Haplotype analysis in Australian hemochromatosis patients: evidence for a predominant ancestral haplotype exclusively associated with hemochromatosis.

Hemochromatosis (HC), an inherited disorder of iron metabolism, shows a very strong founder effect in Australia, with the majority of patients being of Celtic (Scots/Irish) origin. Australian HC patients thus provide an ideal group in which to examine HC-gene-region haplotypes, to analyze the extent of linkage disequilibrium and genetic heterogeneity in HC. We have analyzed chromosomes from 26 multiply affected HC pedigrees, and we were able to assign HC status unambiguously to 107 chromosomes--64 as affected and 43 as unaffected. The haplotypes examined comprise the following highly polymorphic markers: the serological marker HLA-A and the microsatellites D6S248, D6S265, HLA-F, and D6S105. All show highly significant allelic association with HC and no evidence of separation from the disease locus by recombination. Analysis identified a predominant ancestral haplotype comprising alleles 5-1-3-2-8 (marker order: D6S248-D6S265-HLA-A-HLA-F-D6S105), present in 21 (33%) of 64 affected chromosomes, and exclusively associated with HC (haplotype relative risk 903). No other common haplotype was significantly associated with HC. Haplotype analysis in Australian HC patients thus provides strong evidence for (a) the introduction of HC into this population on an ancestral haplotype, (b) a common mutation associated with HC in Australian patients, and (c) a candidate HC-gene region extending between and including D6S248 and D6S105.     

Localization of the hemochromatosis gene close to D6S105.

The hemochromatosis (HC) gene is known to be linked to HLA-A (6p21.3); however, its precise location has been difficult to determine because of a lack of additional highly polymorphic markers for this region. The recent identification of short tandem repeat sequences (microsatellites) has now provided this area with a number of markers with similar polymorphic index to the HLA serological polymorphisms. Using four microsatellites--D6S105, D6S109, D6S89, and F13A--together with the HLA class I loci HLA-A and HLA-B in 13 large pedigrees clearly segregating for HC, we have been able to refine the location of the HC gene. We identified no recombination between HC and HLA-A or D6S105, and two-point analyses placed the HC gene within one centimorgan (cM) of HLA-A and D6S105 (HLA-A maximum of the lod score [Zmax] of 9.90 at recombination fraction [theta] of 0.0, and D6S105 Zmax of 8.26 at theta of 0.0). The markers HLA-B, D6S109, D6S89, and F13A were separated from the HC locus by recombination, defining the centromeric and telomeric limits for the HC gene as HLA-B and D6S109, respectively. A multipoint map constructed using HLA-B, HLA-A, and D6S109 indicates that the HC gene is located in a region less than 1 cM proximal to HLA-A and less than 1 cM telomeric of HLA-A. These pedigree data indicate an association between HC and specific alleles at HLA-A and D6S105 (i.e., HLA-A3 and D6S105 allele 8).(ABSTRACT TRUNCATED AT 250 WORDS)     

Linkage disequilibrium and extended haplotypes in the HLA-A to D6S105 region: implications for mapping the hemochromatosis gene (HFE)

The hemochromatosis gene (HFE) maps to 6p21.3, in close linkage with the HLA Class I genes. Linkage disequilibrium (LD) studies were designed to narrow down the most likely candidate region for HFE, as an alternative to traditional linkage analysis. However, both the HLA-A and D6S105 subregions, which are situated 2–3 cM and approximately 3 Mb apart, have been suggested to contain HFE. The present report extends our previous study based upon the analysis of a large number of HFE and normal chromosomes from 66families of Breton ancestry. In addition to the previously used RFLP markers spanning the 400-kb surrounding HLA-A, we examined three microsatellites: D6S510, HLA-F, and D6S105. Our combined data not only confirm a peak of LD at D6S105, but also reveal a complex pattern of LD over the i82 to D6S105 interval. Within our ethnically well-defined population of Brittany, the association of HFE with D6S105 is as great as that with HLA-A, while the internal markers display a lower LD. Fine haplotype analysis enabled us to identify two categories of haplotypes segregating with HFE. In contrast to the vast majority of normal haplotypes, 50% of HFE haplotypes are completely conserved over the HLA-A to D6S105 interval. These haplotypes could have been conserved through recombination suppression, selective forces and/or other evolutionary factors. This particular haplotypic configuration might account for the apparent inconsistencies between genetic linkage and LD data, and additionally greatly complicates positional cloning of HFE through disequilibrium mapping.The authors contributed equally to this work     

