Gaucher Disease: The N370S Mutation in Ashkenazi Jewish and Spanish Patients has a Common Origin and Arose Several Thousand Years Ago
1999; Elsevier BV; Volume: 64; Issue: 4 Linguagem: Inglês
10.1086/302341
ISSN1537-6605
AutoresAnna Dı́az, Baijin Zeng, Gregory M. Pastores, Amparo Chabás, Lluı̈sa Vilageliu, Magda Montfort, Bru Cormand, Daniel Grinberg,
Tópico(s)Glycogen Storage Diseases and Myoclonus
ResumoTo the Editor: The identification of highly polymorphic markers, which are widely distributed throughout the human genome, has allowed the mapping of several disease genes. These markers have been used to analyze the origin, in time and place, of the most prevalent mutations for different diseases, such as cystic fibrosis (Morral et al. Morral et al., 1994Morral N Bertranpetit J Estivill X Nunes V Casals T Gimenez J Reis A et al.The origin of the major cystic fibrosis mutation (delta F508) in European populations.Nat Genet. 1994; 7: 169-175Crossref PubMed Scopus (283) Google Scholar), idiopathic torsion dystonia (Risch et al. Risch et al., 1995Risch N Deleon D Ozelius L Kramer P Almasy L Singer B Fahn S et al.Genetic analysis of idiopathic torsion dystonia in Ashkenazi Jews and their recent descent from a small founder population.Nat Genet. 1995; 9: 152-159Crossref PubMed Scopus (341) Google Scholar), hereditary colon cancer (Moisio et al. Moisio et al., 1996Moisio AL Sistonen P Weissenbach J de la Chapelle A Peltomäki P Age and origin of two common MLH1 mutations predisposing to hereditary colon cancer.Am J Hum Genet. 1996; 59: 1243-1251PubMed Google Scholar), factor XI deficiency (Peretz et al. Peretz et al., 1997Peretz H Mulai A Usher S Zivelin A Segal A Weisman Z Mittelman M et al.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. 1997; 90: 2654-2659PubMed Google Scholar), and myotonic dystrophy (Tishkoff et al. Tishkoff et al., 1998Tishkoff SA Goldman A Calafell F Speed WC Deinard AS Bonne TB Kidd JR et al.A global haplotype analysis of the myotonic dystrophy locus: implications for the evolution of modern humans and for the origin of myotonic dystrophy mutations.Am J Hum Genet. 1998; 62: 1389-1402Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar). We present the analysis of the origin of N370S, the most common Gaucher disease (GD) mutation among Ashkenazi Jewish and Spanish patients. The results show that both patient populations share the same ancestral haplotype and that this mutation arose several thousand years ago. GD (MIM 230800), caused by mutations in the glucocerebrosidase (GBA) gene, is the most prevalent lysosomal storage disease. It is inherited as an autosomal recessive trait, which is particularly frequent in the Ashkenazi Jewish population, with a disease incidence of ∼1/850 (Beutler and Grabowski Beutler and Grabowski, 1995Beutler E Grabowski GA Gaucher disease.in: Scriver CR Beaudet AL Sly WS Valle D The metabolic and molecular bases of inherited disease. 7th ed. McGraw-Hill, New York1995: 2641-2669Google Scholar). It is also found in other populations, albeit with lower frequency, with a range of 1/40,000–1/60,000 (Grabowski Grabowski, 1993Grabowski GA Gaucher disease: enzymology, genetics, and treatment.in: Harris H Hirschhorn K Advances in human genetics. Vol 21. Plenum Publishing, New York1993: 377-441Google Scholar). Among Ashkenazi Jewish patients with GD, ∼70% of the alleles carry the N370S (1226A→G) mutation (Beutler et al. Beutler et al., 1992aBeutler E Gelbart T Kuhl W Zimran A West C Mutations in Jewish patients with Gaucher disease.Blood. 1992a; 79: 1662-1666PubMed Google Scholar; Horowitz et al. Horowitz et al., 1993Horowitz M Tzuri G Eyal N Berebi A Kolodny EH Brady RO Barton NW et al.Prevalence of 9 mutations among Jewish and non-Jewish Gaucher disease patients.Am J Hum Genet. 1993; 53: 921-930PubMed Google Scholar; Sibille et al. Sibille et al., 1993Sibille A Eng CM Kim SJ Pastores G Grabowski GA Phenotype/genotype correlations in Gaucher disease type I: clinical and therapeutic implications.Am J Hum Genet. 