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PubMed2005

Allelic and haplotypic diversity of HLA-A, -B, -C, -DRB1, and -DQB1 genes in the Korean population.

High-resolution human leukocyte antigen (HLA) typing exposes the unique patterns of HLA allele and haplotype frequencies in each population. In this study, HLA-A, -B, -C, -DRB1, and -DQB1 genotypes were analyzed in 485 apparently unrelated healthy Korean individuals. A total of 20 HLA-A, 43 HLA-B, 21 HLA-C, 31 HLA-DRB1, and 14 HLA-DQB1 alleles were identified. Eleven alleles (A*0201, A*1101, A*2402, A*3303, B*1501, Cw*0102, Cw*0302, Cw*0303, DQB1*0301, DQB1*0302, and DQB1*0303) were found in more than 10% of the population. In each serologic group, a maximum of three alleles were found with several exceptions (A2, B62, DR4, DR14, and DQ6). In each serologic group exhibiting multiple alleles, two major alleles were present at 62-96% (i.e. A*0201 and A*0206 comprise 85% of A2-positive alleles). Multiple-locus haplotypes estimated by the maximum likelihood method revealed 51 A-C, 43 C-B, 52 B-DRB1, 34 DRB1-DQB1, 48 A-C-B, 42 C-B-DRB1, 46 B-DRB1-DQB1, and 30 A-C-B-DRB1-DQB1 haplotypes with frequencies of more than 0.5%. In spite of their high polymorphism in B and DRB1, identification of relatively small numbers of two-locus (B-C and DRB1-DQB1) haplotypes suggested strong associations of those two loci, respectively. Five-locus haplotypes defined by high-resolution DNA typing correlated well with previously identified serology-based haplotypes in the population. The five most frequent haplotypes were: A*3303-Cw*1403-B*4403-DRB1*1302-DQB1*0604 (4.2%), A*3303-Cw*0701/6-B*4403-DRB1*0701-DQB1*0201/2 (3.0%), A*3303-Cw*0302-B*5801-DRB1*1302-DQB1*0609 (3.0%), A*2402-Cw*0702-B*0702-DRB1*0101-DQB1*0501 (2.9%), and A*3001-Cw*0602-B*1302-DRB1*0701-DQB1*0201/2 (2.7%). Several sets of allele level haplotypes that could not be discriminated by routine HLA-A, -B, and -DRB1 low-resolution typing originated from allelic diversity of A2, B61, DR4, and DR8 serologic groups. Information obtained in this study will be useful for medical and forensic applications as well as in anthropology.

Alleles↗

PubMed2005

MHC microsatellite diversity and linkage disequilibrium among common HLA-A, HLA-B, DRB1 haplotypes: implications for unrelated donor hematopoietic transplantation and disease association studies.

Twenty-two human major histocompatibility complex (MHC) region microsatellite (Msat) markers were studied for diversity and linkage disequilibrium (LD) with HLA loci in hematopoietic cell transplant recipients and their HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 allele-matched unrelated donors. These Msats showed highly significant LD over much of the MHC region. The Msat diversity of five common Caucasian haplotypes (HLA-A1-B8-DR3, A3-B7-DR15, A2-B44-DR4, A29-B44-DR7, and A2-B7-DR15) was examined using a new measure called 'haplotype specific heterozygosity' (HSH). Each of the five haplotypes had at least one Msat marker with an HSH value of zero indicating that only one Msat allele was observed for the particular HLA haplotype. In addition, the ability of Msats to predict HLA-A-B-DRB1 haplotypes was studied. Over 90% prediction probability of two common haplotypes (HLA-A1-B8-DR3 and HLA-A3-B7-DR15) was achieved with information from three Msats (D6S265/D6S2787/D6S2894 and D6S510/D6S2810/D6S2876, respectively). We demonstrate how the HSH index can be used in the selection of informative Msats for transplantation and disease association studies. Markers with low HSH values can be used to predict specific HLA haplotypes or multilocus genotypes to supplement the screening of HLA-matched donors for transplantation. Markers with high HSH values will be most informative in studies investigating MHC region disease-susceptibility genes where HLA haplotypic effects are known to exist.

Gene Frequency↗

PubMed1995

Complement component C6 and C7 haplotypes associated with deficiencies of C6.

