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PubMed1986

Order of class III genes relative to HLA genes determined by the haplotype method.

The B18 C4A3 C4BQ0 BfF1 DR3 haplotype was found to be ideal for determining the order of C4 and Bf relative to HLA-B and DR by the haplotype method. All the copies of this haplotype are assumed to be derived from a single ancestral haplotype. Sixteen of the twenty-six BfF1-containing haplotypes carried all of the alleles from this "ancestral" haplotype. Most of the other BfF1-containing haplotypes could be derived from the "ancestral" haplotype by a single crossover event for one of the two possible gene orders. This suggests that B18 C4A3 C4BQ0 BfF1 DR3 is the sole source of the BfF1 allele. The uncommon C4 type on B18 C4A3 C4BQ0 BfF1 DR3 facilitates recognition of the BfF1-containing products of recombination between Bf and C4. One such recombinant haplotype was found which shows that the orientation of the class III genes is as follows: C4 is closest to HLA-B and Bf is closest to HLA-DR. This gene order is supported by all the earlier unequivocal results obtained using the haplotype method (Olaisen et al. 1983, Marshall et al. 1984a). Combining these results with the information on class III genes obtained from overlapping cosmid clones (Carroll et al. 1984) and earlier mapping studies (Robson and Lamm 1984) shows that HLA-B is telomeric to 21B. C4B, 21A, C4A, Bf and C2 then follow 21B in that order covering 120 kb. HLA-DR is located further toward the centromere.

Chromosome Mapping↗

PubMed1985

Human histocompatibility leukocyte antigen (HLA) haplotype frequencies estimated from the data on HLA class I, II, and III antigens in 111 Japanese narcoleptics.

In order to deduce the predominant haplotypes in Japanese narcoleptics, we have studied a total of 111 Japanese patients with narcolepsy and six multiple-case families for HLA class I and class II antigens, and for class III HLA-linked complement markers. In Japanese narcoleptics, the most frequent haplotypes were B35-DR2, B15-DR2, and B51-DR2. These haplotypes were rare in normal Japanese population. In contrast, the most frequent haplotype of HLA-DR2 in normal Japanese, A24-C blank-Bw52-C4A*2 B*Q0-BF *S-C2*C-DR2-DQw1, had a decreased frequency to one-third of the normal controls. Haplotypes B35-DR2, B15-DR2, and B51-DR2, which were more frequent among Japanese narcoleptics, were different from the haplotype found more frequently among Caucasoid narcoleptics, A3-Cw7-B7-DR2-DQw1. Haplotype analysis on six families showed that B35-DR2 and other rare haplotypes in normal Japanese were associated with narcolepsy. There were four cases without any signs of narcolepsy among 19 subjects with the disease susceptibility haplotypes. This finding suggests an incomplete penetrance of hypersomnia. Haplotype analysis of family members was also useful for the early detection of the high risk children to narcolepsy.

Complement C2↗

PubMed2005

A simple loglinear model for haplotype effects in a case-control study involving two unphased genotypes.

Because haplotypes may parsimoniously summarize the effect of genes on disease, there is great interest in using haplotypes in case-control studies of unphased genotype data. Previous methods for investigating haplotypes effects in case-control studies have not allowed for both of the following two scenarios that could have a large impact on results (i) departures from Hardy-Weinberg equilibrium in controls as well as cases, and (ii) an interactive effect of haplotypes and environmental covariates on the probability of disease. A new method is proposed that generalizes the model of Epstein and Satten to incorporate both (i) and (ii). Computations are relatively simple involving a single loglinear design matrix for parameters modeling the distribution of haplotype frequencies in controls, parameters modeling the effect of haplotypes and covariate-haplotype interactions on disease, and nuisance parameters required for correct inference. Based on simulations with realistic sample sizes, the method is recommended with data from two genotypes, a recessive or dominant model linking haplotypes to disease, and estimates of haplotype effects among haplotypes with a frequency greater than 10%. The methodology is most useful with candidate genotype pairs or for searching through pairs of genotypes when scenarios (i) and (ii) are likely. An example without a covariate illustrates the importance of modeling a departure from Hardy-Weinberg equilibrium in controls.