1993; 52: 1094-1101PubMed Google Scholar). It appears that approximately two-thirds of the individuals homozygous for this mutation escape detection because of the very mild clinical manifestation; thus, the N370S frequency in the Ashkenazi Jewish population is higher, ∼90% of all GD mutations (Beutler et al. Beutler et al., 1993Beutler E Nguyen NJ Henneberger MW Smolec JM McPherson RA West C Gelbart T Gaucher disease: gene frequencies in the Ashkenazi Jewish population.Am J Hum Genet. 1993; 52: 85-88PubMed Google Scholar; Grabowski Grabowski, 1997Grabowski GA Gaucher disease: gene frequencies and genotype/phenotype correlations.Genet Test. 1997; 1: 5-12Crossref PubMed Scopus (131) Google Scholar). This mutation is also frequent in other populations of patients with GD, particularly among Spanish patients, in whom it accounts for > 40% of the mutant alleles (Cormand et al. Cormand et al., 1995Cormand B Vilageliu L Burguera JM Balcells S Gonzàlez-Duarte R Grinberg D Chabás A Gaucher disease in Spanish patients: analysis of eight mutations.Hum Mutat. 1995; 5: 303-309Crossref PubMed Scopus (45) Google Scholar, Cormand et al., 1998Cormand B Grinberg D Gort L Chabás A Vilageliu L Molecular analysis and clinical findings in the Spanish Gaucher disease population: putative haplotype of the N370S ancestral chromosome.Hum Mutat. 1998; 11: 295-305Crossref PubMed Scopus (53) Google Scholar). We have recently mapped the GBA gene in relation to several highly polymorphic markers (Cormand et al. Cormand et al., 1997Cormand B Montfort M Chabás A Vilageliu L Grinberg D Genetic fine localization of the beta glucocerebrosidase (GBA) and prosaposin (PSAP) genes: implications for Gaucher disease.Hum Genet. 1997; 100: 75-79Crossref PubMed Scopus (24) Google Scholar), which were then used to identify a putative ancestral haplotype associated with the N370S mutation in chromosomes from Spanish patients (Cormand et al. Cormand et al., 1998Cormand B Grinberg D Gort L Chabás A Vilageliu L Molecular analysis and clinical findings in the Spanish Gaucher disease population: putative haplotype of the N370S ancestral chromosome.Hum Mutat. 1998; 11: 295-305Crossref PubMed Scopus (53) Google Scholar). Preliminary studies of a few Argentinian patients with GD, of Ashkenazi Jewish origin, showed that they have the same conserved haplotype as the Spanish patients with GD. This prompted us to perform the present study on DNA isolated from 66 unrelated Ashkenazi Jewish patients with GD of central and eastern European descent living in the United States, who were evaluated at the New York University Medical Center, and 14 Spanish patients with GD who were referred from different hospitals around Spain and enzymatically diagnosed at the Institut de Bioquímica Clínica in Barcelona. Both groups of patients bore the N370S mutation. A total of 104 N370S Ashkenazi Jewish chromosomes and 20 N370S Spanish chromosomes were analyzed. Forty healthy Ashkenazi Jewish individuals from the United States were used as controls, and CEPH family data were used as non-Jewish controls. The distances (in terms of recombination fractions [θ]) between the markers used for haplotyping and the GBA gene (Cormand et al. Cormand et al., 1997Cormand B Montfort M Chabás A Vilageliu L Grinberg D Genetic fine localization of the beta glucocerebrosidase (GBA) and prosaposin (PSAP) genes: implications for Gaucher disease.Hum Genet. 1997; 100: 75-79Crossref PubMed Scopus (24) Google Scholar) are shown in table 1. Linkage analysis between the GBA gene and one of these markers, D1S1595, has not been previously described (maximum LOD score of 9.33 at θ=.00). Since meiotic mapping showed insufficient resolution capacity for markers closest to the GBA gene (D1S2140, D1S2777, D1S1595, and D1S2721), the Stanford G3 radiation hybrid (RH) panel (Research Genetics) was used to estimate the distances between these markers and the GBA gene. Following Cox et al. (Cox et al., 1990Cox DR Burmeister M Price ER Kim S Myers RM Radiation hybrid mapping: a somatic cell genetic method for constructing high-resolution maps of mammalian chromosomes.Science. 