An unexpectedly high frequency of heterozygosity for a-thalassemia in Ashkenazi Jews Deborah Rund, a, * Dvora Filon, a Naomi Jackson, a Nava Asher, a Varda Oron-Karni, a Tomasz Sacha, b Sylwia Czekalska, b and Ariella Oppenheim a a Hematology Department, Hebrew University and Hadassah Medical School, Jerusalem, Israel IL91120 b Hematology Department, Jagiellonian University, Krakow, Poland Submitted 17 March 2004; revised 20 April 2004 (Communicated by E. Beutler, M.D., 22 April 2004) Available online 28 May 2004 Abstract a-Thalassemia is among the world’s most common single gene disorders, which is most prevalent in the malaria belt. This geographic distribution has been attributed to a selective advantage of heterozygotes against this disease. Unexpectedly, we have found a high frequency of heterozygosity for deletional a-thalassemia (Àa 3.7 ) in Ashkenazi Jews (carrier frequency of 7.9%, allele frequency of 0.04). This population has resided in temperate climates for many centuries and was therefore not subjected to malarial selection pressure. In comparison, heterozygosity for h-thalassemia, which is highly subject to malarial selection pressure, is very low (estimated <0.1%) in this group. It is possible that founder effect and genetic drift have contributed to the high frequency of deletional a-thalassemia in Ashkenazim, as may occur in closed populations. Alternatively, we hypothesize that positive selection pressure for an as yet unknown linked allele on chromosome 16 may be a significant factor leading to this high frequency. D 2004 Elsevier Inc. All rights reserved. Keywords: Globin genes; Selection pressure; Genetic disease; Thalassemia trait; Gene deletions Introduction a-Thalassemia is among the world’s most common single gene disorders [1] generally caused by gene deletions due to unequal crossing over in the a-globin gene cluster [1,2]. Deletions are found at very high frequencies in the ‘‘malaria belt,’’ where falciparum malaria was (or still is) prevalent [3]. Much epidemiological evidence [3,4] supports Haldane’s hypothesis that heterozygosity for a-thalassemia, like other globin disorders, confers a selective advantage against malaria. The mechanism of this protection is not clear but may relate to the hematological phenotype of a- thalassemia trait. Ashkenazi Jews resided for many centuries in a region in which falciparum malaria was not prevalent. Therefore, they would not be expected to have a significant frequency of a-thalassemia or other globin gene disorders. Indeed, h- thalassemia is very rare in Ashkenazim (estimated <0.1% [5]) as well as in other northern European populations [6,7]. Surprisingly, our previous work on a-thalassemia in an Israeli referral population suggested a high frequency: nearly 17% over 300 nonrelated chromosomes, which carried an a-globin gene abnormality, were of Ashkenazi Jewish decent [8]. Of these Ashkenazi chromosomes, 87% carried a single gene deletion, Àa 3.7 . We therefore under- took the present study to assess the frequency of the Àa 3.7 allele in an unselected sample of Ashkenazim. In compar- ison, we studied a smaller sample of individuals of northern European (Polish) extraction. Materials and methods DNA was isolated from peripheral blood leukocytes according to standard procedures [9]. PCR was performed for the Àa 3.7 allele and the aaa anti3.7 as described [8]. One hundred and fifty-one anonymous DNA samples of Ashkenazim were received from three sources: maternity 1079-9796/$ - see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.bcmd.2004.04.009 * Corresponding author. Hematology Department, Hadassah University Hospital, Ein Kerem, Jerusalem, Israel IL91120. Fax: +972-2-642-3067. E-mail address: rund@cc.huji.ac.il (D. Rund). www.elsevier.com/locate/ybcmd Blood Cells, Molecules, and Diseases 33 (2004) 1 – 3