Both complete C6-deficiency (C6*Q0) and subtotal C6-deficiency (C6*SD) have been described as simple recessive traits and C6*SD has been described in combination with subtotal deficiency of the C7 coded at an adjacent locus. The trace of C6 protein found in both C6*SD traits is phenotypically indistinguishable, being smaller than normal C6 and having different isoelectric properties. A defect has been found in the C6 gene which plausibly explains the C6*SD phenotype, and this defect is also common to both C6*SD traits. We present data from seven DNA markers of the C6 and C7 genes which show that although at least four haplotypes are associated with C6*Q0, most South African C6*Q0 patients carry a common defective haplotype. The most common haplotype associated with C6*Q0 has been observed only once among unaffected haplotypes of relatives. In one family, the cases of C6*SD share a complete haplotype with both cases of combined deficiency and are probably heterozygous for this condition and complete deficiency of C6. In another family, the C6*SD is on a slightly different haplotype and C7 is normally expressed. Thus, the C6 defect is not sufficient on its own to explain the C7 deficiency in the combined deficient haplotype. The haplotype associated with the combined deficiency is found not only in normal control subjects, but also in one case of complete C6 deficiency. In this case the molecular defect seen in combined or C6*SD cases is absent.

Alleles↗

PubMed2005

Using tree-based recursive partitioning methods to group haplotypes for increased power in association studies.

Motivated by the increasing availability of high-density single nucleotide polymorphism (SNP) markers across the genome, various haplotype-based methods have been developed for candidate gene association studies, and even for genome-wide association studies. Although haplotype approaches dramatically reduce the multiple comparisons problem (as compared to single SNP analysis), even the number of existing haplotypes is relatively large, which increases the degrees of freedom and decreases the power for the corresponding test statistic. Grouping haplotypes is a way to reduce the degrees of freedom. We propose a procedure that uses a tree-based recursive partitioning algorithm to group haplotypes into a small number of clusters, and conducts the association test based on groups of haplotypes instead of individual haplotypes. The method can be used for both population-based and family-based association studies, with known or ambiguous phase information. Simulation studies suggest that the proposed method has the right type I error rate, and is more powerful than some existing haplotype-based tests.

Algorithms↗

PubMed2005

Haplotype analysis of the DM1 locus in the Serbian population.

OBJECTIVES: Analysis of the CTG-repeat number and three biallelic markers, Alu(+/-), HinfI(+/-), and TaqI(+/-), in the DMPK gene in healthy and myotonic dystrophy type 1 (DM1) Serbian individuals. Also, the consideration of haplotypes in the light of the proposed models of CTG-repeat evolution and origin of the DM1 mutation. MATERIALS AND METHODS: Markers were analyzed by PCR and haplotypes were obtained on 203 unrelated normal chromosomes and 24 unrelated DM1 chromosomes. RESULTS: A strong linkage disequilibrium was detected between the three biallelic markers alone (P <0.0001) and between distinct CTG-repeat size classes and reconstructed haplotypes. Greater than 98% of normal chromosomes contain (+++) and (- - -) haplotypes. The (+++) haplotype is the most common, while the (CTG)(9-17) are the most frequent alleles. We found a complete association of (+++) haplotype with (CTG)(> or =18) and mutated alleles. CONCLUSIONS: (CTG)(9-17)/(+++) haplotype is the ancestral haplotype and DM1 mutation occurred on (CTG)(18-35)/+++ chromosome.

Case-Control Studies↗

PubMed1997

Presence of retroelements reveal the evolutionary history of the human DR haplotypes.

Comparison of intron sequences has been a successful tool for drawing major conclusions about the evolutionary relationship of DRB genes. This complex family of genes is discussed in this review as well as a proposed model for the evolution of HLA-DR haplotypes. The model is based both on phylogenetic analysis of intron sequences as well as presence of ERV9 LTR elements located at identical position in intron 5 of a number of DRB genes. According to this model, two main evolutionary branches of DR haplotypes exist. The DR53 haplotype represents one branch, and the second branch contains the DR51, DR52, DR1, and DR8 haplotypes. After the divergence of the DR53 haplotype, an ERV9 LTR element was inserted in a primordial gene. Consequently, all DRB1 genes as well as the DRB3 gene within haplotypes of the second branch, contain this LTR element. In addition, conserved regulatory sequence motifs are found present within these LTR elements that might regulate DRB gene expression. Novel haplotypes are generated by recombinations and the maintenance of the DR haplotype variation as well as the frequent genetic rearrangements observed might be evolutionary advantageous.

Animals↗

PubMed2002

The structure of haplotype blocks in the human genome.