Fine localization of a major disease-susceptibility locus for diffuse panbronchiolitis

Diffuse panbronchiolitis affecting East Asians is strongly associated with the class I human leukocyte antigen (HLA) alleles. Recent observations suggest that a major disease-susceptibility gene may be located between the HLA-B and HLA-A loci in the class I region of the major histocompatibility complex on chromosome 6. To test this possibility, we analyzed 14 polymorphic markers in 92 Japanese patients and 93 healthy controls. Of these, seven marker alleles, including HLA-B54 and HLA-A11, were significantly associated with the disease. Maximum-likelihood haplotype analysis and subsequent direct determination of individual haplotypes identified a group of disease-associated haplotypes, one of which contained all seven disease-associated marker alleles. Another haplotype, containing HLA-B*5504, was also associated with the disease. All these haplotypes seem to have diverged from a common ancestral haplotype in East Asians and share a specific segment containing three consecutive markers between the S and TFIIH loci in the class I region. Furthermore, one of the markers within the candidate region showed the highest delta value, indicating the strongest association. Of 20 Korean patients with diffuse panbronchiolitis, 17 also shared the combination of the disease-associated marker alleles within the candidate region. These results indicate that an HLA-associated major susceptibility gene for diffuse panbronchiolitis is probably located within the 200 kb in the class I region 300 kb telomeric of the HLA-B locus on the chromosome 6p21.3.     

Haplotype sharing correlation of alcohol dependence on chromosomes 1-6 in 93 nuclear families

Haplotype data contain signatures of ancestral alleles and increased information for mapping genes associated with complex traits. The motivation of this paper is to test the feasibility of a recently developed haplotype reconstruction algorithm and to perform haplotype-sharing correlation (HSC) analysis in nuclear families using data provided by the Genetic Analysis Workshop 14 and the Collaborative Study of the Genetics of Alcoholism. As an exemplary analysis, haplotype data on chromosomes 1-6 were reconstructed from genotype data in 93 nuclear families by minimizing both the recombinants in within-family haplotypes and the tree distance in between-family haplotypes. HSC analysis was performed using the best set of reconstructed haplotypes, and chromosome-wide significance was evaluated using a permutation procedure. Three markers were found to have significant haplotype associations with DSM-IV alcohol dependence that exceeded the 0.05 level of chromosome-wide significance: marker rs895941 at 36.7 cM on chromosome 3 (p = 0.03), marker rs1631833 at 109.1 cM on chromosome 4 (p = 0.008), and marker rs953887 at 74.2 cM on chromosome 6 (p = 0.02). These results indicated the usefulness of HSC analysis and provided further evidence on chromosome regions associated with alcohol dependence.     

Precise genetic mapping and haplotype analysis of the familial dysautonomia gene on human chromosome 9q31

Familial dysautonomia (FD) is an autosomal recessive disorder characterized by developmental arrest in the sensory and autonomic nervous systems and by Ashkenazi Jewish ancestry. We previously had mapped the defective gene (DYS) to an 11-cM segment of chromosome 9q31-33, flanked by D9S53 and D9S105. By using 11 new polymorphic loci, we now have narrowed the location of DYS to <0.5 cM between the markers 43B1GAGT and 157A3. Two markers in this interval, 164D1 and D9S1677, show no recombination with the disease. Haplotype analysis confirmed this candidate region and revealed a major haplotype shared by 435 of 441 FD chromosomes, indicating a striking founder effect. Three other haplotypes, found on the remaining 6 FD chromosomes, might represent independent mutations. The frequency of the major FD haplotype in the Ashkenazim (5 in 324 control chromosomes) was consistent with the estimated DYS carrier frequency of 1 in 32, and none of the four haplotypes associated with FD was observed on 492 non-FD chromosomes from obligatory carriers. It is now possible to provide accurate genetic testing both for families with FD and for carriers, on the basis of close flanking markers and the capacity to identify >98% of FD chromosomes by their haplotype.     

