Jewish Genetics: Abstracts and Summaries

Part 3: Jewish Genetic Diseases and Disease Protections

Last Update: November 26, 2013

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Studies on Jewish genetic diseases

(with special attention on studies that help to confirm Jewish origins, relationships, and migrations)

Parkinson's Disease

Laurie J. Ozelius, Geetha Senthil, R. Saunders-Pullman, E. Ohmann, et al., "LRRK2 G2019S as a Cause of Parkinson's Disease in Ashkenazi Jews." The New England Journal of Medicine 354:4 (January 26, 2006): 424-425. Excerpts:

"... We screened 120 unrelated Ashkenazi Jewish patients with Parkinson's disease ... Ancestry was determined according to the patients' self-descriptions, and all but one patient (who reported being 50 percent Sephardic) reported that both parents were Ashkenazic. ... Among 120 Ashkenazi Jewish patients with Parkinson's disease, the LRRK2 G2019S mutation was detected in 22 (18.3 percent; 95 percent confidence interval, 11.9 to 26.4 percent). ... These rates are 15 to 20 times as high as those in most prior reports involving European subjects. ... A common founder mutation has been reported in the European and North African populations. We evaluated allelic association at individual markers surrounding and within the LRRK2 gene. For six of the seven markers, the associated allele was the same as reported for the common European-North African haplotype, indicating a common ancestral origin. The apparently high frequency among North African patients with Parkinson's disease and controls, particularly those of Arab ancestry as well as among Ashkenazi Jewish subjects as shown here, suggests a likely Middle Eastern origin for the G2019S mutation. It also establishes once again the Middle Eastern origin of Ashkenazim."

Cyrus P. Zabetian, Carolyn M. Hutter, Dora Yearout, Alexis N. Lopez, Stewart A. Factor, Alida Griffith, Berta C. Leis, Thomas D. Bird, John G. Nutt, Donald S. Higgins, John W. Roberts, Denise M. Kay, Karen L. Edwards, Ali Samii, and Haydeh Payami. "LRRK2 G2019S in Families with Parkinson Disease Who Originated from Europe and the Middle East: Evidence of Two Distinct Founding Events Beginning Two Millennia Ago." American Journal of Human Genetics 79 (2006): 752-758. Abstract:

"The leucine-rich repeat kinase 2 (LRRK2) G2019S mutation is the most common genetic determinant of Parkinson disease (PD) identified to date. It accounts for 1-7% of PD in patients of European origin and 20-40% in Ashkenazi Jews and North African Arabs with PD. Previous studies concluded that patients from these populations all shared a common Middle Eastern founder who lived in the 13th century. We tested this hypothesis by genotyping 25 microsatellite and single-nucleotide-polymorphism markers in 22 families with G2019S and observed two distinct haplotypes. Haplotype 1 was present in 19 families of Ashkenazi Jewish and European ancestry, whereas haplotype 2 occurred in three European American families. Using a maximum-likelihood method, we estimated that the families with haplotype 1 shared a common ancestor 2,250 (95% confidence interval 1,650-3,120) years ago, whereas those with haplotype 2 appeared to share a more recent founder. Our data suggest two separate founding events for G2019S in these populations, beginning at a time that coincides with the Jewish Diasporas."

Talia Bloch. "One Big, Happy Family: Litvaks and Galitzianers, Lay Down Your Arms; Science Finds Unity in the Jewish Gene Pool." The Forward (August 22, 2007). Excerpt:

"About a year ago, researchers at several American labs noticed that one particular mutation for Parkinson's -- a disease associated with various mutations -- was much more common among Ashkenazic Jews. Meanwhile, a group of researchers in France had discovered that North African Arabs carried the same mutation. Moreover, in both the Ashkenazic Jews and the North Africans, the mutation was linked to an identical set of genetic markers 'that is very, very rare, so we are confident that it came from a common founder,' or ancestor, said Dr. Cyrus Zabetian, who in addition to serving as assistant professor of neurology at the University of Washington is the lead author of the study, which appeared in The American Journal of Human Genetics in October 2006. When researchers dated these genetic markers, they found they originated some 2,000 years ago -- before the founding of Ashkenazic Jewry."

Deafness

M. M. Carrasquillo, J. Zlotogora, S. Barges, and Aravinda Chakravarti, "Two different connexin 26 mutations in an inbred kindred segregation non-syndromic recessive deafness: implications for genetic studies in isolated populations." Human Molecular Genetics 6(12) (November 1997): 2163-2172. This study examines DFNBs that cause non-syndromic recessive deafness (NSRD), with particular attention to human chromosome 13q11 (DFNB1). It was discovered that some Jews, Palestinian and Israeli Arabs, and other Mediterranean peoples possess the DFNB1 genetic mutation.

Familial Mediterranean Fever

George E. Ehrlich, M.D. "Genetics of Familial Mediterranean Fever and Its Implications." Annals of Internal Medicine 129 (October 1, 1998): 581-582. Excerpts:

"Ashkenazi Jews -- those chiefly from the Pale of Poland, Russia, and central European countries -- seem to be genetically different from their Sephardic coreligionists, who mainly stem from the Mediterranean countries of Africa and Europe. Familial Mediterranean fever is rare among Ashkenazi Jews but common among Sephardim.... In the case of Jews, almost two millennia may not be long enough to account for the genetic differences between the Ashkenazi and Sephardic Jews in their inherited disease propensities (such as diabetes mellitus and Tay-Sachs disease in eastern Ashkenazi Jews and familial Mediterranean fever in Sephardim). Professor Heller was among those who believed that Ashkenazi and Sephardic Jews have different origins. Some speculate that Ashkenazi Jews descended from the Khazars, an early medieval empire that straddled the Volga River and dominated the eastern Black Sea and the Caspian Sea. Their rulers and many of their subjects converted to Judaism, probably in the eighth century, and the Khazars were gradually forced westward after successive losses to Muslim armies from the south, Mongols from the east, and the Rus (Scandinavians who gave Russia its name) from the north. The genetic distribution of the missense mutations reported by Eisenberg and colleagues9 adds further detail to the argument: It distinguishes between the Sephardic (M693V) and Ashkenazi (V726A) Jews, grouping the latter with Iraqi Jews and some Armenians and suggesting that all three groups originated in an area contiguous to or encompassing the Khazar empire (which probably incorporated many of the Jews remaining in that area after the Babylonian captivity). In fact, the Khazars were a Turkic people, and it would be of interest to look for this genetic mutation in contemporary Turks with the clinical signs and symptoms of familial Mediterranean fever."
9. Eisenberg S, Aksentijevich I, Deng Z, Kastner DL, Matzner Y. Diagnosis of familial Mediterranean fever by a molecular genetics method. Ann Intern Med. 1998;129:539-42.
Letters in response to Ehrlich's article were published in the May 4, 1999 issue on pages 780-781.

Shlomit Eisenberg, Ivona Aksentijevich, Zuoming Deng, Daniel L. Kastner, and Yaacov Matzner. "Diagnosis of Familial Mediterranean Fever by a Molecular Genetics Method." Annals of Internal Medicine 129:7 (October 1, 1998): 539-542. Excerpt:

"Familial Mediterranean fever, or recurrent polyserositis, is a recessively inherited disorder that affects Sephardic Jews, Turks, Armenians, and Arabs."

N. Stoffman, N. Magal, T. Shohat, M. Shohat, R. Lotan, S. Koman, A. Oron, Y. Danon, G. J. Halpern, Y. Lifshitz. "Higher than expected carrier rates for familial Mediterranean fever in various Jewish ethnic groups." European Journal of Human Genetics 8(4) (April 2000): 307-310.