1990; 250: 245-250Crossref PubMed Scopus (573) Google Scholar) and Moisio et al. (Moisio et al., 1996Moisio AL Sistonen P Weissenbach J de la Chapelle A Peltomäki P Age and origin of two common MLH1 mutations predisposing to hereditary colon cancer.Am J Hum Genet. 1996; 59: 1243-1251PubMed Google Scholar), a 1 cR/50 kb ratio was used to calculate the distance in centimorgans (900 kb/1 cM), which we transformed into θ values using the Haldane map function. Hybrid DNA was amplified by PCR using standard protocols. Primers used to detect the presence of the GBA gene were as follows: forward, 5′-AACCATGATTCCCTATCTTC-3′; reverse, 5′-GAGGCACATCCTTAGAGGAG-3′. As noted by Moisio et al. (Moisio et al., 1996Moisio AL Sistonen P Weissenbach J de la Chapelle A Peltomäki P Age and origin of two common MLH1 mutations predisposing to hereditary colon cancer.Am J Hum Genet. 1996; 59: 1243-1251PubMed Google Scholar), RH mapping generally yields greater distances between marker loci than does meiotic mapping.Table 1Distances by RH and Meiotic Mapping between the GBA Gene and 1q21 Markers and Estimated Age of the N370S MutationRH MappingMeiotic MappingMarkerDistance (cR/θaObtained from the cR value, assuming 1 cR = 50 kb and 900 kb = 1 cM, and then by use of Haldane map function.)Age of the Mutation (Years/Generations)bAge of the mutation estimated in number of generations, by use of the formula by Risch et al. (1995). Years calculated assuming 25 years/generation.Distance (θ)Age of the Mutation (Years /Generations)bAge of the mutation estimated in number of generations, by use of the formula by Risch et al. (1995). Years calculated assuming 25 years/generation.D1S30545.0/.0241,100/44.0231,300/52D1S214039.4/.0222,675/107.0…D1S277719.8/.01112,675/507.0…D1S159543.8/.0243,125/125.0…D1S272155.0/.030950/38.0…D1S262467.2/.0374,225/169.0259,525/381a Obtained from the cR value, assuming 1 cR = 50 kb and 900 kb = 1 cM, and then by use of Haldane map function.b Age of the mutation estimated in number of generations, by use of the formula by Risch et al. (Risch et al., 1995Risch N Deleon D Ozelius L Kramer P Almasy L Singer B Fahn S et al.Genetic analysis of idiopathic torsion dystonia in Ashkenazi Jews and their recent descent from a small founder population.Nat Genet. 1995; 9: 152-159Crossref PubMed Scopus (341) Google Scholar). Years calculated assuming 25 years/generation. Open table in a new tab Previously, we reported a common disease haplotype in Spanish patients with GD bearing the N370S mutation (Cormand et al. Cormand et al., 1998Cormand B Grinberg D Gort L Chabás A Vilageliu L Molecular analysis and clinical findings in the Spanish Gaucher disease population: putative haplotype of the N370S ancestral chromosome.Hum Mutat. 1998; 11: 295-305Crossref PubMed Scopus (53) Google Scholar). Analyses of 66 Ashkenazi Jewish patients and five additional Spanish patients with GD, using six microsatellite markers, revealed that most of the Jewish and Spanish N370S chromosomes share alleles for five of these markers. Figure 1a shows the haplotype of the 73 Ashkenazi Jewish N370S chromosomes, of the 104 analyzed, for which the phase had been established for all the markers (phases were determined by use of samples from parents and/or siblings). Forty-three (59%) have a conserved haplotype for markers D1S2140, D1S2777, D1S1595, D1S2721, and D1S2624. Marker D1S305 presented many different alleles and was not included in figure 1, to allow sample grouping. If the more distant marker D1S2624 (see meiotic mapping, table 1) is excluded, the proportion of chromosomes with a conserved haplotype rises to 68 (93%) of 73. If only the three markers closest to GBA—D1S2140, D1S2777, and D1S1595, according to RH mapping (see table 1)—are considered, this proportion is increased to 69 (94.6%) of 73. The same analysis of 18 Spanish N370S chromosomes for which the phase is known, is shown in figure 1b. Two chromosomes were excluded because phase could not be established for all the markers. The haplotype for the three closest markers mentioned above is conserved in 16 (88.9%) of 18 of the chromosomes. In addition, all Ashkenazi Jewish and Spanish N370S alleles bear the "−" allele for the HhaI site (data not shown), which corresponds to an adenine at genomic position 6144, one of the GBA internal polymorphisms (Beutler et al. Beutler et al., 1992bBeutler E West C Gelbart T Polymorphisms in the human glucocerebrosidase gene.Genomics. 