Haplotype Analysis of Hemochromatosis: Evaluation of Different Linkage-Disequilibrium Approaches and Evolution of Disease Chromosomes

We applied several types of linkage-disequilibrium calculations to analyze the hereditary hemochromatosis (hh) locus. Twenty-four polymorphic markers in the major histocompatibility complex (MHC) class I region were used to haplotype hh and normal chromosomes. A total of 169 hh and 161 normal chromosomes were analyzed. Disequilibrium values were found to be high over an unusually large region beginning 150 kb centro-meric of HLA-A and extending nearly 5 Mb telomeric of it. Recombination in this region was −28% of the expected value. This low level of recombination contributes to the unusually broad region of linkage disequilibrium found with hh. The strongest disequilibrium was found at locus HLA-H (d = .84) and at locus D6S2239 (d = .85), a marker −10 kb telomeric to HLA-H. All disequilibrium methods employed in this study found peak disequilibrium at HLA-H or D6S2239. The cys282tyr mutation in HLA-H, a candidate gene for hh, was found in 85% of disease chromosomes. A haplotype phylogeny for hh chromosomes was constructed and suggests that the mutation associated with the most common haplotype occurred relatively recently. The age of the hh mutation was estimated to be −60-70 generations. Disequilibrium was maintained over a greater distance for hh-carrying chromosomes, consistent with a recent mutation for hh. Our data provide a reasonable explanation for previous difficulties in localizing the hh locus and provide an evolutionary history for disease chromosomes.     

Genetic dissection of the human leukocyte antigen region by use of haplotypes of Tasmanians with multiple sclerosis

Association of multiple sclerosis (MS) with the human leukocyte antigen (HLA) class II haplotype DRB1*1501-DQB1*0602 is the most consistently replicated finding of genetic studies of the disease. However, the high level of linkage disequilibrium (LD) in the HLA region has hindered the identification of other loci that single-marker tests for association are unlikely to resolve. In order to address this issue, we generated haplotypes spanning 14.754 Mb (5 cM) across the entire HLA region. The haplotypes, which were inferred by genotyping relatives of 152 patients with MS and 105 unaffected control subjects of Tasmanian ancestry, define a genomic segment from D6S276 to D6S291, including 13 microsatellite markers integrated with allele-typing data for DRB1 and DQB1. Association to the DRB1*1501-DQB1*0602 haplotype was replicated. In addition, we found that the class I/extended class I region, defined by a genomic segment of approximately 400 kb between MOGCA and D6S265, harbors genes that independently increase risk of, or provide protection from, MS. Log-linear modeling analysis of constituent haplotypes that represent genomic regions containing class I (MOGCA-D6S265), class III (TNFa-TNFd-D6S273), and class II (DRB1-DQB1) genes indicated that having class I and class II susceptibility variants on the same haplotype provides an additive effect on risk. Moreover, we found no evidence for a disease locus in the class III region defined by a 150-kb genomic segment containing the TNF locus and 14 other genes. A global overview of LD performed using GOLD identified two discrete blocks of LD in the HLA region that correspond well with previous findings. We propose that the analysis of haplotypes, by use of the types of approaches outlined in the present article, should make it possible to more accurately define the contribution of the HLA to MS.     

Localization of the familial Mediterranean fever gene (FMF) to a 250-kb interval in non-Ashkenazi Jewish founder haplotypes. The French FMF Consortium.

Chromosome 16p13.3 harbors a gene (MEF) associated with familial Mediterranean fever (FMF), a recessive disease very common in populations of Mediterranean ancestry. In the course of positional cloning of MEF, we genotyped 26 non-Ashkenazi Jewish FMF pedigrees (310 meioses) with 15 microsatellite markers, most of which were recently developed by Généthon. Identification of recombination events in the haplotypes allowed narrowing of the MEF interval to a region between D16S3124 (telomeric) and D16S475 (centromeric). Two markers, D16S3070 and D16S3275, a microsatellite marker isolated from a YAC that also contains D16S3070, showed no recombination with the disease. Linkage disequilibrium and haplotype analysis highlighted the existence of a founder haplotype in our population. The core ancestral alleles were present in 71% of MEF-bearing chromosomes at loci D16S3070 and D16S3275. Furthermore, identification of historical crossing-over events in these pedigrees indicated that MEF is located between these two loci, which are both contained in a 250-kb genomic fragment.     

Co-selection of the H63D mutation and the HLA-A29 allele: a new paradigm of linkage disequilibrium?