The International FMF Consortium. "Ancient Missense Mutations in a New Member of the RoRet Gene Family are Likely to Cause Familial Mediterranean Fever." Cell 90 (August 22, 1997): 797-807. Abstract excerpt:

"Haplotype and mutational analyses disclosed ancestral relationships among carrier chromosomes in populations that have been separated for centuries."

Nicholas Wade. "Gene From Mideast Ancestor May Link 4 Disparate Peoples" The New York Times (August 22, 1997): A19. Excerpts:

"...there lived a person who bequeathed a particular gene to many present-day descendants... They include Jews, Arabs, [Anatolian] Turks and Armenians. The gene, a variant of a gene that controls fever, has come to light because it causes an unusual disease called familial Mediterranean fever in individuals who inherit a copy from both parents. The gene's presence among a surprising group of populations hints at the rich archeology that lies buried in the human genome, once geneticists and historians have learned how to interpret it... For example, the variant form of the gene found in North African Jews, Iraqi Jews and Armenians is the same, carrying both the same mutation and a pattern of 11 other genetic changes, all harmless... A second variant form of the gene, according to the American team, is shared by Iraqi Jews, Ashkenazi Jews, the Moslem Druze sect and Armenians. The two variants are similar and probably derive from the same founder... He also noted that the variant fever gene established a common genetic lineage between Ashkenazi Jews and Iraqi Jews."

J. Siegel. "Researchers Discover Gene in Familial Mediterranean Fever." Canadian Jewish News (October 1, 1997): 57.

William Kavesh. "Jewish Genetic Diseases." In The Second Jewish Catalog, eds. Sharon Strassfeld and Michael Strassfeld (JPS, 1976). Excerpt from p. 57:

"Among non-Ashkenazic Jews, a number of diseases occur with increased frequency, Familial Mediterranean fever is a relatively rare condition afflicting Arabs, Armenians, and Sephardic Jews with periodic episodes of fever, abdominal and chest pains, and arthritis. How it came to affect these three groups is a question whose answer might provide an incentive to peace in the Middle East."

Pemphigus Vulgaris

R. Loewenthal, Y. Slomov, M.F. Gonzalez-Escribano, I. Goldberg, M. Korostishevsky, S. Brenner, A. Nuez-Roldan, J.S. Conejo-Mir, E. Gazit. "Common ancestral origin of pemphigus vulgaris in Jews and Spaniards: a study using microsatellite markers." Tissue Antigens 63:4 (April 2004): 326-334. Abstract excerpts:

"Pemphigus is a group of autoimmune blistering diseases of the skin and mucous membranes. ... Studies showed that the associated HLA haplotype in Jewish pemphigus vulgaris (PV) patients is HLA-B38, DRB1*0402, and DQB1*0302; or HLA-B35, DRB1*0402, and DQB1*0302. Similar associations with class II genes were found in Spanish non-Jewish PV patients. As Jews lived in Spain for hundreds of years and many converted to Christianity, the presence of the same HLA haplotype in the Jewish and Spanish PV suggests that they may share the same founder. ... The distance between the two PV cohorts is relatively short, but the distance between the Jewish patients and the Jewish controls is greater compared to the distance between Spanish patients and Spanish controls. In both PV populations, the same microsatellite haplotypes in addition to a common class II haplotype were found, suggesting that both patient populations originated from the same genetic stock and, therefore, share the same ancestral disease gene."

N. Mobini, E.J. Yunis, C.A. Alper, J.J. Yunis, J.C. Delgado, D.E. Yunis, A. Firooz, Y. Dowlati, K. Bahar, P.K. Gregersen, A.R. Ahmed. "Identical MHC markers in non-Jewish Iranian and Ashkenazi Jewish patients with pemphigus vulgaris: possible common central Asian ancestral origin." Human Immunology 57:1 (September 15, 1997): 62-67. Abstract:

"Previous studies showed that almost all Ashkenazi Jewish patients with pemphigus vulgaris carried the extended haplotype [HLA-B38, SC21, DRB1*0402, DQB1*0302] or [HLA-B35, SC31, DRB1*0402, DQB1*0302] or class II fragments of them. Non-Jewish patients carried [HLA-B55, SB45, DRB1*1401, DQB1*0503] or its class II fragments. In the present study of 20 Iranian patients with pemphigus vulgaris, 17 were found to carry DRB1*0402, DQB1*0302 haplotypes, also found among normal Iranian haplotypes and the same as that of the Jews. These findings suggest that the pemphigus MHC susceptibility gene among Iranians derived from the same ancestor as that in the Ashkenazim. The ancient Jews were under Persian domination from 500 B.C. until 300 B.C. and in the 8th century A.D., a Tataric people living in the kingdom of Khazar on the Western shore of the Caspian Sea and the Northern shore of the Black Sea, near Persia, converted to Judaism, providing possible opportunities for gene mixing in two populations that are distinct and separate today."

Gaucher Disease

G. A. Diaz, B. D. Gelb, Neil Risch, T. G. Nygaard, A. Frisch, I. J. Cohen, C. S. Miranda, O. Amaral, I. Maire, L. Poenaru, C. Caillaud, M. Weizberg, P. Mistry, and R. J. Desnick. "Gaucher Disease: The Origins of the Ashkenazi Jewish N370S and 84GG Acid beta-Glucosidase Mutations." American Journal of Human Genetics 66:6 (June 2000): 1821-1832. Gaucher Disease is found among Ashkenazic Jews as well as some Europeans (e.g., Portuguese Christians and German Christians).

A. Zimran, T. Gelbart, B. Westwood, G. A. Grabowski, and Ernest Beutler. "High Frequency of the Gaucher Disease Mutation at Nucleotide 1226 among Ashkenazi Jews." American Journal of Human Genetics 49 (1991): 855-859. Excerpts from the Summary:

"[...] The high frequency of Gaucher disease in the Ashkenazi Jewish population is due to the occurrence of a mutation at nucleotide (nt) 1226. We have screened 593 DNA samples from normal Ashkenazi Jews, as well as 62 DNA samples from all of our Ashkenazi Jewish patients with Gaucher disease, for the presence of the 1226 mutation. In the 593 presumed normal Ashkenazi Jewish individuals the 1226 mutation was identified in the heterozygous state in 37 and in the homozygous state in two, giving a gene frequency of .035 for the mutation. This 1226 mutation represented 73% of the 124 Gaucher disease alieles in Jewish Gaucher disease patients. Accordingly we estimate that the gene frequency for Gaucher disease among the Ashkenazi Jewish population is .047, which is equivalent to a carrier frequency of 8.9% and a birth incidence of 1:450."

Idiopathic Torsion

Neil Risch, D. de Leon, L. Ozelius, P. Kramer, L. Almasy, B. Singer, S. Fahn, et al. "Genetic analysis of idiopathic torsion in Ashkenazi Jews and their recent descent from a small founder population." Nature Genetics 9 (February 1995): 152-159.