Journal Article↗

PubMed1999

Polymorphic haplotypes of the interleukin-10 5' flanking region determine variable interleukin-10 transcription and are associated with particular phenotypes of juvenile rheumatoid arthritis.

OBJECTIVE: To determine the distribution of the interleukin-10 (IL-10) 5' flanking region haplotypes in children with arthritis and in controls, and to investigate the functional significance of each haplotype. METHODS: Sequence-specific oligonucleotide probing was used to determine haplotype frequency. Transient transfection studies were used to investigate the transcription of reporter genes driven by each haplotype. Whole blood cultures were performed to assess IL-10 production by each genotype. RESULTS: Patients with arthritis involving >4 joints were more likely to have a genotype with an ATA haplotype than those whose arthritis remained restricted to <4 joints. This ATA haplotype was associated with lower transcriptional activity than the GCC haplotype (P = 0.02), and the ATA/ATA genotype was associated with lower IL-10 production under lipopolysaccharide stimulation than other genotypes (P < 0.02). CONCLUSION: The results of this study demonstrate the functional significance of the ATA haplotype and reveal a significant association of genotypes containing this haplotype with extended oligoarthritis.

Arthritis, Juvenile↗

PubMed2001

HLA haplotype analysis in Finnish patients with rheumatoid arthritis.

OBJECTIVE: To further characterize the HLA gene products that play an important role in the pathogenesis of rheumatoid arthritis (RA). METHODS: One hundred thirty-four haplotypes from 67 Finnish RA patients and 77 control haplotypes were analyzed for HLA-DRB1 loci, associated alleles of the HLA-DQB1 locus, alleles of the type 2 transporter-associated antigen processing (TAP2) genes, and HLA-B27. In addition, a panel of microsatellite markers within the HLA class I and class III regions was studied. RESULTS: The frequency of HLA-DRB1*04 in the haplotypes of RA patients was found to be 34% (45 of 134) compared with 14% (10 of 72) in control haplotypes (P = 0.004). The frequency of HLA-DRB1*13 was decreased in RA haplotypes (4%, or 5 of 134) in contrast to control haplotypes (24%, or 17 of 72) (P = 0.000031). The decrease in DRB1*13 was not secondary to the increase in DRB1*04, since it was also found among DRB1*04-negative haplotypes (P < 0.001). The DRB1*13-associated DQB1*0604 allele was similarly decreased in RA haplotypes (P = 0.025). The TAP2I allele of I/J dimorphism was increased in RA patients (85%, or 114 of 134) as compared with controls (69%, or 49 of 71) (P = 0.011). Of the tumor necrosis factor (TNF) microsatellite alleles, TNFa6 and TNFb5 were found to be increased in RA haplotypes (for a6 27% versus 5% in controls [P = 0.00043], and for b5 43% versus 26% in controls [P = 0.037]). CONCLUSION: Both protection-associated and susceptibility-associated alleles can be found among HLA class II genes, and the results suggest that loci outside DR/DQ may contribute to the pathogenesis of RA.

Arthritis, Rheumatoid↗

PubMed2003

A poly(ADP-ribose) polymerase haplotype spanning the promoter region confers susceptibility to rheumatoid arthritis.

