris: EDK, 1997: 665-820.)

The HLA system has been shown to be very polymorphic, able to be compared among ethnic groups and useful to distinguish populations (HLA allele and haplotype frequencies in Algerians. Relatedness to Spaniards and Basques. Hum Immunol 1995: 43: 259-68.)

Here are but a few of the scientific articles which have all used HLA genes as forensic tools in tracking populations:

- Imanishi T, Wakisaka A, Gojobori T. Genetic relationships among various human populations indicated by MHC polymorphisms. In: Tsuji K, Aizawa M, Sasazuki T, eds. HLA 1991. Vol 1. Oxford: Oxford University Press, 1992: 627-32.
- Clayton J, Lonjou C. Allele and Haplotype frequencies for HLA led in various ethnic groups In: Charron D, ed. Genetic diversily of HLA, functional and medical implications. Vol 1. Paris: EDK, 1997: 665-820.
- Izaabel H, Garchon HJ, Caillat-Zucman S et al. HLA class II DNA polyhiorphism in a Moroccan population from the Souss, Agadir area. Tissue Antigens 1998:51: 106-10,
- Arguello R, Avakian H, Goldman JM, Madrigaij A. A novel method for simultaneous high resolution identification of HLA-A, HLA-B, and HLA-Cw alleles. Proc Natl Acad Sci USA 1996:93:10961-5.
- Kimura A, Sasazuki T. Eleventh International Histocompatibility Workshop reference protocol for the HLA-DNA typing technique. In: Tauji K, Aizawa M Sasazuki T, eds. HLA 1991. Vol 1. Oxford: Oxford University Press, 1992: 397-419.
- Bignon JD, Fernandez-Vif MA. Protocols of the 12th International Histocompatibiity Workshop for typing of HLA class II alleles by DNA amplification by the polymerase chain reaction (PCR) and hybridization with sequence-specific oligonucleotide probes (SSOP). In: Charron D, ed. Genetic diversity of HLA, functional and medical implications. Vol I. Paris: EDK, 1997: 584-95.
- Imanishi T, Akaza T, Kimura A, Tokunaga K, Gojobori T. Estimation of allele and ha frequencies for HLA and complement loci. In: Tsuji K Aizawa M Sasazuki T, eds. HLA 1991. Vol 1. Oxford: Oxford University Press, 1992: 76-9.
- Imanishi T, Akaza T, Kimura A, Tokunaga K, Gojobori T. Allele and haplotype frequencies for HLA and complement loci in various ethnic groups. In: Tsuji K, Aizawa M, Sasazuki T, eds. HLA 1991. Vol 1. Oxford: Oxford University Press, 1992:1065-220.
- Mehra MC, Rajalingam R, Kanga U et al. Genetic diversity of HLA in the populations of India, Sri Lanka and Iran. In: Charron D, ed. Genetic diversity of HLA, functional and medical implications. Vol 1. Paris: EDK, 1997: 314-20.
- Roitberg-Tambur A, Witt CS, Friedmann A et al. Comparative analysis of HLA polymorphism at the serologic and molecular level in Moroccan and Ashkenazi Jews. Tissue Antigens 1995: 46: 104-10.
- Martinez-Laso J, Gazit E, Gómez-Casado E et al. HLA DR and DQ polymorphism in Ashkenazi and non-Ashkenazi Jews: comparison with other Mediterraneans. Tissue Antigens 1996: 47:63-71.
- Degas L Dausset J. Human migrations and linkage disequilibrium of HLA system. Inununogenetics 1974: 1: 195—210.