The major histocompatibility complex (MHC) shows a remarkable conservation of particular HLA antigens and haplotypes in linkage disequilibrium in most human populations, suggesting the existence of a convergent evolution. A recent example of such conservation is the association of particular HLA haplotypes with the HFE mutations. With the objective of exploring the significance of that association, the present paper offers an analysis of the linkage disequilibrium between HLA alleles or haplotypes and the HFE mutations in a Portuguese population. Allele and haplotype associations between HLA and HFE mutations were first reviewed in a population of 43 hemochromatosis families. The results confirmed the linkage disequilibrium of the HLA haplotype HLA-A3-B7 and the HLA-A29 allele, respectively, with the HFE mutations C282Y and H63D. In order to extend the study of the linkage disequilibrium between H63D and the HLA-A29-containing haplotypes in a normal, random population, an additional sample of 398 haplotypes was analyzed. The results reveal significant linkage disequilibrium between the H63D mutation and all HLA-A29-containing haplotypes, favoring the hypothesis of a co-selection of H63D and the HLA-A29 allele itself. An insight into the biological significance of this association is given by the finding of significantly higher CD8(+) T-lymphocyte counts in subjects simultaneously carrying the H63D mutation and the HLA-A29 allele.     

A region of primer binding variation at the D6S265 locus associated with HLA-A25 and HLA-A26 antigens

D6S265 is a polymorphic dinucleotide repeat, mapped within 70 kb centromeric of HLA-A, on chromosome 6p21.3. While genotyping families for genetic linkage analysis, allele non-amplification resulting in apparent non-Mendelian inheritance was observed at the D6S265 locus in 15 individuals, on chromosomes carrying the HLA-A25 and HLA-A26 antigens. The D6S265 locus was sequenced in a variant individual homozygous for allele non-amplification, and in a non-HLA-A25/-A26 individual, homozygous for D6S265 allele 1. Five base changes were identified in the reverse primer binding region of the variant individual, effectively preventing annealing of the 3 primer to the template.     

Ancestral association between HLA and HFE H63D and C282Y gene mutations from northwest Colombia

A significant association between HFE gene mutations and the HLA-A*03-B*07 and HLA-A*29-B*44 haplotypes has been reported in the Spanish population. It has been proposed that these mutations are probably connected with Celtic and North African ancestry, respectively. We aimed to find the possible ancestral association between HLA alleles and haplotypes associated with the HFE gene (C282Y and H63D) mutations in 214 subjects from Antioquia, Colombia. These were 18 individuals with presumed hereditary hemochromatosis (“HH”) and 196 controls. The HLA-B*07 allele was in linkage disequilibrium (LD) with C282Y, while HLA-A*23, A*29, HLA-B*44, and B*49 were in LD with H63D. Altogether, our results show that, although the H63D mutation is more common in the Antioquia population, it is not associated with any particular HLA haplotype, whereas the C282Y mutation is associated with HLA-A*03-B*07, this supporting a northern Spaniard ancestry.     

Founder effect and prevalence of myotonic dystrophy in South Africans: molecular studies.

A high prevalence of myotonic dystrophy (DM) has been described in South African Caucasoid Afrikaans-speaking families in the northern Transvaal. Evidence is presented for a strong founder effect, with a single haplotype occurring on 68% of all Caucasoid DM chromosomes; among the Afrikaans speakers, the proportion was 83%. In addition to this major haplotype, five minor DM haplotypes in the Caucasoids and two minor haplotypes in DM individuals of mixed ancestry were found. All DM chromosomes, however, had a common haplotype core, namely, Alu (ins), HinfI-2 (intron 9), and TaqI-2 (D19S463). We have detected significant linkage disequilibrium between the DM mutation and particular alleles of the extragenic markers D19S112 and D19S207. Significant differences were found in allele and haplotype distributions in the Caucasoid DM and non-DM chromosomes and Negroid non-DM chromosomes. These findings together with the strong association of allele 3 at the D19S63 locus on 93% (14/15) of the South African DM chromosomes suggest that the majority of present-day DM mutations in South African Caucasoids may have originated from a common initial founder who introduced one of the European ancestral mutations.     

Characterization of a recombinant that locates the hereditary hemochromatosis gene telomeric to HLA-F

The gene responsible for hereditary hemochromatosis has been shown to be closely linked to the HLA-A and D6S105 loci on the short arm of chromosome 6. Efforts at mapping the disease gene have been hindered, however, by a lack of informative recombinants in this region. We have identified two recombinant individuals in a single affected family and have confirmed recombination by analysis of 16 polymorphic markers located near HLA-A and D6S105. One of the recombinants provides evidence for the location of the hemochromatosis gene telomeric to HLA-F.     