OBJECTIVE: To investigate the association of the poly(ADP-ribose) polymerase 1 (PARP-1) gene promoter polymorphism with rheumatoid arthritis (RA) predisposition. METHODS: An association study with 213 Spanish RA patients and 242 healthy subjects was carried out to investigate the association of all known PARP-1 gene promoter polymorphisms, i.e., a CA microsatellite repeat, a poly(A)(n), and 3 single point mutations (C410T, C1362T, and G1672A), with disease susceptibility. Additionally, we analyzed the distribution of PARP-1 polymorphisms in 58 Spanish families with 1 or more affected members. RESULTS: Upon complete genotyping of the panel of 455 samples, strong linkage disequilibrium was observed among the 5 PARP-1 polymorphisms. Only 2 PARP-1 haplotypes were detected: haplotype A (410T-[A](10)-[CA](10-12)-1362C, which includes short PARP-1 CA alleles) and haplotype B (410C-[A](11)-[CA](13-20)-1362T, always paired with long PARP-1 CA variants). Regarding the G1672A variation, although linkage disequilibrium was detected, it did not seem to be part of the conserved haplotypes described. Haplotype B was statistically overrepresented in the RA patient group compared with the healthy subjects (odds ratio 1.42, 95% confidence interval 1.06-1.91, P = 0.019). In addition, a significant dose effect of PARP-1 haplotype carriage on disease predisposition was observed. Of note, within haplotype B, the PARP-1 CA 97-bp allele was found to be the RA-predisposing marker (odds ratio 2.17, 95% confidence interval 1.27-3.72, P = 0.003, corrected P < 0.05). CONCLUSION: Our results demonstrate the existence of 2 unique PARP-1 haplotypes in the Spanish population and provide the first evidence that PARP-1 haplotypes play a role in susceptibility to RA.

Arthritis, Rheumatoid↗

PubMed2006

Influence of CTLA4 haplotypes on susceptibility and some extraglandular manifestations in primary Sjögren's syndrome.

OBJECTIVE: Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is a key negative regulator of the T cell immune response, and the CTLA4 gene is highly polymorphic. Many positive associations between CTLA4 single-nucleotide polymorphisms (SNPs) and various autoimmune diseases have been identified. Two CTLA4 SNPs that are important relative to genetic susceptibility in human autoimmune diseases are the +49GA polymorphism in exon 1 and the CT60A/G polymorphism in the 3'-untranslated region. Using these 2 polymorphisms as markers, we investigated possible genetic associations of CTLA4 in Australian patients with primary Sjögren's syndrome. METHODS: One hundred eleven Australian Caucasian patients with primary SS and 156 population-based controls were genotyped for CTLA4 by polymerase chain reaction-restriction fragment length polymorphism methods, using the restriction enzymes BseXI (+49G/A) and HpyCh4 IV (CT60). RESULTS: The CT60 and +49G/A SNPs were in strong linkage disequilibrium, and only 3 haplotypes were observed. Significant differences in the haplotype frequencies between patients with primary SS and controls (P = 0.032) were observed, with susceptibility to primary SS associated with both the +49A;CT60A haplotype and the +49A;CT60G haplotype, whereas the +49G;CT60G haplotype was protective against primary SS. The +49A;CT60G haplotype association was predominantly with Ro/La autoantibody-positive primary SS, and the dose of this haplotype influenced the severity of daytime sleepiness (P = 0.036). The +49A;CT60A haplotype appeared to be protective against the development of Raynaud's phenomenon in patients with primary SS (odds ratio 0.49, 95% confidence interval 0.27-0.91). CONCLUSION: The CTLA4 +49G/A and CT60 haplotypes are associated with susceptibility to primary SS and with some extraglandular manifestations of the disease.

Adult↗

PubMed2004

Maximum-likelihood estimation of haplotype frequencies in nuclear families.

The importance of haplotype analysis in the context of association fine mapping of disease genes has grown steadily over the last years. Since experimental methods to determine haplotypes on a large scale are not available, phase has to be inferred statistically. For individual genotype data, several reconstruction techniques and many implementations of the expectation-maximization (EM) algorithm for haplotype frequency estimation exist. Recent research work has shown that incorporating available genotype information of related individuals largely increases the precision of haplotype frequency estimates. We, therefore, implemented a highly flexible program written in C, called FAMHAP, which calculates maximum likelihood estimates (MLEs) of haplotype frequencies from general nuclear families with an arbitrary number of children via the EM-algorithm for up to 20 SNPs. For more loci, we have implemented a locus-iterative mode of the EM-algorithm, which gives reliable approximations of the MLEs for up to 63 SNP loci, or less when multi-allelic markers are incorporated into the analysis. Missing genotypes can be handled as well. The program is able to distinguish cases (haplotypes transmitted to the first affected child of a family) from pseudo-controls (non-transmitted haplotypes with respect to the child). We tested the performance of FAMHAP and the accuracy of the obtained haplotype frequencies on a variety of simulated data sets. The implementation proved to work well when many markers were considered and no significant differences between the estimates obtained with the usual EM-algorithm and those obtained in its locus-iterative mode were observed. We conclude from the simulations that the accuracy of haplotype frequency estimation and reconstruction in nuclear families is very reliable in general and robust against missing genotypes.

