Genetic archaeologic perspective on the origin of Yakuts

Published data on two cases of linkage disequilibrium in Yakuts are analyzed. These are the disequilibria between loci HLA-A and HLA-B and between the mutation of gene SCA1 responsible for type 1 spinocerebellar ataxia and its flanking microsatellites D6S274 and D6S89. Both cases are regarded as consequences of the founder effect. The genetic archeological approach has been used to calculate the historical period when the mutant SCA1 gene and the HLA-A1\B17 haplotype spread in the population. It has been found that this was approximately 60-70 generations (1500-1750 years) ago in both cases. The time of the segregation of haplotype HLA-A1\B17 has also been calculated for some other populations. Caucasoids have proved to be the oldest carriers of this gene, which agrees with the well-known notion that HLA-A1 originated in Indo-Europeans. The general distribution of HLA genes in Yakuts is similar to that in east-central Asian Mongoloids; therefore, it is concluded that that Yakuts are east-central Asian Mongoloids by origin, except for the founder that had haplotype A1\B17. Historically, the time of the appearance of this haplotype coincided with the period when Saks conquered east-central Asia; therefore, it is hypothesized that the aforementioned founder was a Sak.     

Participation of Indo-European tribes in ethnogeny of the mongoloid population of Siberia: analysis of the HLA antigen distribution in mongoloids of Siberia.

Three hundred forty-three Yakuts (mongoloids of central Asian type living in Siberia) were tested for HLA-A, -B, and -C loci. The HLA antigen distribution corresponds on the whole to a mongoloid population with high frequency of the HLA-A9, -B15, and -B40 antigens (phenotype frequencies .533, .367, and .405, respectively). At the same time a strikingly high frequency for the "Indo-European" HLA-A1 antigen (phenotype frequency .282) was detected, which in Yakuts is found exclusively with HLA-B17 (haplotype frequency x 1,000 = 87.0; linkage disequilibrium value x 1,000 = 63.8). The present paper deals with a new hypothesis of the Yakut ethnogenesis according to which ancient Aryan tribes formed the substratum which was later assimilated by the mongoloid and Turkic populations. Another hypothesis that I have advanced argues that from analysis of the HLA system the ancient Aryans formed, a local group within the Indo-European entity, with high frequency for HLA-A1 and -B17 antigens and for the HLA-A1,B17 haplotype and with a complete absence of or very low frequency for the HLA-B8 antigen and for the HLA-A1,B8 haplotype. Significant linkage disequilibrium, as it is found in Indians and Yakuts, etc., could have resulted from mixing of the Aryans with non-Indo-European tribes. No significant linkage disequilibrium between A1 and B8 characteristic of the European caucasoids was produced in the mixing.     

Polymorphism of the (CTG)n Repeat of the Myotonin Protein Kinase Gene in Populations of the Sakha Republic (Yakutia) and Central Asia

The allele frequency distribution of the (CTG)_n repeat located in the 3′-terminal region of the myotonin protein kinase gene (DMPK) was compared for populations of Yakutia (three ethnogeographic groups of Yakuts, Evenks, Evens, Yukaghirs, and Dolgans) and Central Asia (Kazakhs, Uzbeks, and Uighurs) and other ethnic groups. The populations of the two regions proved to considerably differ from each other: features characteristic of Asian Mongoloids were more distinct in the populations of Yakutia, while the Central Asian populations were closer to European populations. The (CTG)_n allele spectrum of Yakuts was considered in connection with the high incidence of myotonic dystrophy in Yakutia. The results support the hypothesis of the founder effect for the spread of myotonic dystrophy in Yakuts. Data on the (CTG)_n polymorphism were used to estimate the phylogenetic relationships of the populations under study.__________Translated from Molekulyarnaya Biologiya, Vol. 39, No. 3, 2005, pp. 385–393.Original Russian Text Copyright © 2005 by Fedorova, Khusainova, Kutuev, Sukhomyasova, Nikolaeva, Kulichkin, Akhmetova, Salimova, Svyatova, Berezina, Platonov, Khusnutdinova.     