Haplotype-based methods offer a powerful approach to disease gene mapping, based on the association between causal mutations and the ancestral haplotypes on which they arose. As part of The SNP Consortium Allele Frequency Projects, we characterized haplotype patterns across 51 autosomal regions (spanning 13 megabases of the human genome) in samples from Africa, Europe, and Asia. We show that the human genome can be parsed objectively into haplotype blocks: sizable regions over which there is little evidence for historical recombination and within which only a few common haplotypes are observed. The boundaries of blocks and specific haplotypes they contain are highly correlated across populations. We demonstrate that such haplotype frameworks provide substantial statistical power in association studies of common genetic variation across each region. Our results provide a foundation for the construction of a haplotype map of the human genome, facilitating comprehensive genetic association studies of human disease.

Africa↗

PubMed2005

Functional haplotypes of PADI4: relevance for rheumatoid arthritis specific synovial intracellular citrullinated proteins and anticitrullinated protein antibodies.

BACKGROUND: Haplotypes of PADI4, encoding for a citrullinating enzyme, were associated with rheumatoid arthritis in a Japanese population. It was suggested they were related to the presence of anticitrullinated protein antibodies (ACPA). OBJECTIVE: To explore the relation between PADI4 haplotypes, the presence of rheumatoid arthritis specific intracellular citrullinated proteins in synovial membrane, and serum ACPA titres. METHODS: Synovial biopsies and peripheral blood samples were obtained in 59 patients with rheumatoid arthritis. Synovial intracellular citrullinated proteins were detected by immunohistochemistry. Serum ACPA titres were measured by anti-CCP2 ELISA. PADI4 haplotypes were determined by direct sequencing of the four exonic PADI4 single nucleotide polymorphisms. RESULTS: PADI4 haplotype frequencies and the presence of synovial intracellular citrullinated proteins and ACPA were comparable with previous studies. There was no significant association between PADI4 haplotype 1 or 2 and the presence of synovial intracellular citrullinated proteins, although these proteins were associated with higher serum ACPA. There was no correlation between PADI4 haplotypes and serum ACPA, either by continuous analysis using the titres or by dichotomous analysis using the diagnostic cut off. Further analyses in homozygotes for haplotype 1 or 2 or in heterozygotes (1/2) also failed to show an association between PADI4 polymorphisms and ACPA. This contrasted with the clear association between ACPA levels and HLA-DR shared epitope. CONCLUSIONS: The link between synovial intracellular citrullinated proteins and ACPA emphasises the role of deimination of synovial proteins in rheumatoid arthritis, but the biological relevance of the PADI4 haplotypes for this autoimmune process is questionable, at least in a European population.

Adult↗

PubMed2000

RET genotypes comprising specific haplotypes of polymorphic variants predispose to isolated Hirschsprung disease.

BACKGROUND: Hirschsprung disease (HSCR), which may be sporadic or familial, occurs in 1:5000 live births and presents with functional intestinal obstruction secondary to aganglionosis of the hindgut. Germline mutations of the RET proto-oncogene are believed to account for up to 50% of familial cases and up to 30% of isolated cases in most series. However, these series are highly selected for the most obvious and severe cases and large familial aggregations. Population based studies indicate that germline RET mutations account for no more than 3% of isolated HSCR cases. Recently, we and others have noted that specific polymorphic sequence variants, notably A45A (exon 2), are over-represented in isolated HSCR. PURPOSE: In order to determine if it is the variant per se, a combination thereof, or another locus in linkage disequilibrium which predisposes to HSCR, we looked for association of RET haplotype(s) and disease in HSCR cases compared to region matched controls. METHODS: Seven loci across RET were typed and haplotypes formed for HSCR cases, their unaffected parents, and region matched controls. Haplotype and genotype frequencies and distributions were compared among these groups using the transmission disequilibrium test and standard case-control statistic. RESULTS: Twelve unique haplotypes, labelled A-L, were obtained. The distributions of haplotypes between cases and controls (chi(11)(2) =81.4, p<<0.0001) and between cases and non-transmitted parental haplotypes were significantly different (chi(2)(11)=53.1, p<0.0001). Genotypes comprising pairs of haplotypes were formed for cases and controls. There were 38 different genotypes among cases and controls combined. Inspection of the genotypes in these two groups showed that the genotype distribution between cases and controls was distinct (chi(37)(2)=93. 8, p<<0.0001). For example, BB, BC, BD, and CD, all of which contain at least one allele with the polymorphic A45A, are prominently represented among HSCR cases, together accounting for >35% of the case genotypes, yet these four genotypes were not represented among the population matched normal controls. Conversely, AA, AG, DD, GG, and GJ, none of which contains A45A, are commonly represented in the controls, together accounting for 43% of the control genotypes, and yet they are never seen among the HSCR cases. CONCLUSIONS: Our data suggest that genotypes comprising specific pairs of RET haplotypes are associated with predisposition to HSCR either in a simple autosomal recessive manner or in an additive, dose dependent fashion.

