Genes and Immunity (2000) 1, 358–361 2000 Macmillan Publishers Ltd All rights reserved 1466-4879/00 $15.00 www.nature.com/gene Evidence for recent selection of the CCR5-⌬32 deletion from differences in its frequency between Ashkenazi and Sephardi Jews S Maayan1, L Zhang2, E Shinar3,JHo2,THe2, N Manni1, LG Kostrikis2 and AU Neumann4 1Hadassah Hospital, Jerusalem 91000, Israel; 2The Aaron Diamond AIDS Research Center, New York, NY 10016, USA; 3MDA – Israel National Blood Services, Ramat-Gan, Israel; 4Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 52900, Israel Recent studies have shown higher frequencies of the CCR5-⌬32 allele and the CCR5-⌬32/⌬32 genotype, which confers protection against HIV infection, in northern Europe as compared to Mediterranean countries. Here, we analyse the prevalence of CCR5-⌬32 in 922 HIV seronegative blood donors in Israel to verify its frequency in Jews of Ashkenazi and Sephardi origin. A significant difference (P Ͻ 0.001) was found between the CCR5-⌬32 allele frequency in Ashkenazi (13.8%) vs (4.9%) Jews. In contrast, no significant difference was observed in the frequency of the CCR2–64I mutation between Ashkenazi (9.2%) and Sephardi (13.4%) Jews. Using the Island model we calculate that a minimal genetic migration rate of 3% per generation would have been necessary if the higher CCR5-⌬32 prevalence in Ashkenazi is to be fully explained by mixing with the indigenous north-European populations. This putative migration rate is 20-fold higher than that currently estimated from other genes, and would correspond to a non-realistic minimal current admixture of 80%. Thus, our results suggest that a positive selection process for CCR5-⌬32 should have occurred in northern Europe at most a 1000 years ago, after the Ashkenazi Jews separated from their Sephardi kin and moved to north Europe. Genes and Immunity (2000) 1, 358–361. Keywords: HIV-1 co-receptors; CCR5-⌬32 mutation; CCR2–64I mutation; genetic polymorphism; population genetics; mathematical modeling Introduction mutation,12–14 which was also associated with slower HIV disease progression, as function of the two origin groups. Recently, a homozygous mutation of 32 base-pairs In addition, we discuss a number of possible mechanisms ⌬ deletion ( 32) in the CC-chemokine receptor 5 (CCR5) to explain the differences in genetic frequencies between locus has been described as conferring in vitro resistance Ashkenazi and Sephardi, considering that both groups of CD4 lymphocytes to infection by HIV-1 of the originated from the same ancestry about a 1000 years 1–3 macrophage-tropic R5 strains. In retrospective analy- ago. ses, the homozygous ⌬32/⌬32 genotype has been associa- ted with protection against HIV-R5 infection,4–6 while the heterozygous wt/⌬32 genotype was associated with a Results 5,6 7–11 slower rate of progression to AIDS. Recent data sug- The overall allelic frequency of CCR5 in this Israeli cohort ⌬ gests an allelic frequency of 9–18% for the CCR5- 32 was 9.8% (see Table 1). Of the 922 blood donors, 363 were deletion among Caucasians in northern Europe and of Ashkenazi origin and 257 of Sephardi origin (or 443 North America compared to only 3–6% among Mediter- donors of Ashkenazi descent and 304 of Sephardi descent 6 ranean populations and 0% among Africans. The highest using more flexible criteria, see methods). The CCR5-⌬32 7 allelic frequency (20.9%) in this survey was observed allele frequency among Israeli Jews of Ashkenazi descent = among a small number (n 43) of Ashkenazi Jews. We was 13.8%, which is significantly different (P Ͻ 0.001) in studied Israeli Jewish blood donors of known ancestry in comparison to that of 4.9% for Israelis of Sephardi order to expand on that initial observation and look for descent. The mixed group and second generation Israelis ⌬ differences in the distribution of the CCR5- 32 allele and had intermediate frequencies. In addition, a significant genotypes between Ashkenazi and Sephardi Jews. As a difference (P Ͻ 0.001) was noted in the prevalence of the control we study the frequency of the CCR2–64I homozygous CCR5 ⌬32/⌬32 genotype between Israeli Jews of Ashkenazi (3%) and Sephardi (0.7%) origins. The genotype distributions of the various Israeli sub- Correspondence: Avidan U Neumann, Faculty of Life Sciences, Bar-Ilan populations were in equilibrium as predicted by the Ȱ University, Ramat-Gan 52900, Israel. E-mail: neumann mail.biu.ac.il Hardy-Weinberg theory, although the total population This work was supported by the committee for the advancement was out of equilibrium. of research and the Gonda-Goldschmied Medical Diagnostic Center ⌬ at the Bar-Ilan University; and the National Institutes of Health The CCR5- 32 allele frequency (13.8%) among Israeli under RO1 AI 43868 (LGK). donors of Ashkenazi descent was comparable to that Received 28 March 2000; accepted 10 April 2000 measured (10–16%) in recent large surveys of low-HIV- CCR5⌬32 in Ashkenazi and Sephardi Jews S Maayan et al 359 Table 1 CCR5-⌬32 allele and genotype frequencies in Israel according to various Jewish origin groups Parents’ origin Number of CCR5 wt/wt CCR5 wt/⌬32 CCR5 ⌬32/⌬32 CCR5-⌬32 Allele HWE samples (%) (%) (%)b (%)b P-value Ashkenazi 363a 75 22 3b 13.8b 0.17 Sephardi 257a 90 9 0.7b 4.9b 0.12 Israeli – 2nd generation 148 83 17 0 8.4 0.53 Mixed origin 27 85 11 4 9.3 0.08 Total 992a 82 16.0 2 9.8 0.01 aAccording to the more relaxed criteria, in which one parent could be born in Israel, there are 443 Ashkenazi and 304 Sephardi (thus total n = 922) with no significant changes in the allele and genotype frequencies in these groups. bDifference between Ashkenazi and Sephardi is statistically significant (P Ͻ 0.001). risk populations in north-eastern Europe,8,9 from where frequencies of the CCR2–64I mutation between Ashken- the Ashkenazi Jews originate. The Ashkenazi CCR5-⌬32 azi and Sephardi Jews in Israel. This result was expected allele and ⌬32/⌬32 genotype frequencies are, however, since there are no reported differences in the CCR2–64I higher (P Ͻ 0.001) than those reported (8–9% and 1–1.5% mutation between individuals of northern European or respectively) for North America and central/western Mediterranean origin.14 The difference in the CCR5-⌬32 Europe Caucasians.6–9 No significant differences (P Ͼ 0.1) frequency between Ashkenazi and Sephardi Jews corre- were found when comparing Israeli donors of Sephardi sponds to the difference in CCR5-⌬32 prevalence origin to large Greek-Cypriot10 or Italian11 cohorts. We between north European and Mediterranean populations have checked and ruled out the possibilities that exten- in general.7–11 Thus, the high frequency of the CCR5-⌬32 sive family ties among the blood donors, or that individ- allele in Ashkenazi, as compared to Sephardi Jews, could uals with high risk for HIV, may have influenced the be explained by mixing of indigenous north European mutation prevalence in the different sub-groups. In genes into the Ashkenazi population.17–18 According to addition, our allele frequency data among individuals of that scenario, Ashkenazi and Sephardi Jews had the same Ashkenazi descent are similar to those obtained in recent CCR5-⌬32 frequency until the Ashkenazi separated and smaller surveys of CCR5-⌬32 based on samples of the moved to north-eastern Europe, where they mixed with National Centers for Genetic Diseases in Israel15 and in a local population rich in CCR5-⌬32 and acquired it France,16 in which high risk of HIV is not expected. through the ensuing genetic migration from indigenous In order to verify if differences between Ashkenazi and north Europeans. Sephardi Jews exist also in other CC-chemokine receptor Here, we use the next assumptions in order to obtain genes we have analysed in our cohort the frequency of a minimal estimate of the necessary migration rate that the CCR2–64I mutation (see Table 2), which is associated will give the current high frequency of CCR5-⌬32 in Ash- with slower progression to AIDS in a number of retro- kenazi Jews: (a) the gene migration took at most G=50 spective analyses.12–13 We have found no significant dif- generations, starting at the time when Ashkenazi Jews ference in the frequency of the CCR2–64I allele between first moved to north-eastern Europe (about 1000 AD). (b) the Ashkenazi (9.2%, n = 142) and the Sephardi (13.4%, The CCR5-⌬32 allele frequency of the Ashkenazi popu- n = 67, P Ͼ 0.2). Although these results are only for a lation before admixture with the indigenous population subset of our cohort, note that the difference in CCR5- was maximally equal to that of the Sephardi Jews today, ⌬ = ⌬ 32 is already significant in that subset. P0 0.049. (c) The CCR5- 32 allele frequency of the non- Jewish north-eastern European population was always = Analysis and discussion equal to its maximal present frequency, Pm 0.16. Using these parameters in a calculation based on the Island In this report we summarize findings from the largest model19 (Eq. 1 in Methods) gives a minimal migration rate survey of the frequency of CCR5-⌬32 mutation among of M=0.03 per generation. Thus (using Eq. 2 in Methods), Israeli Jews. Our main finding is the significant difference the present genetic admixture of north-European origin in allele frequency, and homozygous ⌬32/⌬32 genotype, in Ashkenazi Jews should have been minimally of the between Israelis of Ashkenazi descent and of Sephardi order of A=80% if the high allele frequency of CCR5-⌬32 descent.