Algorithms↗

PubMed2004

The haplotype runs test: the parent-parent-affected offspring trio design.

The increasing availability of maps of dense polymorphic markers makes use of haplotype data in family-based association analyses an attractive alternative to single marker association tests. We describe a novel class of statistics designed to test for an association between marker haplotypes and a qualitative trait using the parent-parent-affected-offspring trio design. Our haplotype runs test (HRT) is based on consecutive allele-sharing between pairs of haplotypes. We assign weights according to the relative frequencies of the alleles for which the two haplotypes match. Herein, we compare the HRT to the maximum-identity-length-contrast (MILC) statistic, the single-locus transmission/disequilibrium test (TDT), and the generalized test of transmission disequilibrium for haplotype data, as implemented in the software TRANSMIT, using both simulated data and published haplotype data from the recessive disorder ataxia-telangiectasia. Our simulation results suggest that the HRT outperforms the MILC and that the HRT provides comparable power to the TDT and TRANSMIT when the number of distinct founder haplotypes with a disease susceptibility allele is small but substantially outperforms the TDT and TRANSMIT when the number of distinct founder haplotypes with a disease susceptibility allele is even of modest size.

Adult↗

PubMed2004

Algorithms for inferring haplotypes.

Haplotype phase information in diploid organisms provides valuable information on human evolutionary history and may lead to the development of more efficient strategies to identify genetic variants that increase susceptibility to human diseases. Molecular haplotyping methods are labor-intensive, low-throughput, and very costly. Therefore, algorithms based on formal statistical theories were shown to be very effective and cost-efficient for haplotype reconstruction. This review covers 1) population-based haplotype inference methods: Clark's algorithm, expectation-maximization (EM) algorithm, coalescence-based algorithms (pseudo-Gibbs sampler and perfect/imperfect phylogeny), and partition-ligation algorithm implemented by a fully Bayesian model (Haplotyper) or by EM (PLEM); 2) family-based haplotype inference methods; 3) the handling of genotype scoring uncertainties (i.e., genotyping errors and raw two-dimensional genotype scatterplots) in inferring haplotypes; and 4) haplotype inference methods for pooled DNA samples. The advantages and limitations of each algorithm are discussed. By using simulations based on empirical data on the G6PD gene and TNFRSF5 gene, I demonstrate that different algorithms have different degrees of sensitivity to various extents of population diversities and genotyping error rates. Future development of statistical algorithms for addressing haplotype reconstruction will resort more and more to ideas based on combinatorial mathematics, graphical models, and machine learning, and they will have profound impacts on population genetics and genetic epidemiology with the advent of the human HapMap.

Algorithms↗

PubMed2005

Direct analysis of unphased SNP genotype data in population-based association studies via Bayesian partition modelling of haplotypes.

We describe a novel method for assessing the strength of disease association with single nucleotide polymorphisms (SNPs) in a candidate gene or small candidate region, and for estimating the corresponding haplotype relative risks of disease, using unphased genotype data directly. We begin by estimating the relative frequencies of haplotypes consistent with observed SNP genotypes. Under the Bayesian partition model, we specify cluster centres from this set of consistent SNP haplotypes. The remaining haplotypes are then assigned to the cluster with the "nearest" centre, where distance is defined in terms of SNP allele matches. Within a logistic regression modelling framework, each haplotype within a cluster is assigned the same disease risk, reducing the number of parameters required. Uncertainty in phase assignment is addressed by considering all possible haplotype configurations consistent with each unphased genotype, weighted in the logistic regression likelihood by their probabilities, calculated according to the estimated relative haplotype frequencies. We develop a Markov chain Monte Carlo algorithm to sample over the space of haplotype clusters and corresponding disease risks, allowing for covariates that might include environmental risk factors or polygenic effects. Application of the algorithm to SNP genotype data in an 890-kb region flanking the CYP2D6 gene illustrates that we can identify clusters of haplotypes with similar risk of poor drug metaboliser (PDM) phenotype, and can distinguish PDM cases carrying different high-risk variants. Further, the results of a detailed simulation study suggest that we can identify positive evidence of association for moderate relative disease risks with a sample of 1,000 cases and 1,000 controls.