In addition, Arnaiz-Villena himself, demonized by Pontikos because he does not like this particular HLA gene report, has previously published a huge number of articles, all dealing with HLA genes and their ability to track population – all without ever being challenged:
- Arnaiz-Villena A, Benmamar D, Alvarez M et al. HLA allele and haplotype frequencies in Algerians. Relatedness to Spaniards and Basques. Hum Immunol 1995: 43: 259-68.
- Arnaiz-Villena A, Timón M, Corell A, Perez-Aciego P, Martin-Villa JM, Regueiro JR. Primary immunodeficiency caused by mutations in the gene encoding the CD3-y subunit of the T-lymphocyte receptor. N EngIf Med 1992: 327: 529-33.
- Arnaiz-Villena A, Martinez-Laso J, Gómez Casado E et al. Relatedness among Basques, Portuguese Spaniards, and Algerian studied by HLA allelic frequencies and haplotypes. Immunogenetics 1997: 47: 37—43.
- Arnaiz-Villena A, Iliakis P, Gonzalez Hevilla M et al. The origin of Cretan population as determined by characterization of HLA alleles. Tissue Antigens 1999:53: 213—26.
- Arnaiz-Villena A, Rodriguez de Côrdoba 5, Vela F, Pascual JC, Cervero J, Bootello A. HLA antigens in a sample of the Spanish population: common features among Spaniards, Basques and Sardinians. Hum Genet 1981: 58: 344—8.
- Martinez-Laso J, De Juan D, Martinez-Quiles N, Gomez-Casado E, Cuadrado E, Arnaiz Villena A. The contribution of the HLA-A, -B, -C and -DR, -DQ DNA typing to the study of the origins of Spaniards and Basques. Tissue Antigens 1995:45: 237—45.

“Greeks are almost outliers together with Japanese and San (Bushmen).. . In fact, a gradient from Western (both African and European) to Middle Eastern Mediterraneans is observed, placing distinctly Greeks, Japanese and San (Bushmen) as outliers.”

- (Gomez-Casadao, Arnaiz et. al. HLA Genes in Moroccans).

1. http://www.centerspan.org/pubs/transplantation/1998/0127/tr029800285o.pdf

“A Unique African HLA Haplotype May Identify a Population at Increased Risk for Kidney Graft Rejection”

By Pauline C Creemers (immunology Department, UCT Medical School Cape Town, South Africa) and Delawir Khan (Nephrology Department, University of Cape Town Medical School)

“Unique HLA alleles and MHC haplotypes have been identified in the Cape Colored and in the black South African populations. . . . Because HLA haplotypes are inherited ‘en-bloc’ as ancestral haplotypes that vary considerably between races.”

(Source: Lee, TD, Lee A, Shi WX, HLA-A, -B, -DR, -DQ Antigens in black North Americans, Tissue Antigens, 1991, 37, 39;  and  Fraser PA, Moore B, Stein R, et al, Complotypes in individuals of African origin, frequencies and possible extended MHC haplotypes, Immunogenetics, 1990 – 31, 81;)

2. http://haem.nus.edu.sg/ishapd/2002/832.pdf

“HLA Diversity: Detection and Impact on Unrelated Hematopoietic Stem Cell Donor Characterization and Selection”

By Carlyn Katovich Hurley, Georgetown University Medical Center, Washington DC, USA, as published in the International Journal of Hematology, 76 (2002) Supplement II.

“The alleles differ also in frequency in different populations. Thus, the search for a DRB1*0302 marched donor, for example, should be focused on populations of direct African origin since this allele is extremely rare in Caucasian or Oriental populations.”

“These frequencies must be taken into account as patients are evaluated for unrelated donor transplantation in order to estimate their probability of finding an allele matched donor to design a search strategy.”

3. http://www.ebi.ac.uk/imgt/hla/help/ethnic_help.html

The European Bioinformatics Institute has the following to say on race and HLA alleles:

“The ethnic origins qualifier is used to describe the ethnic group and geographical location of the cell donor. The ethnic origin qualifier allows the user to query the ethnic group or geographical location of the cell donor. This can be used in population genetics studies of the HLA alleles. The origin of the cell donor can be used to infer which alleles are found in particular ethnic groups, and the geographical spread of HLA alleles.”

The European Bioinformatics Institute has, on the site given above, a searchable HLA database where it is possible to look up specific HLA alleles and see in which racial groups they are dominant.