Modulating action of the new polymorphism L436F detected in the<Emphasis Type="Italic"> GLB1</Emphasis> gene of a type-II GM1 gangliosidosis patient

Mutations in the GJB2 gene encoding connexin 26 (Cx26) are a major cause of autosomal recessive and sporadic cases of congenital deafness in most populations. The 235delC mutation of GJB2 is the most frequent known mutation in some east Asian populations, with a carrier frequency of approximately 1%. In order to study the origin of 235delC among east Asians, we analyzed single-nucleotide polymorphisms (SNPs) within the coding region of GJB2 and flanking the 235delC mutation. We observed significant linkage disequilibrium between 235delC and five linked polymorphic markers, suggesting that 235delC arose from a common founder. The detection of 235delC only in east Asians, but not in Caucasians, and the small chromosomal interval of the shared haplotype suggest that 235delC is an ancient mutation that arose after the divergence of Mongoloids and Caucasians. Similarly, the finding that this mutation appears on a single haplotype provides no support for the possibility that recurrent mutation is the explanation for the high frequency of the allele.D. Yan, H.-J. Park and X.M. Ouyang contributed equally to this work     

Analysis of Mitochondrial DNA Lineages in Yakuts

To study the mitochondrial gene pool structure in Yakuts, polymorphism of mtDNA hypervariable segment I (16,024–16,390) was analyzed in 191 people sampled from the indigenous population of the Sakha Republic. In total, 67 haplotypes of 14 haplogroups were detected. Most (91.6%) haplotypes belonged to haplogroups A, B, C, D, F, G, M*, and Y, which are specific for East Eurasian ethnic groups; 8.4% haplotypes represented Caucasian haplogroups H, HV1, J, T, U, and W. A high frequency of mtDNA types belonging to Asian supercluster M was peculiar for Yakuts: mtDNA types belonging to haplogroup C, D, or G and undifferentiated mtDNA types of haplogroup M (M*) accounted for 81% of all haplotypes. The highest diversity was observed for haplogroups C and D, which comprised respectively 22 (44%) and 18 (30%) haplotypes. Yakuts showed the lowest genetic diversity (H = 0.964) among all Turkic ethnic groups. Phylogenetic analysis testified to common genetic substrate of Yakuts, Mongols, and Central Asian (Kazakh, Kyrgyz, Uighur) populations. Yakuts proved to share 21 (55.5%) mtDNA haplotypes with the Central Asian ethnic groups and Mongols. Comparisons with modern Paleoasian populations (Chukcha, Itelmen, Koryaks) revealed three (8.9%) haplotypes common for Yakuts and Koryaks. The results of mtDNA analysis disagree with the hypothesis of an appreciable Paleoasian contribution to the modern Yakut gene pool.     

Population frequency and age of c.806 C>T mutation in CYB5R3 gene as cause of recessive congenital methemoglobinemia in Yakutia

Type-I recessive congenital methemoglobinemia (RCM) is a rare autosomal disease characterized by a deficiency of the soluble form of nicotineamide adenine dinucleotide (NADH)-cytochrome b5 reductase (b5R) and clinically manifests as cyanosis of skin and mucous membranes. In the Russian Federation, type-I RCM is widely disturbed in Yakutia due to the local founder effect. The molecular genetics cause of type-I RCM in Yakutia is mutation c.806C>T in the CYB5R3 gene. In this work we used 13 polymorphic markers, which flanking the CYB5R3 gene to establish the founder haplotype. The age of the mutation was estimated as about 285 ± 135 years. In this work, we have evaluated the frequency of the c.806C>T mutation in Yakutia, which averaged 55 : 1000 Yakuts. The calculated frequency of disease was 1: 1250 Yakuts.     

p53 polymorphisms in Russia and Belarus: correlation of the 2-1-1 haplotype frequency with longitude

Four different polymorphisms in the human p53 gene (a 16-bp duplication in intron 3, and three RFLPs: for Bsh1236I at codon 72, for MspI in intron 6 and for BamHI in the 3 flanking region) and extended haplotypes were studied in nine geographically diverse populations from Russia and Belarus. The Yakuts differed from all other populations, as they had a significantly higher frequency of the BamHI A1 allele. Most populations did not differ significantly from each other in the frequency of the Bsh1236I polymorphism. The 16-bp duplication A1 allele and MspI A2 allele frequencies were significantly higher in the Yakut and Khant populations. Linkage disequilibrium values (D) between BamHI and other polymorphic sites were not significant in many cases; for this reason we have used the 16 bp–Bsh1236I–MspI haplotype frequencies only. Of eight possible haplotypes, five were observed in the populations investigated. Haplotype 1-2-2 was the most frequent in all populations. The next most common haplotype, 1-1-2, was present at very similar frequencies among the Byelorussians and Russians from Smolensk, but was more frequent in other populations. The frequency of haplotype 2-1-1 showed a nearly continuous decrease from West to East (from 17.857% among the Byelorussians to 0.685% in the Yakuts from the Verkhoyansk) and correlated with longitude (Spearmans r=–0.8667, P=0.0025), which may be due to natural selection and adaptation. The relationships among populations were evaluated by means of Neis D_A distances for the 16 bp–Bsh1236I–MspI haplotype frequencies. Based on the multidimensional scaling analysis a correlation between p53 haplotype frequencies and ethnicity is supposed.     