Algorithms↗

PubMedDate not supplied

Glucose-6-phosphate dehydrogenase deficiency in Portugal: biochemical and mutational profiles, heterogeneity, and haplotype association.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common human enzymopathy. This deficiency in erythrocytes has a prevalence of 0.51 +/- 0.109 in the Caucasoid male population of Portugal. The frequency for deficiency-conferring genes is 0.39% in the Portuguese population. In the herein study populations males from areas of Portugal presenting with the highest prevalence of G6PD deficiency (Castelo Branco, Setúbal, Faro, and Lisbon) as well as similar subjects located in the border Center/North area of the country (Viseu) have been analyzed for biochemical parameters and screened for mutations and haplotype-associated mutations commensurate with G6PD deficiency. Six intragenic restriction fragment length polymorphisms (RFLPs) were studied: exon 5, nt 376 A -->G, FokI; intron 5, nt 611 C--> G, PvuII; intron 8, nt 163 C--> T, BspHI; exon 10, nt 116 G --> A, PstI; exon 11, nt 1311 C--> T, BclI; and intron 11, nt 93 T -->C, NlaIII. New haplotypes were constructed with the inclusion of intron 11, nt 93 T--> C, NlaIII, and only 5 of 64 possible haplotypes were found to show a marked linkage disequilibrium for several RFLPs and also for mutations and specific haplotypes. The control population (n = 168 males) presented the G6PD B variant and corresponded to haplotypes I (- - + + - -), Ia (- - + + - +), and VIIa (- - + + + +), in 91.8, 2.3, and 5.9%, respectively. The PCR and sequencing analysis of extracted DNAs from the deficient G6PD group showed 48.6% (16/33) of individuals with the G6PD A- mutation, corresponding to haplotype VIa (+ + - + - +); 9% (3/33) with the Betica mutation and 18% (6/33) with the Santa Maria mutation, both of them associated with haplotype IVa (+ - - + \- +); 6.1% (2/33) with the Mediterranean mutation associated with haplotype VIIa; 12.3% (4/33) with the Seattle mutation, 3.0% (1/33) with Gaohe mutation; and a new mutation, 3.0% (1/33), which we designated by G6PD Flores, all of them associated with haplotype I.

Adolescent↗

PubMed1995

Phenylketonuria mutations and their relation to RFLP haplotypes at the PAH locus in Czech PKU families.

A detailed study of the mutant phenylalanine hydroxylase (PAH) gene from the eastern part of the Czech Republic (Moravia) is reported. A total of 190 mutant alleles from 95 phenylketonuria (PKU) families were analyzed for 21 prevalent Caucasian mutations and restriction fragment length polymorphism/variable number of tandem repeats (RFLP/VNTR) haplotypes. Eighty per cent of all mutant alleles were found to carry 11 mutations. The most common molecular defect was the mutation R408W (55.3%), with a very high degree of homozygosity (34.6%). Each of four other mutations (R158Q, R243X, G272X, IVS12nt1) accounted for more than 3% of PKU alleles. Rarely present were mutations IVS10nt546 (2.6%), R252W (2.6%), L48S (2.1%), R261Q (1.6%), Y414C (1.0%) and 165T (0.5%). Mutations that have been predominantly described in southern Europe (IVS7nt1, A259V, Y277D, R241H, T278N) were not detected. A total of 14 different mutant haplotypes were observed. Three unusual genotype-haplotype associations were identified (R158Q on haplotypes 2.3 and 7.8 and R252W on haplotype 69.3). There was a strong association between the mutation R408W and haplotype 2.3 (54.7%). Heterogeneity was found at mutations R408W (haplotypes 2.3 and 5.9), R158Q (haplotypes 4.3, 2.3 and 7.8) and IVS10nt546 (haplotypes 6.7 and 34.7). The molecular basis of PKU in the Moravian area appears to be relatively homogeneous in comparison with other southern and western European populations, thus providing a good starting point for prenatal diagnosis and early clinical classification.