4. http://www.dalitstan.org/journal/dalitism/dal000/rac_ocsv.html

Here, the Indian based Dalistan Journal, discusses how HLA haplotypes were used to distinguish between Indo-European origin and non-Indo-European population elements in India:

“Racial Origin of Caste System Vindicated”

by Senthil Veliappa, Dalitstan Journal, Volume 2, Issue 6, Dec. 2000

“While all non-Dalit, non-Adivasi castes in North India are of Aryan descent, in South India only the Brahmins are Aryans. Here are two abstracts from two papers establishing that the South Indian Brahmins are of Caucasoid origin, in contrast to the Dravidians who are of Negroid stock [ Iyer ] [ Caste ] [ Ravi ] -

Abstract - "Seventy-four randomly sampled Iyers, a Brahmin population of Tamil Nadu and preachers and followers of the Advaita philosophy, living in Madurai, were studied for their HLA-A, HLA-B, HLA-C, HLA-DR, HLA-DQ, C4A, C4B, and BF polymorphisms and compared with other populations. HLA alleles A1, A11.1, A24, A33, B35, B44, B51, B52, B57, Cw4, Cw6, Cw7, DR4, DR7, DR8, DR10, DR11, DR15, and DQ1 and C4A*3, C4A*4, C4A*6, C4A*Q0, C4B*1, and BF*S were represented in 15% of the samples studied. HLA alleles A25, A69, Cw3, Cw8, B45, B14, B39, B18, B50, and B56 were not identified. Various populations of Tamil Nadu were compared, but the Iyers of Madurai formed a separate cluster with Sourashtrans of Madurai and major group 4 (various Brahmin populations of Tamil Nadu); hill tribes (Irulas, Malayalis, and Badagas) and caste groups in the plains (Kallars and Nadars) formed distinct clusters. Comparison of the Iyers with other Indian and world populations revealed that Iyers form a distinct branch of the Indo-European and Central Asian tree. The Bhargavas of Lucknow, another Brahmin caste group from Uttar Pradesh, did not cluster with the Iyers but clustered with Central Asian populations. The Punjabis of Delhi clustered with European and Middle Eastern populations.”

(Sources: [Caste] = ` HLA antigens in South India: II. Selected caste groups of Tamil Nadu', Rajasekar, R., Kakkanaiah, V. N. and Pitchappan, R. M., Department of Immunology, School of Biological Sciences, Madurai Kamaraj University, India; Tissue Antigens. 30(3):113-8, September 1987.

[Iyer] = ` HLA affinities of Iyers, a Brahmin population of Tamil Nadu, South India.', Balakrishnan, K., Pitchappan, R. M., Suzuki, K., Kumar, U. S., Santhakumari, R. and Tokunaga, K., Unit of Immunogenetics, School of Biological Sciences, Madurai Kamaraj University, Madurai, India; Human Biology. 68 (4) pp. 523-37, August, 1996.

5. http://www.askemilyss.com/bites/bite0701/race.htm

HCV Info and Support Monthly Magazine July 2001

“Race and HLA-II Alleles Combine to Influence Hepatitis C Persistence”

“WESTPORT, CT (Reuters Health) Jul 26 - Race combines with class II human leukocyte antigens (HLAs) to determine whether hepatitis C virus (HCV) infection persists, according to a report in the July 1st issue of the Journal of Infectious Diseases.

Vigorous CD4+ T-cell responses, mediated by class II HLAs, contribute to viral clearance in early HCV infection, the authors explain, and a previous association between viral clearance and the class II allele DQB1*0301 was shown in European individuals.

Dr. Chloe L. Thio from the Johns Hopkins Medical Institutions in Baltimore and colleagues sought to determine whether other class II HLA alleles contributed to viral clearance and whether these contributions differed according to the race of the individual.

Besides confirming the increased frequency of DQB1*0301 in subjects with viral clearance, the authors report a significantly increased frequency of DQB1*0501 and DRB1*0101, but only in whites.

In combination, the DQB1*0501-DRB1*0101 haplotype was associated with HCV clearance in whites, but not in blacks, the report indicates.

Similarly, DRB1*0301 and the haplotypes DQB1*0201-DRB1*0301 and DQA1*0501-DQB1*0201-DRB1*0301 were more strongly associated with viral persistence in whites than in blacks, the researchers note.

"The genes associated with HCV outcomes are different based on ethnic groups," Dr. Thio told Reuters Health. "The hope is to find genes that are associated with HCV outcomes to help us understand HCV pathogenesis which could help us to find treatments. Such HLA findings can also be used in vaccine development."