Spinocerebellar ataxias in Spanish patients: genetic analysis of familial and sporadic cases

Autosomal dominant cerebellar ataxias (ADCA) are a clinically heterogeneous group of neurodegenerative disorders caused by unstable CAG repeat expansions encoding polyglutamine tracts. Five spinocerebellar ataxia genes (SCA1, SCA2, SCA3, SCA6 and SCA7) and another related dominant ataxia gene (DRPLA) have been cloned, allowing the genetic classification of these disorders. We present here the molecular analysis of 87 unrelated familial and 60 sporadic Spanish cases of spinocerebellar ataxia. For ADCA cases 15% were SCA2, 15% SCA3, 6% SCA1, 3% SCA7, 1% SCA6 and 1% DRPLA, an extremely rare mutation in Caucasoid populations. About 58% of ADCA cases remained genetically unclassified. All the SCA1 cases belong to the same geographical area and share a common haplotype for the SCA1 mutation. The expanded alleles ranged from 41 to 59 repeats for SCA1, 17 to 29 for SCA2, 67 to 77 for SCA3, and 38 to 113 for SCA7. One SCA6 case had 25 repeats and one DRPLA case had 63 repeats. The highest CAG repeat variation in meiotic transmission of expanded alleles was detected in SCA7, this being of +67 units in one paternal transmission and giving rise to a 113 CAG repeat allele in a patient who died at 3 years of age. Meiotic transmissions have also shown a tendency to more frequent paternal transmission of expanded alleles in SCA1 and maternal in SCA7. All SCA1 and SCA2 expanded alleles analyzed consisted of pure CAG repeats, whereas normal alleles were interrupted by 1–2 CAT trinucleotides in SCA1, except for three alleles of 6, 14 and 21 CAG repeats, and by 1–3 CAA trinucleotides in SCA2. No SCA or DRPLA mutations were detected in the 60 sporadic cases of spinocerebellar ataxia, but one late onset patient was identified as a recessive form due to GAA-repeat expansions in the Friedreich’s ataxia gene. Received: 6 January 1999 / Accepted: 18 March 1999     

Gly118Asp is a SCA14 founder mutation in the Dutch ataxia population

Missense mutations in the PRKCG gene have recently been identified in spinocerebellar ataxia 14 (SCA14) patients; these include the Gly118Asp mutation that we found in a large Dutch autosomal dominant cerebellar ataxia (ADCA) family. We subsequently screened the current Dutch ataxia cohort (approximately 900 individuals) for SCA14 mutations in the Cys2 region of the PRKCG gene. We identified the Gly118Asp mutation in another eight individuals from five small families. Haplotype analysis identified a shared chromosomal region surrounding the SCA14 gene, and genealogical research was able to link all these ADCA patients to a single common ancestor. We therefore confirmed that the Gly118Asp mutation is a SCA14 founder mutation in the Dutch ADCA population.     

Population frequency and age of mutation G5741→A in gene <Emphasis Type="Italic">NBAS</Emphasis> which is a cause of SOPH syndrome in Sakha (Yakutia) Republic

SOPH syndrome (Short stature with Optic nerve atrophy and Pelger–Huët anomaly syndrome, OMIM#614800) is an autosomal recessive hereditary disease characterized by the following main clinical symptoms: postnatal hypoplasia, proportionately short stature, facial dysmorphism, micromelia of feet and hands, limp and loose skin, optic nerve atrophy, and Pelger–Huët anomaly of neutrophils. For the first time, this disease was described in Yakuts. The molecular-genetic study showed that its cause in Yakuts is mutation G5741→A in gene NBAS. On the basis of disequilibrium analysis for linkage of ten microsatellite markers flanking the NBAS gene with the disease, the haplotype of the founder chromosome was determined. The age of the mutation in Yakutia was estimated to be about 804 ± 140 years. The frequency of heterozygous carriers of mutation G5741→A (R1914H) in gene NBAS was found, which averaged 13 per 1000 healthy Yakuts.     

