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Genetic origin of contemporary Maltese

I refer to Roderick Bovingdon's interview with Professor Alexander Borg (The Sunday Times, July 22). In particular, I want to discuss the statements made by both regarding the genetic origin of the Maltese.

I am surprised that both your correspondents failed to refer to the only major study connected with the matter, and that has been published in the mainstream scientific literature.

Together with colleagues from other institutions across the Mediterranean and in collaboration with the group led by David Goldstein at the University College, London, we have shown that the contemporary males of Malta most likely originated from Southern Italy, including Sicily and up to Calabria. There is a minuscule amount of input from the Eastern Mediterranean with genetic affinity to Christian Lebanon.

Of course, females may have moved, or been moved, along a different route. We used a number of validated DNA markers on the Y chromosome, which are transmitted from male to male. The samples were obtained from an anonymous DNA bank of random newborn DNA that has approval of the research ethics committee of the University of Malta and is a founding member of Euro-Bio-Bank, thus providing for high standards in banking. The methods included state-of-the-art molecular biology and advanced IT tools.

We documented clustering of the Maltese markers with those of Sicilians and Calabrians. The study is published in the Annals of Human Genetics by C. Capelli, N. Redhead, N. Novelletto, L. Terrenato, P. Malaspina, Z. Poulli, G. Lefranc, A. Megarbane, V. Delague, V. Romano, F. Cali, V.F. Pascali, M. Fellous, A.E. Felice, and D.B. Goldstein; "Population Structure in the Mediterranean Basin; A Y Chromosome Perspective", AHG, 69, 1-20, 2005.

These data are fully consistent with other genetic data that we have collected over the last few years of intensive research connected with our service obligations in diagnostic molecular genetics. They are conducted from our Laboratory of Molecular Genetics, in the University of Malta for the Department of Health, Division of Pathology, St Luke's Hospital, and connected with our research program about the epidemiology of genetic disease in Malta. Many aspects of this research have been supported by competitive funding from the Framework Programmes for Research and Development of the Commission of the European Union (EU Avicenne and FP5-7).

In addition to the Y chromosome DNA typing, we have strong data about the distribution of haemoglobin disorders (Thalassaemia and Haemoglobin Variants, Scerri, 1998, Ph.D. thesis, University of Malta, and A.E. Felice et al., "Molecular Epidemiology of Haemoglobin and the Molecular Biology of in vivo Globin Gene Expression. Life Chemistry reports 15,1, 27-36, 1997) and "Human Leukocyte Antigens" (G. Dean, T.W. Yeo, A. Goris, C.J. Taylor, R.S. Goodma, M. Elian, A. Galea-Debono, A. Aquilina, A. Felice, M. Vella, S. Sawcer and D.A.S. Compston:. "HLA-DRB1 and multiple sclerosis in Malta", Neurology, 2007 in press).

We are aware of conflicting conclusions published as an interview in the popular National Geographic magazine. Despite an intensive search we cannot find them reproduced in the mainstream scientific literature. We consider that data somewhat flawed, and furthermore, unsound. National Geographic is not a peer-reviewed academic journal and thus the weight of the evidence is poor compared to other peer-reviewed academic journals that are also in the public domain. One cannot be comfortable with data that have not passed the scrutiny of peer review.

We stand to be corrected, but again, the DNA markers used appear to be limited and pre-date by far the population movements under investigation. The IT tools used also appear below today's standards. As far as we can tell, that study did not have research ethics approval of any research ethics committee in Malta, of the Department of Health or the University. We do not know what consent procedures have been used and consequently what bias could have been introduced into that study.

The most alarming observation is that, without an institutional base in Malta, we do not know what material transfer agreements were employed. We argue very strongly against the shipping of any human DNA from Malta to other organisations unless it is done within the context of specific agreements that determine the fate of the DNA after the contracted work, whether for diagnosis or discovery, has been finished.

Repopulation

The public should be cautious with regard to wild statements such as that "half of the Maltese are of Phoenician origin" and even more of the purveyors of testing kits supposedly intended to predict ancestry but based on weak science as I explained above. Contrary to the opinion of Bovingdon and Borg, it seems to me that the simplest explanation that cannot be excluded by any of the scientific data thus far available is that Malta was indeed barely inhabited at the turn of the tenth century.

Repopulation is likely to have occurred by a clan or clans (possibly of Arab or Arab-like speaking people) from neighbouring Sicily and Calabria. Possibly, they could have mixed with minute numbers of residual inhabitants, with a constant input of immigrants from neighbouring countries and later, even from afar. There seems to be little input from North Africa.

Populations have a genetic structure. It is not easy to define, although it reflects origins to a certain extent. It often impairs association studies in the search for genes that have to do with common, complex disorders such as hypertension, heart disease, diabetes and others. Conditions such as these are thought to be due to the interplay of multiple genes with quantitative effects and that could differ in population origin.

One could say, for instance, that the genetics of Malta could be partly accounted for by assuming a relatively small number of relatively large families. Yet, there may be so-called "founder effects" by which a single person with a particular DNA abnormality, or mutation, that over time, spread it across a large segment of a population by virtue of an albeit unknown selective advantage. Thalassaemia could be a good example, if one believed that in a very distant time Malta was wet and marshy with good habitats for the mosquitoes.

The alternative explanation is that of "genetic drift". It occurs by random expansion without a specific advantage. It is easy to simulate on computers. We have strong evidence for "founding effects" only in two situations that we have studied intensively, that is, the Haemoglobinopathies and the Dopa Responsive Dystonias, or as we call them, the BH4 deficiencies or atypical phenylketonuria, with a carrier rate of around three per cent (see A.E. Felice et al., op. cit., R. Farrugia, C.A. Scerri, S. Attard Montalto, R. Parascandalo, B.R.G. Neville and A.E. Felice: "Molecular Pathology of TetrahydroBiopterin (BH4) Deficiency in the Maltese Population. Molecular Genetics and Metabolism" doi:10.1016/j.ymgme.2006.10.013 and B.R.G. Neville, R. Parascandalo, S. Attard Montalto, R. Farrugia and A.E. Felice: "A Congenital Dopa Responsive Motor Disorder: a Maltese Variant due to Sepiapterin Reductase Deficiency", Brain, 128, 2291-2296, 2005).

Scientific research of this kind, although apparently for the uninstructed basic and untargeted, is in fact very important beyond the unique cultural interests as to the origin of populations. It bears on public health issues as much as on fundamental knowledge into gene interaction, the molecular biology of common disease and the discovery of innovative genetic medicines.

Alex E. Felice, MD, Ph.D., is head of the Laboratory of Molecular Genetics, Department of Bio-Medical Science, University of Malta, and of the Division of Pathology, St Luke's Hospital.

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