Tay-Sachs Disease

Amos Frisch, Roberto Colombo, Elena Michaelovsky, Mazal Karpati, Boleslaw Goldman, and Leah Peleg. "Origin and spread of the 1278insTATC mutation causing Tay-Sachs disease in Ashkenazi Jews: genetic drift as a robust and parsimonious hypothesis." Human Genetics 114:4 (March 2004): 366-376. Abstract:

"The 1278insTATC is the most prevalent Beta-hexosaminidase A (HEXA) gene mutation causing Tay-Sachs disease (TSD), one of the four lysosomal storage diseases (LSDs) occurring at elevated frequencies among Ashkenazi Jews (AJs). To investigate the genetic history of this mutation in the AJ population, a conserved haplotype (D15S981:175-D15S131:240-D15S1050:284-D15S197:144-D15S188:418) was identified in 1278insTATC chromosomes from 55 unrelated AJ individuals (15 homozygotes and 40 heterozygotes for the TSD mutation), suggesting the occurrence of a common founder. When two methods were used for analysis of linkage disequilibrium (LD) between flanking polymorphic markers and the disease locus and for the study of the decay of LD over time, the estimated age of the insertion was found to be 40+/-12 generations (95% confidence interval: 30-50 generations), so that the most recent common ancestor of the mutation-bearing chromosomes would date to the 8th-9th century. This corresponds with the demographic expansion of AJs in central Europe, following the founding of the Ashkenaz settlement in the early Middle Ages. The results are consistent with the geographic distribution of the main TSD mutation, 1278insTATC being more common in central Europe, and with the coalescent times of mutations causing two other LSDs, Gaucher disease and mucolipidosis type IV. Evidence for the absence of a determinant positive selection (heterozygote advantage) over the mutation is provided by a comparison between the estimated age of 1278insTATC and the probability of the current AJ frequency of the mutant allele as a function of its age, calculated by use of a branching-process model. Therefore, the founder effect in a rapidly expanding population arising from a bottleneck provides a robust parsimonious hypothesis explaining the spread of 1278insTATC-linked TSD in AJ individuals."

Gloria M. Petersen, Jerome I. Rotter, Rita M. Cantor, L. Leigh Field, Susan Greenwald, Joyce S. T. Lim, Chitra Roy, Victor Schoenfeld, J. Alexander Lowden, and Michael Kaback. "The Tay-Sachs Disease Gene in North American Jewish Populations: Geographic Variations and Origin." American Journal of Human Genetics 35 (1983): 1258-1269. Summary:

Tay-Sachs disease is found in a high frequency among Hungarian Jews. The geneticists Petersen et al. mention the possibility that the Hungarian Jews are descended from the Khazars, and allege that their data support this contention. Separately from this article, it came to my attention years ago that a scientist at a conference in Israel also proposed that Tay-Sachs came from the Khazars, though I have no details on this other scientist's research. But if Tay-Sachs comes from Khazars then why would Austrian Jews have a greater percentage of it than Hungarian Jews? Daniel Friedman suggests this is from a founder effect that may have nothing to do with Khazars. Excerpts from Petersen et al.:

"Relative to Jews of Polish and Russian origins, there was at least a twofold increase in the TSD carrier frequency in Jews of Austrian, Hungarian, and Czechoslovakian origins (P < .005). These findings suggest that the TSD gene proliferated among the antecedents of modern Ashkenazi Jewry after the Second Diaspora (70 A.D.) and before their major migrations to regions of Poland and Russia (before 1100 A.D.).... Our study was conducted (1) to obtain an estimate of the Jewish TSD heterozygote frequency and its ancestral variation by direct count of individuals screened for Tay-Sachs disease, and (2) to test the hypothesis of a Polish-Russian origin of the TSD gene in the Jewish population by estimating TSD heterozygote frequencies by European country of origin.... Based on direct assessment, we determined the overall TSD carrier frequency in the Jews tested to be .0324 with a standard error of +/- .0008, giving a 95% confidence interval of (.0308, .0340)... With the data sorted by individual countries of origin for all of Europe (see table 2 and fig. 1), the TSD carrier frequencies are significantly higher for Austria (.1092), Czechoslovakia (.0853), and Hungary (.0723), rather than for Poland (.0343), Russia (.0335), or Germany (.0269). In addition, further tests of difference in proportion indicate that the TSD carrier frequency of the Austria/Czechoslovakia/Hungary region (obtained by combining the results from individual countries) differs significantly from the frequencies both of the Polish/Russia region and of Germany (P < .0001)... [A]s an independent second test, we computed the frequency in those groups of individuals who indicated as their origin a mixture of these countries. None of these individuals was included in the above single-country-of-origin analysis. Table 3 shows that the group fo mixed origin from the Austria/Hungary/Czechoslovakia region has a TSD carrier frequency (.0928) significantly higher than that of any group of mixed origins from Poland, Russia, or Germany (.0278-.0369). Data from an independent TSD screening program in Canada also show a higher carrier frequency in Jews who had originated from Middle Europe relative to Poland and Russia (table 4).... There are several important implications of this observation.... Third, the Khazar people, a Turkic tribe that lived to the north of the Caucasus Mountains from 400 to 1200 A.D. and who converted to Judaism during this period, have been suggested by Neel [5] (based on Koestler's hypothesis [38]) as a possible source of the TSD 'private polymorphism' for the Ashkenazic Jewish population. There is historical evidence of specific migrations of Khazars to Magyar territory (including present-day Hungary). Our results are consistent with this possibility. Further, Lowden, in analyzing the high TSD gene frequency among Canadian Jews of Polish-Russian origin, observed that the Russian Jews in his study tended to come from southern Russia [25]."
5. NEEL JV: History and the Tay-Sachs allele, in Genetic Diseases among Ashkenazi Jews, edited by GOODMAN RM, MOTULSKY AG, New York, Raven Press, 1979, pp 285-299
25. LOWDEN JA: Tay-Sachs screening and prevention: the Canadian experience, in Tay-Sachs Disease: Screening and Prevention, edited by KABACK MM, RIMOIN DL, O'BRIEN JS, New York, Alan R. Liss, 1977, pp 37-46
38. KOESTLER AC: The Thirteenth Tribe. New York, Random House, 1976

James V. Neel. "History and the Tay-Sachs allele", in Genetic Diseases among Ashkenazi Jews, eds. Richard M. Goodman and Arno G. Motulsky (New York: Raven Press, 1979), pages 285-299. Excerpt from page 297:

"The Khazars are the one identified group in European history who might have contributed the TSD allele in the necessary numbers to Ashkenazim."

Jared Diamond. "Curse and Blessing of the Ghetto." Discover Magazine 12[3] (March 1991): 60-61. Excerpts:

"As a second possibility, the Ashkenazim might have acquired the Tay-Sachs gene from some other people who already had the gene at high frequency. Arthur Koestler's controversial book The Thirteenth Tribe, for example, popularized the view that the Ashkenazim are really not a Semitic people but are instead descended from the Khazar, a Turkic tribe whose rulers converted to Judaism in the eighth century. Could the Khazar have brought the Tay-Sachs gene to Eastern Europe? This speculation makes good romantic reading, but there is no good evidence to support it. Moreover, it fails to explain why deaths of Tay-Sachs children didn't eliminate the gene by natural selection in the past 1,200 years, nor how the Khazar acquired high frequencies of the gene in the first place."

Philip Evans. "Some of My Best Friends are Khazars." World Medicine 12 (June 15, 1977): 85-86. Suggests that Ashkenazic genetic diseases like Tay-Sachs may have derived from the Khazars.

"Non-Jews hit by 'Jewish' diseases fall through the cracks of genetic screening." The Forward (August 12, 2013). Notes that besides Ashkenazi Jews, other ethnic groups that are at an elevated risk for Tay-Sachs include "French-Canadians, Irish and Cajuns".

Factor XI Deficiency

David B. Goldstein, David E. Reich, Neil Bradman, Sali Usher, Uri Seligsohn, and Hava Peretz. "Age Estimates of Two Common Mutations Causing Factor XI Deficiency: Recent Genetic Drift is Not Necessary for Elevated Disease Incidence Among Ashkenazi Jews." American Journal of Human Genetics 64:4 (April 1999): 1071-1075. Abstract excerpt:

"The type II and type III mutations at the FXI locus, which cause coagulation factor XI deficiency, have high frequencies in Jewish populations. The type III mutation is largely restricted to Ashkenazi Jews, but the type II mutation is observed at high frequency in both Ashkenazi and Iraqi Jews, suggesting the possibility that the mutation appeared before the separation of these communities."