1992b; 12: 795-800Crossref PubMed Scopus (58) Google Scholar). Table 2 shows the allele frequencies and linkage disequilibrium (LD) analysis for markers in chromosomes bearing the N370S mutation in Ashkenazi Jewish and Spanish patients and in the control population. The degree of LD was assessed by the parameter δ [δ=(pD-pN)/(1-pN)], in which pD is the frequency of the associated allele on disease chromosomes and pN is the frequency of the same allele on normal chromosomes, as in the study by Risch et al. (Risch et al., 1995Risch N Deleon D Ozelius L Kramer P Almasy L Singer B Fahn S et al.Genetic analysis of idiopathic torsion dystonia in Ashkenazi Jews and their recent descent from a small founder population.Nat Genet. 1995; 9: 152-159Crossref PubMed Scopus (341) Google Scholar), and statistical significance was measured by the χ2 test. All markers were found to be in strong LD with the N370S mutation in Ashkenazi Jewish patients (P<.001), except marker D1S305, for which the significance is very low (P<.05). For the Spanish chromosomes, only the central markers (D1S2140, D1S2777, D1S1595, and D1S2721) are in marked LD with the N370S mutation. The fact that the highest values of δ, in both patient populations, correspond to markers D1S2140, D1S2777, D1S1595, and D1S2721, is consistent with meiotic mapping, which places the GBA gene at a distance of θ=.0 (see table 1). LD for the five markers (all except D1S305) was confirmed in the Ashkenazi Jewish patients, with the D′=D/Dmax standardized coefficient (Lewontin Lewontin, 1988Lewontin RC On measures of gametic disequilibrium.Genetics. 1988; 120: 849-852PubMed Google Scholar) and the likelihood ratio test described by Terwilliger (Terwilliger, 1995Terwilliger JD A powerful likelihood method for the analysis of linkage disequilibrium between trait loci and one or more polymorphic marker loci.Am J Hum Genet. 1995; 56: 777-787PubMed Google Scholar) (data not shown), since this information was relevant for the dating analysis.Table 2Haplotype and LD Analyses in N370S Chromosomes of Ashkenazi Jewish and Spanish PatientsFrequency of Ashkenazi Jewish ChromosomesFrequency of Spanish ChromosomesMarkerAlleleN370SControlsχ2 (P value)δN370SControlsaCEPH data.χ2 (P value)δD1S305158.6 (41/70)40.0 (32/80)5.2 (P<.05).3147.4 (9/19)23.2 (13/56)4.0 (P<.05).31D1S2140495.6 (86/90)47.5 (38/80)49.6 (P<.001).9290.0 (18/20)30.4 (17/56)21.1 (P<.001).86D1S2777197.8 (89/91)63.8 (51/80)33.3 (P<.001).9490.0 (18/20)57.1 (32/56)7.1 (P<.01).77D1S1595592.8 (77/83)45.0 (36/80)43.7 (P<.001).8790.0 (18/20)28.2 (35/124)28.3 (P<.001).86D1S2721393.6 (88/94)33.8 (27/80)69.1 (P<.001).9070.0 (14/20)23.1 (12/52)13.8 (P<.001).61D1S2624457.8 (52/90)20.0 (16/80)25.2 (P<.001).4720.0 (4/20)17.9 (10/56).05 (NS)bNS = not significant..03a CEPH data.b NS = not significant. Open table in a new tab To date the N370S mutation among the Ashkenazi Jewish patients, we applied the following formula by Risch et al. (Risch et al., 1995Risch N Deleon D Ozelius L Kramer P Almasy L Singer B Fahn S et al.Genetic analysis of idiopathic torsion dystonia in Ashkenazi Jews and their recent descent from a small founder population.Nat Genet. 