Polymorphism of CTG-repeats in the DMPK gene in populations of Yakutia and central Asia

Allele frequency distribution of CTG-repeat in the 3'-flanking region of DMPK gene was analyzed in populations of Yakutia (three ethnogeographical groups of Yakuts, Evenks, Evens, Yukaghirs, Dolgans) and Central Asia (Kazakhs, Uzbeks, Uighurs). Frequencies of CTG alleles were found to be significantly different in two regions. Allele frequency distribution in populations of Yakutia was similar to Asian populations, whereas Central Asian populations showed similarity to European populations. The features of allele spectrum in Yakut populations were discussed in terms of high prevalence of myotonic dystrophy in Yakuts. Our result supports the hypothesis of founder effect in spread of myotonic dystrophy in Yakuts. The phylogenetic relationships between the investigated populations based on polymorphism of CTG-locus of the DMPK gene have been analyzed as well.     

HLA Haplotypes with C4B5; evidence for further allelic heterogeneity

Twenty-three individuals from various disease groups and normal controls were identified by immunofixation with anti-C4, C4-dependent lysis, determination of Rg (Rodgers) and Ch (Chido) phenotypes, and immunoblotting with C4-specific mouse monoclonal antibody. We found that one haplotype predominates with the C4B ^* 5 allele, HLA-A11, B22(55), Cw3, Bf ^* S, C4A ^* 4B ^* 5, which also carries the Ch ^{1,–2, 3} haplotype. The B5 allotype was also found with HLA-1360, HLA-1335 in Caucasoids, and HLA-B18 in non-Caucasoids; these carried the Ch ^{–1, –2, –3} haplotype. Our results are in accord with an earlier report of two B5 subtypes, B5Rg⁺ and B5Rg^– (Roos et al. 1984). The specificity of the mouse monoclonal antibodies IC4 and 21312 had been previously related to C4A and C4B, respectively, but our results suggest that they relate more closely to Rg and Ch determinants.     

Polymorphism of Human Thermoreceptor Genes <Emphasis Type="Italic">TRPV1</Emphasis> and <Emphasis Type="Italic">TRPA1</Emphasis> in Populations of the Altai-Sayan Region and the Far East

Genotyping of TRPV1 and TRPA1 genes encoding thermoreceptors in the populations of the Altai-Sayan region and the Far East was conducted. The sample consisted of 15 populations comprising 1482 individuals. The analysis of TRPV1 rs222747 demonstrated that the frequency of M315I was closest to East Asian populations only in Nanais and Koryaks (56 and 64%, respectively). Siberian Tatars, Yakuts, and Evenks were closest to European populations. All populations of the Altai-Sayan region reported an intermediate position between the Caucasoids and the Eastern Mongoloids on the basis of the frequency of M315I. No deviations from the Hardy–Weinberg distribution were observed. The observed heterozygosity exceeded the expected one in eight populations. The analysis of TRPA1 rs13268757 revealed that Chukchi, Yukaghir, Koryak, Tuvinian, Southern Altaian, and Telengit populations were closest to the East Asian populations on the basis of the frequency of R3C substitution (3–7%). At the same time, populations of Siberian Tatars, Nanais, Evenks, Yakuts, Shorians, Khakases, and Kazakhs were intermediate between the Caucasoids (18–23%) and the Mongoloids from East Asia (3–7%) on the basis of the frequency of this polymorphism. A deviation from the Hardy–Weinberg distribution was detected only in the Yukaghir population. The observed heterozygosity was higher than the expected one in nine populations. A trans-association of TRPA1 and TRPV1 gene polymorphisms was carried out in 14 populations via regression analysis. A negative correlation of–0.545 was determined, the number of degrees of freedom (df) was 13, and the P-value was 0.048. The data obtained indicate that the analyzed polymorphisms are correlated, which confirms an earlier conclusion of the TRPA1-dependent inhibition of TRPV1 function. The results may evidence in the co-evolution of analyzed genes.     