Analysis of the spectra of mutations and polymorphic loci of cystic fibrosis transmembrane conductance regulator in the population of Bashkortostan

The spectra of mutations and polymorphic loci of the gene of cystic fibrosis transmembrane conductance regulator (CFTR) was studied in 60 cystic fibrosis (CF) families from Bashkortostan. Mutations delF508, 394delTT, CFTRdele2,3(21 kb), R334W, and S1196X (33.3, 3.3, 1.7, 0.8, and 0.8%, respectively) were identified. The frequencies of tandem tetranucleotide repeat (TTR) alleles were determined for locus IVS6a-GATT of intron 6 of the CFTR gene and two extragenic loci flanking the CFTR gene, D7S23 and MET (probes CS.7 and MetH) in mutant and normal chromosomes. Allelic and haplotypic associations of these loci with the mutations found were estimated. An absolute linkage between the 6TTR allele of locus IVS6a-GATT and the delF508 mutation was ascertained. A considerable linkage disequilibrium between the delF508 mutation and the C2 allele of locus D7S23 and between this mutation and the A1 allele of locus MET was found. Most of the other mutant chromosomes carried marker alleles 7TTR, C1, and A2. It was demonstrated that 67% of CF chromosomes carrying delF508 had haplotype 6-2-1 for loci IVS6a-GATT/D7S23/MET, respectively. The frequency distribution of haplotypes in CF chromosomes without delF508 had a high variance and did not differ significantly from the distribution in normal chromosomes (chi 2 = 9.415; p > 0.05).     

Linkage disequilibrium between the juvenile neuronal ceroid lipofuscinosis gene and marker loci on chromosome 16p 12.1.

The neuronal ceroid lipofuscinoses (NCL; Batten disease) are a collection of autosomal recessive disorders characterized by the accumulation of autofluorescent lipopigments in the neurons and other cell types. Clinically, these disorders are characterized by progressive encephalopathy, loss of vision, and seizures. CLN3, the gene responsible for juvenile NCL, has been mapped to a 15-cM region flanked by the marker loci D16S148 and D16S150 on human chromosome 16. CLN2, the gene causing the late-infantile form of NCL (LNCL), is not yet mapped. We have used highly informative dinucleotide repeat markers mapping between D16S148 and D16S150 to refine the localization of CLN3 and to test for linkage to CLN2. We find significant linkage disequilibrium between CLN3 and the dinucleotide repeat marker loci D16S288 (chi 2(7) = 46.5, P < .005), D16S298 (chi 2(6) = 36.6, P < .005), and D16S299 (chi 2(7) = 73.8, P < .005), and also a novel RFLP marker at the D16S272 locus (chi 2(1) = 5.7, P = .02). These markers all map to 16p12.1. The D16S298/D16S299 haplotype "5/4" is highly overrepresented, accounting for 54% of CLN3 chromosomes as compared with 8% of control chromosomes (chi 2 = 117, df = 1, P < .001). Examination of the haplotypes suggests that the CLN3 locus can be narrowed to the region immediately surrounding these markers in 16p12.1. Analysis of D16S299 in our LNCL pedigrees supports our previous finding that CLN3 and CLN2 are different genetic loci. This study also indicates that dinucleotide repeat markers play a valuable role in disequilibrium studies.     

Batten disease gene, CLN3: linkage disequilibrium mapping in the Finnish population, and analysis of European haplotypes.

The gene for Batten disease (juvenile-onset neuronal ceroid lipofuscinosis, or Spielmeyer-Sjögren disease), CLN3, maps to 16p11.2-12.1. Four microsatellite markers--D16S288, D16S299, D16S298, and SPN--are in strong linkage disequilibrium with CLN3 in 142 families from 16 different countries. These markers span a candidate region of approximately 2.1 cM. CLN3 is most prevalent in northern European populations and is especially enriched in the isolated Finnish population, with an incidence of 1:21,000. Linkage disequilibrium mapping was applied to further refine the localization of CLN3 in 27 Finnish families by using linkage disequilibrium data and information about the population history of Finland to estimate the distance of the closest markers from CLN3. CLN3 is predicted to lie 8.8 kb (range 6.3-13.8 kb) from D16S298 and 165.4 kb (132.4-218.1 kb) from D16S299. Enrichment of allele "6" at D16S298 (on 96% of Finnish and 92% of European CLN3 chromosomes) provides strong evidence that the same major mutation is responsible for Batten disease in Finland as in most other European countries and that it is therefore not a Finnish mutation. Genealogical studies show that Batten disease is widespread throughout the densely populated regions of Finland. The ancestors of two Finnish patients carrying rare alleles "3" and "5" at D16S298 in heterozygous form originate from the southwestern coast of Finland, and these probably represent other foreign mutations. Analysis of the number and distribution of CLN3 haplotypes from 12 European countries provides evidence that more than one mutation has arisen in Europe.     