Article excerpt:

"Since the best estimate for the coalescent time of the type II mutation is 120 or 185 generations, depending on which allele was ancestral, this analysis also provides evidence that the ancestry of at least some members of both Iraqi and Ashkenazi Jewish populations can, in fact, be traced to a single ancestral population, presumably residing in the kingdoms of Israel and Judah before the various dispersions."

Hava Peretz, Avital Mulai, Sali Usher, Ariella Zivelin, Avihai Segal, Zahavi Weisman, Moshe Mittelman, Hannah Lupo, Naomi Lanir, Benjamin Brenner, Ofer Shpilberg, and Uri Seligsohn. "The Two Common Mutations Causing Factor XI Deficiency in Jews Stem From Distinct Founders: One of Ancient Middle Eastern Origin and Another of More Recent European Origin." Blood 90:7 (October 1, 1997): 2654-2659.

Ofer Shpilberg, Hava Peretz, Ariella Zivelin, R. Yatuv, A. Chetrit, T. Kulka, C. Stern, et al. "One of the two common mutations causing factor XI deficiency in Ashkenazi Jews (type II) is also prevalent in Iraqi Jews, who represent the ancient gene pool of Jews." Blood 85 (1995): 429-432.

(1) Avshalom Zoossmann-Diskin. "Two Common Mutations Causing Factor XI Deficiency in Ashkenazi Jews May Point to a European Origin." Blood 86(8) (1995): 3267. (2) Avshalom Zoossmann-Diskin. "ITD in Ashkenazi Jews - genetic drift or selection?" Nature Genetics 11 (1995): 13-14. And other works. According to Zoossmann-Diskin, genetics shows that Jews genetically resemble the populations surrounding them. Elsewhere, Zoossmann-Diskin claims that the genetic composition of an ancestral Jewish population cannot accurately be calculated by averaging the genetic composition of 4 modern Jewish populations (as Hammer et al. attempted to do in 2000). Nor, he argues, is the percentage of admixture between Jews and non-Jews accurately calculated in studies like Hammer et al. (Note: ITD = Idiopathic torsion dystonia)

Colorectal Cancer

Bethany L. Niell, Jeffrey C. Long, Gad Rennert, and Stephen B. Gruber. "Genetic Anthropology of the Colorectal Cancer-Susceptibility Allele APC I1307K: Evidence of Genetic Drift within the Ashkenazim." American Journal of Human Genetics 73 (2003): 1250-1260. Abstract excerpts:

"The adenomatous polyposis coli (APC) I1307K allele is found in 6% of the Ashkenazi Jewish population and in 1%-2% of Sephardi Jews; it confers a relative risk of 1.52.0 for colorectal cancer (CRC) on all carriers. ... A common progenitor haplotype spanned across APC I1307K from the centromeric marker D5S135 to the telomeric marker D5S346 and was observed in individuals of Ashkenazi, Sephardi, and Arab descent. The ancestor of modern I1307K alleles existed 87.9118 generations ago (~2,200-2,950 years ago)."

Breast Cancer

Jeffrey N. Weitzel, Kathleen R. Blazer, Deborah J. MacDonald, Julie O. Culver, and Kenneth Offit. "Genetics, Genomics, and Cancer Risk Assessment: State of the Art and Future Directions in the Era of Personalized Medicine." CA: A Cancer Journal for Clinicians 61:5 (September/October 2011): 327-359. From Table 8's Glossary of Terms on page 353:

"Genetic isolates: A population that has a similar genetic background because of common ancestry, often due to geographical isolation, natural selection, or other mechanisms. This sometimes leads to 'founder' mutations (mutations common in a specific population, such as the 3 specific BRCA gene mutations that account for most BRCA-related breast and ovarian cancer in persons of Ashkenazi Jewish heritage)."

Nancy Hamel, Bing-Jian Feng, Lenka Foretova, Dominique Stoppa-Lyonnet, Steven A. Narod, Evgeny Imyanitov, Olga Sinilnikova, Laima Tihomirova, Jan Lubinski, Jacek Gronwald, Bohdan Gorski, Thomas van Overeem Hansen, Finn C. Nielsen, Mads Thomassen, Drakoulis Yannoukakos, Irene Konstantopoulou, Vladimir Zajac, Sona Ciernikova, Fergus J. Couch, Celia M. T. Greenwood, David E. Goldgar, and William D. Foulkes. "On the origin and diffusion of BRCA1 c.5266dupC (5382insC) in European populations." European Journal of Human Genetics 19 (March 2011): 300-306. Advance online publication, December 1, 2010. Abstract:

"The BRCA1 mutation c.5266dupC was originally described as a founder mutation in the Ashkenazi Jewish (AJ) population. However, this mutation is also present at appreciable frequency in several European countries, which raises intriguing questions about the origins of the mutation. We genotyped 245 carrier families from 14 different population groups (Russian, Latvian, Ukrainian, Czech, Slovak, Polish, Danish, Dutch, French, German, Italian, Greek, Brazilian and AJ) for seven microsatellite markers and confirmed that all mutation carriers share a common haplotype from a single founder individual. Using a maximum likelihood method that allowsfor both recombination and mutational events of marker loci, we estimated that the mutation arose some 1800 years ago in either Scandinavia or what is now northern Russia and subsequently spread to the various populations we genotyped during the following centuries, including the AJ population. Age estimates and the molecular evolution profile of the most common linked haplotype in the carrier populations studied further suggest that c.5266dupC likely entered the AJ gene pool in Poland approximately 400-500 years ago. Our results illustrate that (1) BRCA1 c.5266dupC originated from a single common ancestor and was a common European mutation long before becoming an AJ founder mutation and (2) the mutation is likely present in many additional European countries where genetic screening of BRCA1 may not yet be common practice."

R. B. Bar-Sade, A. Kruglikova, B. Modan, E. Gak, G. Hirsh-Yechezkel, L. Theodor, I. Novikov, R. Gershoni-Baruch, S. Risel, M. Z. Papa, G. Ben-Baruch, and E. Friedman. "The 185delAG BRCA1 mutation originated before the dispersion of Jews in the diaspora and is not limited to Ashkenazim." Human Molecular Genetics 7:5 (May 1998): 801-805. Shows that the 185delAG breast cancer mutation originates from around the 1st century CE and is found among some Ashkenazi Jews and some Moroccan Jews.

Schelly Talalay Dardashti. "How Do Sephardic Jews Figure Into The Genetic Equation?" Forward (August 25, 2006). Excerpt:

"A recent Tel Aviv University study, along with others conducted in Colorado and Montreal, has shown that the BRCA1 'Ashkenazic' breast-cancer mutation began to appear before the Jewish people's major exiles and diasporas. The identical mutation appears in Ashkenazim and Sephardim, indicating an ancient common founder. The marker has been found in Mizrahim (Jews from North Africa and the Middle East) and among Hispanics in Los Angeles and other cities. It also appears in Spain, Chile, Turkey, Yemen, Iraq, Morocco, Greece, Iran, Pakistan and Egypt -- all lands with histories of Jewish migration."