Linkage disequilibrium of HLA-SB1 with the HLA-A1, B8, DR3, SCO1 and of HLA-SB4 with the HLA-A26, Bw38, Dw10, DR4, SC21 extended haplotypes

Homozygous typing cells from 13 normal HLA-A1, B8, Dw3, DR3 and five normal HLA-A26, Bw38, Dw10, DR4 individuals were typed for the following markers: HLA-SB, MB, MT; complement proteins BF, C2, C4A, C4B; and GLO. Ninety-one percent of A1, B8, Dw3, DR3 homozygous individuals (HI) tested were homozygous for BF ^* S, C2 ^* C, C4A ^* QO, and C4B ^*1 (SCO1 complotype), which indicates that the SCO1 complotype is in linkage disequilibrium with the A1, B8, DR3 haplotype in randomly selected normal populations. Sixty-seven percent of HLA-A1, B8, Dw3, DR3, SCO1 positive HI also expressed SB1; since the frequency of SB 1 in random Caucasian populations is 11.2%, this finding indicates that SB1 is in linkage disequilibrium with the A1, B8, DR3, SCO1 extended haplotype. All HI with the A26, Bw38, Dw10, DR4 haplotype were homozygous for both SC21 and SB4, suggesting that SC21 and SB4 should be included in the A26, Bw38, Dw10, DR4 extended haplotype. On the other hand, neither of the GLO markers were found in association with either haplotype. The results of this study indicate that HLA-SB is included in some extended haplotypes and may be important in these markers for diseases such as insulin-dependent diabetes mellitus. This study also demonstrated an apparent influence of HLA-SB on primary mixed lymphocyte culture (MLC) responses. The mean relative response of primary MLCs between individuals matched for HLA-A, B, D, DR, MB and MT but not SB was 40% of that for the MLCs with mismatched HLA-D, significantly higher than the MLCs matched for all HLA and complotypes.     

Spinocerebellar ataxia: multipoint linkage analysis of genes associated with the disease locus

Summary Spinocerebellar ataxia (SCA) was studied in a seven-generation (Schut-Swier) kindred using linkage analysis to localize further the autosomal dominant, HLA-linked, disease-producing SCA1 locus relative to four other loci that map to the short arm of human chromosome 6. Genotypes for each locus were determined in as many individuals as possible from a total of 162 affected and unaffected family members that were studied. A maximum pairwise lod score of 8.52 ( _m = 0.10, _f = 0.22) for linkage between SCA1 and HLA-A was observed. Multipoint linkage analyses for the SCA1, HLA-A, F13A, D6S7, and GLO1 loci revealed that the SCA1 locus is most probably located telomeric to HLA-A, with a likely location between HLA-A and F13A.     

Autosomal dominant cerebellar ataxia type I in Martinique (French West Indies): Genetic analysis of three unrelated SCA2 families

Autosomal dominant cerebellar ataxias (ADCAs) are a group of neurodegenerative disorders that are clinically and genetically heterogeneous. We report here a genetic linkage study, with five chromosome 12q markers, of three Martinican families with ADCA type I, for which the spinocerebellar ataxia 1 (SCA1) locus was excluded. Linkage to the SCA2 locus was demonstrated with a maximal lod score of 6.64 at = 0.00 with marker D12S354. Recombinational events observed by haplotype reconstruction demonstrated that the SCA2 locus is located in an approximately 7-cM interval flanked by D 12S 105 and D12S79. Using thez _max-l method, multipoint analysis further reduced the candidate interval for SCA2 to a region of 5 cM. Two families shared a common haplotype at loci spanning 7 cM, which suggests a founder effect, whereas a different haplotype segregated with the disease in the third family. Finally, a mean anticipation of 12 ± 14 years was found in parent-child couples, with no parental sex effect, suggesting that the disease might be caused by an expanded and unstable triplet repeat.     

Paternal phylogeography and genetic diversity of East Asian goats

This study was a first analysis of paternal genetic diversity for extensive Asian domestic goats using SRY gene sequences. Sequencing comparison of the SRY 3′‐untranslated region among 210 Asian goats revealed four haplotypes (Y1A, Y1B, Y2A and Y2B) derived from four variable sites including a novel substitution detected in this study. In Asian goats, the predominant haplotype was Y1A (62%) and second most common was Y2B (30%). Interestingly, the Y2B was a unique East Asian Y chromosomal variant, which differentiates eastern and western Eurasian goats. The SRY geographic distribution in Myanmar and Cambodia indicated predominant the haplotype Y1A in plains areas and a high frequency of Y2B in mountain areas. The results suggest recent genetic infiltration of modern breeds into South‐East Asian goats and an ancestral SRY Y2B haplotype in Asian native goats.     