A genome-wide scanning and fine mapping study of COGA data

A thorough genetic mapping study was performed to identify predisposing genes for alcoholism dependence using the Collaborative Study on the Genetics of Alcoholism (COGA) data. The procedure comprised whole-genome linkage and confirmation analyses, single locus and haplotype fine mapping analyses, and gene x environment haplotype regression. Stratified analysis was considered to reduce the ethnic heterogeneity and simultaneously family-based and case-control study designs were applied to detect potential genetic signals. By using different methods and markers, we found high linkage signals at D1S225 (253.7 cM), D1S547 (279.2 cM), D2S1356 (64.6 cM), and D7S2846 (56.8 cM) with nonparametric linkage scores of 3.92, 4.10, 4.44, and 3.55, respectively. We also conducted haplotype and odds ratio analyses, where the response was the dichotomous status of alcohol dependence, explanatory variables were the inferred individual haplotypes and the three statistically significant covariates were age, gender, and max drink (the maximum number of drinks consumed in a 24-hr period). The final model identified important AD-related haplotypes within a candidate region of NRXN1 at 2p21 and a few others in the inter-gene regions. The relative magnitude of risks to the identified risky/protective haplotypes was elucidated.     

Extended haplotype analysis in the HLA complex reveals an increased frequency of the HFE-C282Y mutation in individuals with multiple sclerosis

In order to resolve a multiple sclerosis (MS) susceptibility locus that we had identified in earlier work at the telomeric end of the HLA complex, we genotyped another 34 microsatellite markers (47 in total) across the class I/extended class I region in 166 Tasmanian MS case and 104 control families (D6S299-D6S265). Extended MS susceptibility haplotypes, up to 9 Mb in length, were observed in 11% of MS cases and 4% of controls. Direct comparison of the telomerically extended portion of the MS susceptibility haplotype in HFE-Cys282Tyr (C282Y)-homozygous haemochromatosis patients identified a common ancestry for this genomic segment, which translated into an increased frequency of the C282Y allele in 489 MS cases from Tasmania and Victoria (10.2%) compared with controls (6.7%). Six C282Y homozygotes (1.2%), a three-fold increased rate over the general population, and 88 heterozygotes (18%) were identified. One C282Y-homozygous female was identified who had MS and was being treated for symptoms of iron overload. Interestingly, for 71 Victorian MS cases not of north western European (NWE) ancestry, a DR15-independent reduction in the frequency of the C282Y allele was observed, supporting the theory of a NWE origin for the C282Y-variant of the DR15 ancestral haplotype (C282Y-HLA-A*0301-B*0702-DRB1*1501-DQB1*0602). The results of linkage disequilibrium (LD) and log linear modelling analyses suggest that C282Y is increased in MS cases of NWE ancestry because it is in LD with the ancestral DR15 susceptibility haplotype (7.1) and that it does not play an independent role in predisposition to MS. However, our findings provide the impetus for further investigations into the role of iron metabolism in the severity of MS.Electronic Supplementary Material Supplementary material is available in the online version of this article at Electronic database information: URLs for the data in this article are as follows:Division of Genetics and Bioinformatics, WEHI, (http://bioinf.wehi.edu.au) for LINKPREP and HAPLO.PLAustralian Genome Research Facility, for genotypingUniversity of California Santa Cruz Human Genome Project working draft, UniSTS at National Center for Biotechnology Information, Genome Database, for genomic information and primer sequencesOnline Mendelian Inheritance in Man (OMIM), for MS and HH informationAustralian Bureau of Statistics, for 2001 census data     

Toward understanding MHC disease associations: partial resequencing of 46 distinct HLA haplotypes

We carried out a resequencing project that examined 552 kb of sequence from each of 46 individual HLA haplotypes representing a diversity of HLA allele types, generating nearly 27 Mb of fully phased genomic sequence. Haplotype blocks were defined extending from telomeric of HLA-F to centromeric of HLA-DP including in total 5186 MHC SNPs. To investigate basic questions about the evolutionary origin of common HLA haplotypes, and to obtain an estimate of rare variation in the MHC, we similarly examined two additional sets of samples. In 19 independent HLA-A1, B8, DR3 chromosomes, the most common HLA haplotype in Northern European Caucasians, variation was found at 11 SNP positions in the 3600-kb region from HLA-A to DR. Partial resequencing of 282 individuals in the gene-dense class III region identified significant variability beyond what could have been detected by linkage to common SNPs.