Patricia Hartge, Jeffery P. Struewing, Sholom Wacholder, Lawrence C. Brody, and Margaret A. Tucker. "The prevalence of common BRCA1 and BRCA2 mutations among Ashkenazi Jews." American Journal of Human Genetics 64:4 (April 1999): 963-970. Excerpts from the Abstract:

"Three founder mutations in the cancer-associated genes BRCA1 and BRCA2 occur frequently enough among Ashkenazi Jews to warrant consideration of genetic testing outside the setting of high-risk families with multiple cases of breast or ovarian cancer. We estimated the prevalence of these founder mutations in BRCA1 and BRCA2 in the general population of Ashkenazi Jews according to age at testing, personal cancer history, and family cancer history. [...] For example, 11 (10%) of 109 Jewish women who had been given a diagnosis of breast cancer in their forties carried one of the mutations. [...]"

E. Levy-Lahad, Raphael Catane, Shlomit Eisenberg, Bella Kaufman, Gila Hornreich, Ella Lishinsky, Mordechai Shohat, Barbara L. Weber, Uziel Beller, Amnon Lahad, and David Halle. "Founder BRCA1 and BRCA2 mutations in Ashkenazi Jews in Israel: frequency and differential penetrance in ovarian cancer and in breast-ovarian cancer families." American Journal of Human Genetics 60:5 (May 1997): 1059-1067. Excerpts from the Abstract:

"Germ-line BRCA1 and BRCA2 mutations account for most of familial breast-ovarian cancer. In Ashkenazi Jews, there is a high population frequency (approximately 2%) of three founder mutations: BRCA1 185delAG, BRCA1 5382insC, and BRCA2 6174delT. This study examined the frequency of these mutations in a series of Ashkenazi women with ovarian cancer unselected for family history, compared with the frequency of these mutations in families ascertained on the basis of family history of at least two affected women. [...] There was a high frequency (10/22; [45%]) of germ-line mutations in Ashkenazi women with ovarian cancer, even in those with minimal or no family history (7/18 [39%]). In high-risk Ashkenazi families, a founder mutation was found in 59% (25/42). [...]"

C. Oddoux, J. P. Struewing, C. M. Clayton, S. Neuhausen, Lawrence C. Brody, Michael Kaback, Bruce Haas, Larry Norton, P. Borgen, S. Jhanwar, D. Goldgar, Harry Ostrer, and Kenneth Offit. "The carrier frequency of the BRCA2 6174delT mutation among Ashkenazi Jewish individuals is approximately 1%." Nature Genetics 14:2 (October 1996): 188-190. Abstract:

"Certain germline mutations in either BRCA1 or BRCA2 confer a lifetime risk of developing breast cancer that may approach 90%. The BRCA1 185delAG mutation was found in 20% and the BRCA2 6174delT mutation in 8% of Ashkenazi Jewish women with early-onset breast cancer. The 185delAG mutation was observed in 0.9% of 858 Ashkenazi Jews unselected for a personal or family history of cancer. Assuming comparable age-specific penetrances, a carrier frequency of 0.3% was estimated for the 6174delT BRCA2 mutation. To test this hypothesis, we performed a population survey of 1,255 Jewish individuals. In two independent groups, a prevalence of approximately 1% (C.I. 0.6-1.5) was observed for the 6174delT mutation. The relative risk of developing breast cancer by age 42 was estimated to be 9.3 (C.I. 2.5-22.5) for 6174delT, compared to 31 (C.I. 11-77) for 185delAG. Analysis of 107 Ashkenazi Jewish women with breast cancer and a family history of breast or ovarian cancer confirmed a four-fold greater prevalence for the BRCA1 185delAG mutation compared to the BRCA2 6174delT mutation. Our findings suggest a difference in cumulative life-time penetrance for the two mutations. Genetic counseling for the one in 50 Ashkenazi Jewish individuals harbouring specific germline mutations in BRCA1 or BRCA2 must be tailored to reflect the different risks associated with the two mutations."

Memorial Sloan-Kettering Cancer Center. "More Ashkenazi Jews Have Gene Defect that Raises Inherited Breast Cancer Risk." The Oncologist 1:5 (October 1996): 335. Excerpts:

"An inherited genetic mutation that increases the risk of breast cancer in Jewish women of Eastern European descent is three times more common than previously estimated, according to a study led by researchers at Memorial Sloan-Kettering Cancer Center in New York. In the October issue of Nature Genetics, the team reports that the BRCA2 gene mutation is found in one out of every 100 Ashkenazi Jews, [...] The new estimate is based on an analysis of blood samples from more than 1,200 men and women of Ashkenazi descent. The study shows the BRCA2 mutation is just as common among Ashkenazis as a similar mutation in the BRCA1 gene that also increases the risk of breast cancer in this ethnic group. [...] The findings will likely affect how Ashkenazis are counseled about their risk of inherited breast cancer. 'From a public health perspective, we suspect that one in every 50 Ashkenazis carries either the BRCA1 or the BRCA2 mutation, a frequency that is quite high,' Dr. [Kenneth] Offit says. 'We now plan to tailor genetic counseling for individuals based on the origin of their ancestors and the specific mutation they have inherited.' [...] The BRCA1 and BRCA2 mutations studied by the researchers also have been linked to an increased risk of inherited ovarian cancer, and the BRCA2 mutation appears to play a role in male breast cancer, which occurs rarely. [...]"

Kenneth Offit, T. Gilewski, P. McGuide, A. Schluger, H. Hampel, K. Brown, J. Swensen, S. Neuhausen, M. Skolnick, L. Norton, and D. Goldgar. "Germline BRCA1 185delAG mutations in Jewish women with breast cancer." The Lancet 347(9016) (June 15, 1996): 1643-1645.

Background:

"We aimed to find out the proportion of breast cancers in Ashkenazi Jewish women attributable to the frameshift mutation at position 185 involving the deletion of adenine and guanine (185delAG) in the breast cancer gene BRCA1."

Findings:

"Of the 80 women diagnosed before the age of 42 years, 16 (20%, 95% CI 11.2-28.8) were heterozygous for the mutation. All 16 women had at least one first-degree or second-degree relative with breast or ovarian cancer. Of 27 probands diagnosed with breast cancer between the ages of 42 and 50 years who had at least one first-degree relative affected with breast or ovarian cancer, 8 (30%, 95% CI 12-47) had 185delAG mutations."

Patricia N. Tonin, B. Weber, Kenneth Offit, F. Couch, T. R. Rebbeck, S. Neuhausen, A. K. Godwin, M. Daly, J. Wagner-Costalos, D. Berman, G. Grana, E. Fox, M. F. Kane, R. D. Kolodner, M. Krainer, D. A. Haber, J. P. Struewing, E. Warner, B. Rosen, C. Lerman, B. Peshkin, L. Norton, O. Serova, W. D. Foulkes, J. E. Garber, et al. "Frequency of recurrent BRCA1 and BRCA2 mutations in Ashkenazi Jewish breast cancer families." Nature Medicine 2:11 (November 1996): 1179-1183.

S. Neuhausen, T. Gilewski, L. Norton, T. Tran, P. McGuide, J. Swensen, H. Hampel, P. Borgen, K. Brown, M. Skolnick, D. Shattuck-Eidens, S. Jhanwar, D. Goldgar, and Kenneth Offit. "Recurrent BRCA2 6174delT mutations in Ashkenazi Jewish women affected by breast cancer." Nature Genetics 13:1 (May 1996): 126-128.

Canavan Disease

Sybil Blau. "New Fairfield teen lives with Canavan disease." The News-Times (Danbury, CT) (April 4, 2009). Excerpts:

"Canavan disease is a rare genetic disease that occurs most often when both parents are Ashkenazi Jews from eastern Poland, Lithuania or western Russia, or Saudi Arabia. Because of the mutation of a single gene, Canavan sufferers have a buildup of N-acetylaspartate acid, or NAA, in the brain. This prevents them from growing myelin, the fatty sheath that normally insulates nerve cells and allows the cells to carry messages."