Ancestral Origin of the ATTCT Repeat Expansion in Spinocerebellar Ataxia Type 10 (SCA10)

Spinocerebellar ataxia type 10 (SCA10) is an autosomal dominant neurodegenerative disease characterized by cerebellar ataxia and seizures. The disease is caused by a large ATTCT repeat expansion in the ATXN10 gene. The first families reported with SCA10 were of Mexican origin, but the disease was soon after described in Brazilian families of mixed Portuguese and Amerindian ancestry. The origin of the SCA10 expansion and a possible founder effect that would account for its geographical distribution have been the source of speculation over the last years. To unravel the mutational origin and spread of the SCA10 expansion, we performed an extensive haplotype study, using closely linked STR markers and intragenic SNPs, in families from Brazil and Mexico. Our results showed (1) a shared disease haplotype for all Brazilian and one of the Mexican families, and (2) closely-related haplotypes for the additional SCA10 Mexican families; (3) little or null genetic distance in small normal alleles of different repeat sizes, from the same SNP lineage, indicating that they are being originated by a single step mechanism; and (4) a shared haplotype for pure and interrupted expanded alleles, pointing to a gene conversion model for its generation. In conclusion, we show evidence for an ancestral common origin for SCA10 in Latin America, which might have arisen in an ancestral Amerindian population and later have been spread into the mixed populations of Mexico and Brazil.     

Polymorphism of 2′-5′-oligoadenylate synthetase (<Emphasis Type="Italic">OAS</Emphasis>) genes,associated with predisposition to severe forms of tick-borne encephalitis,in human populations of North Eurasia

2′-5′-oligoadenylate synthetases are a family of interferon-induced enzymes playing an important role in antiviral defense in mammals. In the human genome, three genes encoding functional synthetases (OAS1, OAS2 and OAS3) form a cluster. Previously, we found that particular genotypes and/or alleles of five single nucleotide polymorphisms (SNPs) of OAS2 and OAS3 are associated with predisposition to severe forms of tick-borne encephalitis (TBE) in Russians. In the current study, we investigated the distribution of three of the above SNPs, OAS3 rs2285932 (C/T, Ile438Ile), OAS3 rs2072136 (G/A, Ser567Ser), and OAS2 rs15895 (G/A, Trp720Ter relative to p71 isoform), in seven populations of North Eurasia: Caucasians (Russians, Germans from Altai region), Central Asian Mongoloids (Altaians, Khakass, Tuvinians, and Shorians), and Arctic Mongoloids (Chukchi). Interpopulational differences in genotype, allele and haplotype frequencies and in linkage disequilibrium structure for these SNPs were detected. These frequencies correlated with the ethnicity of the populations and with their supposed differential exposure to the TBE virus. In particular, the lowest frequencies of G/G genotype for OAS3 SNP rs2072136 (which, according to our earlier results, is associated with predisposition to severe forms of TBE) were found in Altaians, Khakass, Tuvinians, and Shorians, who commonly contact with the TBE virus in their habitation regions. Thus, the data obtained suggest that the TBE virus might act as a selection factor for particular OAS variants in Central Asian Mongoloids.     

Linkage between C2 deficiency and theHLA-A10,B18,Dw2/BfS haplotype in a French family

A linkage between C2 deficiency and the HLA-A10,B18/BfS antigens has been found in a French family from the Strasbourg area. The propositus, suffering from a chronic glomerulonephritis, is homozygous forHLA-A10,B18/BfS and totally C2-deficient. The parents and the brother are heterozygous for C2 deficiency and share theHLA-A10,B18/BfS haplotype. MLC tests and HLA-D typing revealed that the homozygous C2-deficient patient is also homozygous at theHLA-D locus for the w2 specificity. Evidence was obtained for a heterogeneity of the HLA-Dw2 specificity. This observation confirms the remarkable association between C2 deficiency and theHLA-A10,B18,Dw2 haplotype.