Base Sequence↗

PubMed1991

Extended MHC haplotypes and CYP21/C4 gene organisation in Irish 21-hydroxylase deficiency families.

We have analysed fifteen classical 21-hydroxylase deficiency families from throughout Southern Ireland and report the serologically defined HLA-A, HLA-B, HLA-Cw, HLA-DR, C4A and C4B polymorphisms that characterize the inferred disease haplotypes. Additionally, we have used a combination of short and long range restriction mapping procedures in order to characterize the CYP21/C4 gene organization associated with individual serologically defined haplotypes. The results obtained indicate that disease haplotypes are characterized by a high frequency (33%) of CYP21B gene deletion and 8 out of 10 such deletion haplotypes are represented by the extended haplotype HLA-DR1, C4BQo, C4A3, HLA-B40(w60), HLA-Cw3, HLA-A3. Large scale length polymorphism in the CYP21/C4 gene cluster was found to conform strictly to a variable number of tandem repeats model with 4 alleles being detected. Disease haplotypes in which defective CYP21B gene expression is inferred to result from pathological point mutations show extensive diversity of associated HLA markers and include two examples of the extended HLA haplotype HLA-DR3, B8, Cw7, A1 haplotype, which has previously been reported to be negatively associated with 21-hydroxylase deficiency. One unusual disease haplotype has two CYP21 + C4 units, both of which appear to contain CYP21B-like genes.

Adrenal Hyperplasia, Congenital↗

PubMed1992

Beta S haplotypes in various world populations.

We have determined the beta S haplotypes in 709 patients with sickle cell anemia, 30 with SC disease, 91 with S-beta-thalassemia, and in 322 Hb S heterozygotes from different countries. The methodology concerned the detection of mutations in the promoter sequences of the G gamma- and A gamma-globin genes through dot blot analysis of amplified DNA with 32P-labeled probes, and an analysis of isolated Hb F by reversed phase high performance liquid chromatography to detect the presence of the A gamma T chain [A gamma 75(E19)Ile----Thr] that is characteristic for haplotype 17 (Cameroon). The results support previously published data obtained with conventional methodology that indicates that the beta S gene arose separately in different locations. The present methodology has the advantage of being relatively inexpensive and fast, allowing the collection of a vast body of data in a short period of time. It also offers the opportunity of identifying unusual beta S haplotypes that may be associated with a milder expression of the disease. The numerous blood samples obtained from many SS patients living in different countries made it possible to compare their hematological data. Such information is included (as average values) for 395 SS patients with haplotype 19/19, for 2 with haplotype 17/17, for 50 with haplotype 20/20, for 2 with haplotype 3/3, and for 37 with haplotype 31/31. Some information on haplotype characteristics of normal beta A chromosomes is also presented.

Africa↗

PubMed1992

HLA haplotypes in type 1 (insulin-dependent) diabetes mellitus: molecular analysis of the HLA-DQ locus. The DIME Study Group.