D. Joanne Lynn, Herbert B. Newton, and Alexander D. Rae-Grant. The 5-Minute Neurology Consult. 1st edition. Lippincott Williams and Wilkins, 2003. An excerpt from page 164:

"Canavan disease affects all ethnic groups but is especially prevalent among Ashkenazi Jews and Saudi Arabians."

Hereditary Inclusion Body Myopathy

Anne Cohen. "Genetic Testing For Sephardic Jews Faces Reluctant Community." Forward (published online August 11, 2013 and in print on August 16, 2013). Excerpts:

"[...] hereditary inclusion body myopathy, a rare, recessive genetic disease that causes late-onset muscle degeneration. The carrier rate in the Persian Jewish community is 1 in 15 -- more common than Tay-Sachs is for Ashkenazi Jews. Cases of HIBM have also been documented among non-Jews, including Japanese, Caucasian Americans, Asian Indians and Kurdish Iranians. [...] Argov discovered the disease by chance in 1979, [...] In 1994 he joined forces with Mitrani-Rosenbaum, and in 2001 her lab discovered the gene mutations causing the condition. Then, Argov noted something peculiar: Researchers in other countries had documented similar cases, without connecting the dots. 'It turned out that it's not unique to Persian Jews,' he said. 'It exists worldwide with other mutations.'"

Mucolipidosis Type 4 (ML4)

Debra Goldschmidt. "Parents push for standardized screening of Jewish genetic diseases." CNN.com (September 10, 2013). This article discusses a child afflicted by Mucolipidosis Type IV (called ML4 for short) and mentions that it's more common among Ashkenazi Jews than non-Jews. ML4 causes severe mental and visual problems in childhood and eventually results in early death.

Other articles

Saurav Guha, Jeffrey A. Rosenfeld, Anil K. Malhotra, Annette T. Lee, Peter K. Gregersen, John M. Kane, Itsik Pe'er, Ariel Darvasi, and Todd Lencz. "Implications for health and disease in the genetic signature of the Ashkenazi Jewish population." Genome Biology (January 25, 2012). Excerpts from the provisional version of the Abstract:

"[...] We genotyped more than 1300 Ashkenazi Jewish healthy volunteers [...] Using clustering, principal components, and pairwise genetic distance as converging approaches, we identified an Ashkenazi Jewish-specific genetic signature that differentiated these subjects from both European and Middle Eastern samples. Most notably, gene ontology analysis of the Ashkenazi Jewish genetic signature revealed an enrichment of genes functioning in transepithelial chloride transport, such as CFTR, and in equilibrioception, potentially shedding light on cystic fibrosis, Usher syndrome and other diseases over-represented in the Ashkenazi Jewish population. Results also impact risk profiles for autoimmune and metabolic disorders in this population. Finally, residual intra-Ashkenazi population structure was minimal, primarily determined by Class 1 MHC alleles, and not related to host country of origin. [...]"

Megan Goldin. "Geneticists Study Jewish Genes for Disease Clues." Reuters (December 16, 2001). Excerpts:

"``The population of Ashkenazi Jews is relatively homogenous which facilitates gene discovery,'' said Ariel Darvasi, IDgene's president and a geneticist at Jerusalem's Hebrew University.... The forefathers of the Ashkenazi community began to settle in parts of Europe during the Roman Empire... They moved to Spain, France, Italy and other Mediterranean basin countries, but spread over the centuries to the Rhineland in Germany, Poland and Russia. Frequent persecution kept their numbers small. Modern Ashkenazi Jews are believed to descend from about 1,500 Jewish families dating back to the 14th century. But Darvasi said the forefathers of today's Ashkenazis came from an even smaller gene pool. Darvasi said ``maybe 500 families were really the source of the total (Ashkenazi) population today...probably in the order of 100 independent chromosomes,'' because they enjoyed better nutrition and had lower infant mortality rates than less affluent Jews.... For religious and historical reasons, most Ashkenazi Jews married within their community, a phenomena that Darvasi said shows up in the Ashkenazi genes he studies which tend to have a high degree of similarity."

Stanford University Medical Center. "Stanford Research Points To Chance As Cause Of Genetic Diseases In Ashkenazi Jews." Press Release. February 28, 2003. Excerpts:

"Some disease mutations unusually common in Ashkenazi Jews... include Tay-Sachs disease and some forms of breast cancer, high cholesterol and hemophilia. ... It just happened that those who founded the Ashkenazi Jewish population had disease mutations and passed them along to their children. Because Ashkenazi Jews tend to marry within their own population, those mutations remained common.... He [Dr. Neil Risch of Stanford University Medical Center, working with colleagues] found three points in time when mutations entered the population. One mutation has been in the Jewish population for 120 generations - around the time that the Jewish people formed a distinct population in the Middle East. This mutation causes a type of hemophilia called Factor 11 deficiency type II. The majority of the mutations - including all of the mutations in lysosomal storage genes - entered the population when the Ashkenazi Jews formed a coherent group about 50 generations ago. The final mutations cropped up in the Lithuanian Ashkenazi Jews about 12 generations ago."

Lauren John. "Genetic Diseases in Ashkenazi Jews." GeneticHealth.com (2000). Excerpts:

"Scholars disagree about how the Jews, living for thousands of years in the Middle East, first arrived in Eastern Europe.... Stanford University geneticist Neil Risch explains the range of genetic diseases unique to the Ashkenazi Jewish population by theorizing that most of today's Ashkenazi Jews descend from a group of perhaps only a few thousand people -- the privileged Ashkenazi that lived 500 years ago in Eastern Europe."

David Pollack. "Studies Casting New Light On Origin of Europe's Jews: Stanford's Risch Puts Mythic Theory To Rest." Forward (August 17, 2001). The subtitle of the article, using the word "mythic" and with its quick "end" to a complicated debate, is the most biased I have ever seen. Jews have lived in Lithuania since at least the 14th century. The fact that a mutation for idiopathic torsion dystonia first occurred around the 16th-17th centuries does not necessarily have a bearing upon Lithuanian Jewish origins. Other problems with the article are that Risch's comments contradict the results of genetic studies that show that Ashkenazi Jews are closely related not only to Arabs but also to Anatolian Turks, and that mtDNA studies are not discussed. Excerpts:

"....Dr. Neil Risch, a researcher at the Department of Genetics at Stanford University, is at the forefront of a field that has brought evidence that may help to break the deadlock between historians who argue over the history and makeup of Ashkenazi Jewry.... Among the theories seeking to explain the origins of the Ashkenazim is a theory propagated by the late writer Arthur Koestler. Koestler contended that the predecessors of Ashkenazi Jews did not originate in Palestine, but rather in Khazaria, a medieval empire populated by a people of Turkish stock whose nobility converted to Judaism.... But... geneticists such as Dr. Risch defend the traditional history of Jewish origin. 'If you made a [genetic] map of Europe and the Middle East and you put Ashkenazi Jews on it,' Dr. Risch said, 'they would not end up in Turkey or in the middle of Europe, but in the Mediterranean.' ...Dr. Risch studies the mutated genes that cause some of the diseases commonly found in the Ashkenazi Jewish population. In 1995, he and a team of other researchers investigated the history of idiopathic torsion dystonia, a movement disorder that affects the Jewish population at a much higher frequency than it does any gentile population. Using the family history of his patients and a dating technique called linkage disequilibrium analysis, Dr. Risch determined that the mutation arose less than four centuries ago in present-day Lithuania and Byelorussia. In the paper, Dr. Risch notes that the mutation 'first appeared approximately 350 years ago ... [and] that the carriers preferentially originate from the northern part of the historic Jewish Pale of settlement.' The fast proliferation of the disease, Dr. Risch argues, can be explained by the migratory patterns of the population. 'Our data from that study,' he said, 'suggests that there was a 'bottleneck' during the period of time that the Ashkenazi Jews went into Lithuania.... It could either be that the mutation first arose at that time, or, more likely, that it was carried by somebody who, by chance, had a lot of children.' Accepting the latter scenario, Dr. Risch rejects the possibility that the Khazar migration could have brought the mutation - which, according to Dr. Risch's study, now exists at a frequency 'between 1 in 6,000 to 1 in 2,000 in Ashkenazi Jews' - in the population. 'I'm not sure I would make that argument,' Dr. Risch said. 'The timing is wrong. The mutation that causes torsion dystonia entered the Ashkenazi population 400 or 500 years ago at the most, rather than the much earlier time that the Khazars probably migrated.' Dr. Risch's more recent work in the field provides further evidence in support of the traditional theory of Jewish history. In a study published in April of last year, Dr. Risch and another team of researchers analyzed two mutations that cause Gaucher disease, a storage disorder that is more widespread in the Jewish population than is dystonia. Finding that the mutations had a longer history than that which causes dystonia, Dr. Risch also noted that the disease is not restricted to the Jewish population. 'We dated one mutation to the period of time that the Ashkenazi population probably first coalesced as a distinct group, 1,100 or 1,200 years ago,' Dr. Risch said. 'We also have evidence that the other mutation actually predates the formation of the Ashkenazi Jews because it exists in non-Jews also. It has a reasonable frequency in the Portuguese community and exists in many Caucasian groups.' To Dr. Risch, these facts place the antecedents of today's Ashkenazi Jewish population in Central Europe, and not Khazaria, during the Middle Ages. 'My interpretation is that this evidence is more in line with the founding of the Ashkenazi population in Central Europe,' he said. 'The Khazar contribution to the Ashkenazi gene pool is probably not that significant.' Dr. Harry Ostrer, a researcher in the Department of Genetics at New York University Medical School, contends that the Ashkenazi Jewish population is undoubtedly closer to other Jewish populations, at least genetically, than it is to non-Jewish groups outside the Middle East.... Another finding of Dr. Ostrer's study is that while the Ashkenazi Jews are not very close genetically to European gentiles, they are genetically close to some Arab groups. Reinforcing this evidence is a study by Aravinda Chakravarti, director of the McKusick-Nathans Institute of Genetic Medicine at Johns Hopkins University, who found that a certain genetic mutation causing deafness, DFNB1, affects Jews, Palestinians and other groups of the Mediterranean."
A letter in response to David Pollack's article was published in Forward's August 31, 2001 issue.

In the January 22, 1998 issue of the Northern California Jewish Bulletin, Dr. Risch was quoted as saying: "Several studies have shown that Ashkenazi Jews have a unique genetic make-up."

Studies on beneficial/protective mutations

Protection Against AIDS

Marc M. Buhler, Anne Proos, Viive Howell, Bruce H. Bennetts, Leslie Burnett, and Graeme J. Stewart. "Could Admixture of the CCR5-D32 Allele into Ashkenazi Jews and Vikings be Explained by an Origin in the Kingdom of the Khazars?" Papers of the XIX International Congress of Genetics (Melbourne, Australia, July 2003); also scheduled for publication in a journal. The D in D32 represents the Greek letter Delta both in the presentation title above and in the abstract below. Abstract:

"CCR5 is the major co-receptor for viral entry used by macrophage-tropic HIV strains and protection from infection is seen in homozygotes for the 32-basepair deletion mutation CCR5-D32. Global surveys of the CCR5--D32 allele have confirmed a single mutation event in a Northeastern European population as the source of this allele. While the initial population survey of CCR5--D32 showed the highest frequency in Ashkenazi Jews and another study did support this, other reports including Ashkenazi samples have not shown such increase. Here, Australian Ashkenazi Jews (n = 807) were found to have a CCR5--D32 allele frequency of 14.6% while Australian Sephardic Jews (n = 35) had a frequency of 5.7% and non-Jewish Australian controls (n = 311) had an allele frequency of 11.25%. Homozygotes (n = 23) for CCR5--D32 were genotyped with 3p21 region microsatellites including D3S4579, D3S4580, D3S3559, D3S663, D3S1578, afmb362wb9 and chlc.gaat12d11. This defined an ancestral haplotype on which the mutation first occurred and helped to date this event to about 50 generations, or just over a thousand years ago. Data on birthplace of grandparents showed a gradient with highest CCR5--D32 frequencies from Eastern European Ashkenazim (~19.5% for those whose four grandparents come only from Russia, Poland, Hungary, Austria and Czechoslovakia; n = 197) which differs significantly from the frequency seen in Ashkenazi Jews from Western Europe (n = 101, p = 0.001). This gradient, combined with the dating of the mutation by microsatellite allele frequencies, suggests an origin for the CCR5--D32 allele in the kingdom of Khazaria with subsequent admixture into both Swedish Vikings and Ashkenazi Jews."

Deborah Smith. "From an ancient kingdom, the mutant that can fight off AIDS." The Sydney Morning Herald (July 12, 2003). Excerpts:

"It's a story about ... a genetic mutation that arose in just one person who was probably living in the lost Kingdom of Khazars in southern Russia more than 1200 years ago. Today the mutation is widespread among Caucasians and helps protect carriers against infection with the AIDS virus. Marc Buhler, a Sydney geneticist, has pieced together this colourful history of the mutation's origins to explain its particularly high prevalence in populations as disparate as Jewish people in Australia and people living in Iceland. The mutation, in a gene known as CCR5, was discovered in 1996. People with one copy usually take several years to become ill if they acquire HIV. People with two copies rarely become infected. Mr Buhler ... tested DNA from about 1400 Australians and found about 15 per cent of Ashkenazi Jews (from Germany and Eastern Europe) were carriers, but only 6 per cent of Sephardic Jews (from southern Europe and Africa). ... he found about 20 per cent of Ashkenazi Jews had the mutation if their grandparents had come from Russia, Poland, Hungary or Czechoslovakia. ... But how to explain its prevalence in Iceland and other Nordic countries? ... If a person in Khazar had developed the CCR5 mutation it would have spread back to Scandinavia with the Vikings [suggested Buhler]."
Observations:
Marc Buhler indicates that the article contains erroneous statistics: "the values in the article are given for individuals where I was describing alleles (so there are twice the value cited, so to speak). What the writer of that article did was take 'allele frequencies' and put them in terms of individuals. Each person has two alleles, so to speak, but that was not corrected for." Buhler also provides the following specific data about his study: "Of 807 Australian Ashkenazi Jews, 216 individuals (26.6%, i.e. about 1 in 4) carried the deletion. 197 were 'heterozygoytes', that is carriers with one wild-type allele and one allele with the deletion. 19 were 'homozygotes' for the allele. In terms of allele frequency, these 807 individuals have 1614 alleles in total and the allele frequency of the deletion was 14.6% ( (38+197) / 1416 ) since all homozygotes have two of the alleles and heterozygotes have one. The general frequency found for European caucasian groups is an allele frequency of about 10% (or about one in five individuals). This frequency is slightly greater in countries to the north and east of Europe. An allele frequency of ~15% was reported for Iceland, and Sweden has three reports of about 14%. The allele frequency I reported for the Sephardic Jews was 5.7% or just over 1 in 10 individuals. When the grandparents of the individuals we tested came from a group of countries (Russia, Poland, Austria, Czechoslovakia, or Hungary) the frequency was seen to be 19.5%. (197 individuals with 30% carriers and 4.6% homozygotes, or 1 out of 3 individuals.) Note that 'Austria' somehow dropped from the SMH report. Elevated frequency of Ashkenazi Jews from Eastern Europe was initally reported by Martinson in 1997 (~21% allele frequency for 43 Ashkenazi) and also reported by Lucotte, but our numbers are quite large. The Australian Ashkenazi Jews with grandparents from Western Europe had an allele frequency more in line with the general caucasian frequency. Of 123 Western Europe Ashkenazi, an allele frequency of 11.8% was seen (about one in five individuals). Our non-Jewish Australian sample was of 311 individuals and the allele frequency was 11.3%. ...[I]n general, the Middle East groups, while often not zero, are still just a few percent and not as high as the ~10% seen in European caucasians and certainly not above that. One group that has been pointed out with an elevated frequency are the Mordvinians (reported allele frequency of ~17%)."