1995; 9: 152-159Crossref PubMed Scopus (341) Google Scholar): g=log[(1-Q)/(1-pN)]log(1-θ)·log(δ)log(1-θ),in which g is the number of generations, Q is the probability that an N370S-bearing chromosome does not carry a progenitor marker allele, and pN and δ are as described above. The estimation of the age of the mutation is based on the calculated distance between the gene of interest and the flanking markers. Marker D1S2624 is the only one for which the distance to the gene could be estimated by both meiotic and RH mapping (table 1), and it is in LD with the mutation (marker D1S305 is not). Using these estimated distances for marker D1S2624, we obtained a result of 381 or 169 generations, respectively, and, assuming 25 years/generation, an estimated age for the N370S mutation of ∼9,500 or 4,200 years, with an average of ∼7,000 years. The values for the rest of the markers are shown in table 1. To conclude, a similar haplotype was found to be associated with the common N370S mutation in the Spanish and Ashkenazi Jewish patients. This suggests a common origin for the mutation. The high frequency of particular mutations among Ashkenazi Jews has been explained either by a selective advantage of heterozygote carriers or by a founder effect and genetic drift (Motulsky Motulsky, 1995Motulsky AG Jewish diseases and origins.Nat Genet. 1995; 9: 99-101Crossref PubMed Scopus (100) Google Scholar; Peretz et al. Peretz et al., 1997Peretz H Mulai A Usher S Zivelin A Segal A Weisman Z Mittelman M et al.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. 1997; 90: 2654-2659PubMed Google Scholar). Our data strongly support a founder effect as opposed to recurrence of the N370S mutation: all the chromosomes with this mutation had the "−" allele for the GBA internal HhaI-site polymorphism, and most of them share the alleles for several markers close to the gene. The few exceptions could be explained by historic recombinations. Although a new occurrence of N370S cannot be ruled out, it seems very unlikely. If we assume a founder effect, both genetic drift and selective advantage could explain the expansion of the mutated allele in the population. Our data do not contribute to this discussion, which is beyond the scope of the present work. Several studies have attempted to date mutations for diseases that are prevalent among the Ashkenazi Jews, such as idiopathic torsion dystonia (Risch et al. Risch et al., 1995Risch N Deleon D Ozelius L Kramer P Almasy L Singer B Fahn S et al.Genetic analysis of idiopathic torsion dystonia in Ashkenazi Jews and their recent descent from a small founder population.Nat Genet. 1995; 9: 152-159Crossref PubMed Scopus (341) Google Scholar), familial dysautonomia (Blumenfeld et al. Blumenfeld et al., 1993Blumenfeld A Slaugenhaupt SA Axelrod FB Lucente DE Maayan C Liebert CB Ozelius LJ et al.Localization of the gene for familial dysautonomia on chromosome 9 and definition of DNA markers for genetic diagnosis.Nat Genet. 1993; 4: 160-164Crossref PubMed Scopus (125) Google Scholar), Bloom syndrome (Ellis et al. Ellis et al., 1994Ellis NA Roe AM Kozloski J Proytcheva M Falk C German J Linkage disequilibrium between the FES, D15S127, and BLM loci in Ashkenazi Jews with Bloom syndrome.Am J Hum Genet. 1994; 55: 453-460PubMed Google Scholar), and factor XI deficiency (Peretz et al. Peretz et al., 1997Peretz H Mulai A Usher S Zivelin A Segal A Weisman Z Mittelman M et al.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. 1997; 90: 2654-2659PubMed Google Scholar). Whereas the dystonia mutation seems to have occurred ∼300 years ago, one of the mutations causing factor XI deficiency is supposed to be quite old (>2,000 years), as determined on the basis of the shared haplotype found among Ashkenazi and Iraqi Jews. Our data provide information on the most frequent mutation in GD, N370S, which occurred several thousand years ago. It should be noted that the method of dating the mutation is subject to statistical fluctuation resulting from sampling variance and from uncertainty in the estimates of θ (Risch et al. Risch et al., 1995Risch N Deleon D Ozelius L Kramer P Almasy L Singer B Fahn S et al.Genetic analysis of idiopathic torsion dystonia in Ashkenazi Jews and their recent descent from a small founder population.Nat Genet. 