In Caucasians the predisposition to Type 1 (insulin-dependent) diabetes mellitus has been shown to associate with HLA-DR3,DQw2 and DR4,DQw8 and with the presence of amino acids other than aspartic acid at position 57 on the HLA-DQ beta chain. In Finland the haplotype-specific absolute risk for developing Type 1 diabetes differs between various DR3 and DR4 positive haplotypes. The aim of our present analysis was to find out whether this variation is attributable to polymorphism at the DQ locus. As part of a nationwide prospective study including 757 serologically HLA genotyped families, we determined HLA-DQ alpha and DQ beta restriction fragment polymorphisms in 17 selected families with important susceptibility haplotypes. Additionally, the DQA1 alleles were determined from 19 haplotypes using sequence-specific oligonucleotide probes, and the DQB1 second exon was sequenced from nine haplotypes. The DR3 as well as DR4 positive haplotypes frequently found in Type 1 diabetic patients showed no variation at the HLA-DQ locus, and they were DQw2 and DQw8, respectively. The absolute risk for Type 1 diabetes for DR4,DQw8 positive haplotypes A2,Cw4,Bw35,DR4 A3,Cw3,Bw62,DR4, A24,Cw7,Bw39,DR4, A2,Cw3,Bw62, DR4, and A2,Cw1,Bw56,DR4 was 35/100,000, 130/100,000, 166/100,000, 196/100,000, and 218/100,000, respectively. The absolute risks for DR3,DQw2 positive haplotypes A1, Cw7,B8,DR3 and A2,Cw7,B8,DR3 were 68/100,000 and 103/100,000, respectively. These results provide further evidence that not only the polymorphism at the DQ locus but also other genes of the haplotypes contribute to susceptibility to Type 1 diabetes.

Adolescent↗

PubMed2003

Rapid assignment of swine leukocyte antigen haplotypes in pedigreed herds using a polymerase chain reaction-based assay.

We present a simple assay to determine the swine leukocyte antigen (SLA) haplotypes of animals within two experimental populations of MHC defined miniature pigs. The Yucatan miniature pigs have four founder haplotypes ( w, x, y, z) and one recombinant haplotype ( q). The NIH miniature pigs have three founder haplotypes ( a, c, d) and two recombinant haplotypes ( f, g). Because most crossovers occur between the class I and class II regions, haplotypes can be assigned by typing one class I locus and one class II locus for practical purposes. We have previously characterized these seven founder haplotypes by sequencing the cDNA of three SLA class I loci, designated as SLA-1, SLA-3 and SLA-2 and four SLA class II loci, SLA-DQA1, SLA-DQB1, SLA-DRA1 and SLA-DRB1. These sequences were used to design allele-specific primers to amplify one MHC class I and one MHC class II gene for each haplotype. Primers were tested for specificity in homozygous and heterozygous animals. Positive control primers were also designed to amplify a portion of the E-selectin or alpha-actin gene and multiplexed with the allele-specific primers to check for false negatives. This combination of allele-specific and positive control primers produced specific and robust PCR-site-specific primer assays for assigning SLA haplotypes in the two populations.

Animals↗

PubMed1998

The natural history of an HLA haplotype and its recombinants.

The presence of haplotype-specific recombination sites can be determined by analyzing the conservation of extended haplotypes in the population. This approach considers all meioses in the history of the population and requires the presence of characteristic markers that easily allow the identification of the haplotype or of its recombined segments. The recombination breakpoint can then be mapped by looking for shared alleles between haplotypes selected through the specific marker/s. We identified a rare perfect tandem duplication of a 145 base pair segment in the LTA promoter, which tags a B60 (B60D) haplotype. The duplication was detected in 16/90 B60+ Europeans, while absent in 101 B60+ Orientals. The conservation of the class I end and the extreme variability of the class II end suggested that the present-day B60D haplotypes originated from an ancestral haplotype by recombination events centromeric to the duplicated sequence. Through a fine mapping using markers of the HLA central region a preferential recombination site was localized in the 60 kilobase interval between TNFd,e, and D6S273/K11 Amicrosatellite loci (i.e., between LST1 and BAT3 genes). This site behaves as a potent recombination enhancer leading to fragmentation in most of the extant B60D haplotypes and can be considered responsible for their "instability". In the relatively recently founded Finnish population, where the LST1/BAT3 interval recombination has probably not yet had the chance to occur, a founder effect can explain the presence of a rare DP (DPB1(*)1601) allele in most B60D haplotypes in this population.

Base Sequence↗