Other studies have shown that the CCR5-D32 allele appears to have a protective effect not only against HIV infection, but also rheumatoid arthritis and smallpox, and possibly also multiple sclerosis, Crohn's Disease, and type 1 diabetes.

See also the July 25, 2003 news release from the University of Sydney by Alison Handmer.

Laura Spinney. "HIV protection via the Vikings?" BioMedNet News (July 23, 2003). Excerpts:

"A common genetic mutation that confers protection against HIV and possibly also multiple sclerosis and type 1 diabetes may have arisen over 1000 years ago in a lost kingdom in what is now Russia, according to an Australian geneticist. Marc Buhler of the Institute for Immunology and Allergy Research at the University of Sydney thinks that the delta32 deletion mutation in the CCR5 gene is now a target for selection because it protects against certain strains of HIV, but that initially it may have been selected for because carriers survived small pox... The CCR5-delta32 mutation is particularly common among Ashkenazi Jews... among Ashkenazis from Western Europe, for instance, it occurs with the same frequency as in Caucasian non-Jews... He then genotyped the 26 Ashkenazi Jewish individuals who turned out to be homozygous for the mutation, and measured the degree of recombination that had taken place in the region in which the mutation occurs to come up with an estimate of when the mutation first arose. To his surprise, his calculations generated an age of 50 generations, or just over 1000 years. The Ashkenazi Jews left Israel around 2000 years ago... Since the mutation is not common among the Sephardic Jews who stayed in the Middle East, and since it appears to be older than the Ashkenazis' Germanic period - the last time they were concentrated as a population - Buhler surmises that it had its origins elsewhere [other than Germany]. There were several other pieces to fit into the jigsaw: for instance, the incidence of CCR5-delta32 is relatively high among Scandinavians... When he gathered information about his Ashkenazi volunteers' forebears, he found that the frequency of the mutation leapt to 20% in a subgroup whose grandparents came from Russia or Eastern Europe - almost 10% higher than the frequency among Western European Ashkenazis... Since small pox kills around one third to a half of its untreated victims, Buhler says selection would have been very strong for CCR5-delta32 if heterozygotes did indeed avoid death... [U]pper class Khazars adopted Judaism in the mid-10th century... 'The Jewish Khazars had the main block of the mutation,' says Buhler, 'But a few [Khazar] slaves kidnapped by the Vikings would have been enough for them to take it away as a souvenir.' Khazaria ceased to exist around the 13th century, when it was absorbed by Russia, and from then on the Khazar Jews would have blended with the Ashkenazi ancestors of Buhler's Australian volunteers."

"Geneticist finds Ashkenazi immunity." Australian Jewish News (August 22, 2003). Excerpts:

"...In a study of 1400 subjects, Marc Buhler found that Jews originating from Austria, Hungary, Czechoslovakia, Poland and Russia are prone to carry CCRS-delta 32 - a gene modifier that alters the immune system. ...Buhler said that the gene modifier fends off the symptoms of HIV/AIDS for anywhere between four years and a lifetime. ... Presented in Melbourne at the International Congress of Genetics, the study found CCRS-delta 32 in as many as 35 per cent of Jewish subjects originating from Austria, Hungary, Czechoslovakia, Poland and Russia. The proportion for non-Jewish subjects hailing from that part of the world was around 25 per cent. However, Jews from other parts of Europe, Asia and the Middle East are no more likely to carry the gene modifier than their non-Jewish counterparts from the same region, he said. CCRS-delta 32 was also discovered in nearly 30 per cent of subjects from Iceland - an observation that prompted Buhler to speculate that the mutation first emerged among medieval Russian Jewish communities and was spread to Northern Europe by the Vikings. Buhler believes that the first carrier of the gene mutation was probably born in Khazaria (in Southern Russia) between 800 and 1000AD. ... Buhler said that CCRS-delta 32 may have also protected Jews against the smallpox. The gene modifier has thrived, he said, because it can ward off adverse symptoms and keep carriers alive long enough to procreate."

"Um reino perdido e o HIV." O Globo (August 4, 2003): Ciência e Vida, Segunda-feira. Excerpt:

"Um geneticista australiano apresentou uma das mais interessantes teses sobre a origem de uma mutação genética cujos portadores apresentam maior resistência à Aids. A mutação no gene CCR5 chama-se delta 32. Após analisar amostras genéticas e mergulhar em livros de história, Marc Buhler, da Universidade de Sydney, concluiu que ela vem do esquecido reino de Khazaria, que existiu até o século XIII, na região que hoje é o sul da Rússia. Buhler chegou à Khazaria através da análise de DNA de judeus ashkenazes, população que apresenta a maior incidência da mutação protetora. Ela teria sido naturalmente selecionada por proteger também contra a varíola. Os judeus migraram em massa para Khazaria por volta do século XI. A tese é interessante, mas Buhler ainda precisará de mais provas."

Protection Against Alcoholism

David Derbyshire. "Gene helps Jews resist alcoholism." The Daily Telegraph (U.K., September 17, 2002). Excerpts:

"A study has shown that a genetic mutation carried by at least a fifth of Jews appears to protect against alcoholism. The same inherited trait is fairly common in Asian people, but is much rarer in white Europeans.... The study's author, Dr Deborah Hasin, from Columbia University and New York State Psychiatric Institute, said: 'This finding adds to the growing body of evidence that this genetic variation has a protective effect against alcoholism among Jewish groups.' The mutation, called ADH2*2, is involved in the way the body breaks down alcohol in the bloodstream.... Almost all white Europeans lack the ADH2*2 variation.... Past research has shown that the variant is found in 20 per cent of Jewish people. Those with the variant tend to drink less frequently, consume less alcohol overall or have more unpleasant reactions to drink. The new study, published today in the journal Alcoholism: Clinical and Experimental Research, looked at the relationship between the gene variant and alcoholism among 75 Israeli Jews aged 22 to 65."

Deborah Hasin, Efrat Aharonovich, Xinhua Liu, Ziona Mamman, Karen Matseoane, Lucinda G. Carr, and Ting-Kai Li. "Alcohol dependence symptoms and Alcohol Dehydrogenase 2 Polymorphism: Israeli Ashkenazis, Sephardics and recent Russian immigrants." Alcoholism: Clinical Experimental Research 26 (2002): pages 1315-1321.

Deborah Hasin, Efrat Aharonovich, Xinhua Liu, Ziona Mamman, Karen Matseoane, Lucinda G. Carr, and Ting-Kai Li. "Alcohol and ADH2 in Israel: Ashkenazis, Sephardics and recent Russian Immigrants." American Journal of Psychiatry 159 (2002): pages 1432-1434.


Of related interest:

  • About Jewish Genetic Disorders


    Jewish Genetics: Abstracts and Summaries - Index

    Books About Jewish Genetics