1995; 9: 152-159Crossref PubMed Scopus (341) Google Scholar); therefore any accuracy beyond an estimation of several thousand years for the age of the mutation is meaningless. However, the relatively short length of the chromosomal region in which LD is conserved strongly supports the idea of an ancient origin for the N370S mutation. The data presented here suggest a common origin for this mutation in the Ashkenazi Jewish and Spanish patient populations. It could be speculated that the Spanish N370S chromosomes derive from Jewish alleles, since this mutation, very prevalent among Ashkenazi Jews, is more frequent in Spain (Cormand et al. Cormand et al., 1998Cormand B Grinberg D Gort L Chabás A Vilageliu L Molecular analysis and clinical findings in the Spanish Gaucher disease population: putative haplotype of the N370S ancestral chromosome.Hum Mutat. 1998; 11: 295-305Crossref PubMed Scopus (53) Google Scholar) and Portugal (Amaral et al. Amaral et al., 1996Amaral O Pinto E Fortuna M Lacerda L Miranda M Type 1 Gaucher disease: identification of N396T and prevalence of glucocerebrosidase mutations in the Portuguese.Hum Mutat. 1996; 8: 280-281Crossref PubMed Scopus (28) Google Scholar) than in the rest of Europe and since it is known that many Jews converted to Catholicism by the time of their expulsion from Spain in the 15th century. Although Jewish individuals from the Iberian Peninsula are believed to be of Sephardic origin, the results of haplotype analysis for the Ashkenazi Jewish chromosomes in our study suggest that the mutation may have been introduced before the Ashkenazim and Sephardim became relatively independent populations. This event took place ∼800–1,000 years ago (Baron Baron, 1968Baron SW Social and religious history of the Jews. Vol 4. Columbia University Press, New York1968Google Scholar; Ankori Ankori, 1979Ankori Z Origins and history of Ashkenazi Jewery (8th to 18th century).in: Goodman R Motulsky A Genetic diseases among Ashkenazi. Jews Raven, New York1979Google Scholar), although contacts between the two communities are known to have occurred after that time. Against the hypothesis of a Jewish origin for the Spanish N370S chromosomes is the fact that overall LD values are lower among Spanish than among Ashkenazi Jewish chromosomes (table 2). Because lower LD values are indicative of a larger number of generations (Jorde Jorde, 1995Jorde LB Linkage disequilibrium as a gene-mapping tool.Am J Hum Genet. 1995; 56: 11-14PubMed Google Scholar), our data support the hypothesis of an ancient European, non-Jewish origin of the "Spanish" mutation. Conversion of pagans to Judaism during the Roman period could be an explanation for a possible way by which the mutation could have entered the Jewish population. The preliminary data presented recently by Díaz et al. (Díaz et al., 1998Díaz GA Risch N Nygaard T Maire I Poenaru L Caillau C Sá Miranda C et al.Gaucher disease: the Ashkenazi Jewish N370S mutation occurred on an ancient European haplotype.Am J Hum Genet Suppl. 1998; 63: A211Google Scholar), showing that Ashkenazi Jewish N370S chromosomes have higher LD values than those found in Portuguese and French N370S chromosomes, are consistent with the data presented here. The analysis of N370S haplotypes in Sephardim and in other European populations would be extremely useful, to clarify this issue. This work was supported by Comisión Interministerial de Ciencia y Technologia (SAF 97-0074). We are grateful to Dr. E. Beutler for critical reading of the manuscript; to L. Gort, M. Martínez, and J. Armstrong for technical assistance; to R. Rycroft for revising the English; and to Dr. N. Espiro and Dr. J. Israel for helpful comments on Jewish history. Errata et al.The American Journal of Human GeneticsJune, 1999In BriefTwo sentences were dropped from the end of the address for correspondence and reprints for the letter "Gaucher Disease: The N370S Mutation in Ashkenazi Jewish and Spanish Patients Has a Common Origin and Arose Several Thousand Years Ago," by Díaz et al., which appeared in the April 1999 issue of the Journal (64:1233–1238). "*These authors contributed equally to this paper" and "†Present affiliation: Folkhälsan Institute of Genetics, Helsinki" should have been printed between the address for correspondence and reprints and the copyright line. Full-Text PDF Open Archive
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