Alleles↗

PubMed2002

Specific haplotypes of the RET proto-oncogene are over-represented in patients with sporadic papillary thyroid carcinoma.

BACKGROUND: Papillary thyroid carcinoma (PTC), which may be sporadic (95%) or familial (5%), has a prevalence adjusted for age in the general population of 1:100 000. Somatic rearrangements of the RET proto-oncogene are present in up to 66% of sporadic tumours, while they are rarely found in familial cases. PURPOSE: In order to determine if some variants of this gene, or a combination of them, might predispose to PTC, we looked for an association of RET haplotype(s) in PTC cases and in controls from four countries matched for sex, age, and population. METHODS: Four single nucleotide polymorphisms (SNPs) across the RET coding sequence were typed and haplotype frequencies were estimated. Genotype and haplotype distributions were compared among these cases and controls. RESULTS: Ten haplotypes were observed, the seven most frequent of which have been previously described in sporadic Hirschsprung patients and controls. The single locus analyses suggested association of exon 2 and exon 13 SNPs with sporadic PTC. The haplotype analysis showed over-representation of one haplotype in French and Italian sporadic PTC, whereas a different haplotype was significantly under-represented in French familial PTC. CONCLUSIONS: Our data suggest that some variants of RET and some specific haplotypes may act as low penetrance alleles in the predisposition to PTC.

Age Factors↗

PubMed2004

Deriving haplotypes through recombination and gene conversion pathways.

Retracing the trajectories of past genetic events is crucial to understand the structure of the genome, both in individuals and across populations. A haplotype describes a string of polymorphic sites along a DNA segment. Haplotype diversity is due to mutations creating new variants, and to recombinations and gene conversions that mix and redistribute these variants among individual chromosomes in populations. A number of studies have revealed a relatively simple pattern of haplotype diversity in the human genome, dominated by a few common haplotypes representing founder ancestral ones. New haplotypes are usually rare and have a limited geographic distribution. We propose a method to derive a new haplotype from a set of putative ancestral haplotypes, once mutations in place, through minimal recombination and gene conversion pathways. We describe classes of pathways that represent the whole set of minimal pathways leading to a new haplotype. We show that obtaining this set of pathways can be represented as a problem of finding "secondary structures" of minimum energy. We present a polynomial algorithm solving this folding problem.

Algorithms↗

PubMed2005

The association of XRCC1 haplotypes and chromosomal damage levels in peripheral blood lymphocyte among coke-oven workers.

Theoretically, a haplotype has a higher level of heterozygosity than individual single nucleotide polymorphism (SNP) and the association study based on the haplotype may have an increased power for detecting disease associations compared with SNP-based analysis. In this study, we investigated the effects of four haplotype-tagging SNPs (htSNP) and the inferred haplotype pairs of the X-ray cross-complementing group 1 (XRCC1) gene on chromosome damage detected by the cytokinesis-block micronucleus assay. The study included 141 coke-oven workers with exposure to a high level of polycyclic aromatic hydrocarbons and 66 nonexposed controls. The frequencies of total MN and MNed cells were borderline associated with the Arg(194)Trp polymorphism (P = 0.053 and P = 0.050, respectively) but not associated with the Arg(280)His, Arg(399)Gln and Gln(632)Gln polymorphisms among coke-oven workers. Five haplotypes, including CGGG, TGGG, CAGG, CGAG, and CGGA, were inferred based on the four htSNPs of XRCC1 gene. The haplotype CGGG was associated with the decreased frequencies of total MN and MNed cells, and the haplotypes TGGG and CGAG were associated with the increased frequencies of total MN and MNed cells with adjustment for covariates among coke-oven workers. This study showed that the haplotypes derived from htSNPs in the XRCC1 gene were more likely than single SNPs to correlate with the polycyclic aromatic hydrocarbon-induced chromosome damage among coke-oven workers.

Adult↗

PubMedDate not supplied

Beta-globin gene cluster haplotypes of Amerindian populations from the Brazilian Amazon region.

We have determined the beta-globin cluster haplotypes for 80 Indians from four Brazilian Amazon tribes: Kayapó, Wayampí, Wayana-Apalaí, and Arára. The results are analyzed together with 20 Yanomámi previously studied. From 2 to 4 different haplotypes were identified for each tribe, and 7 of the possible 32 haplotypes were found in a sample of 172 chromosomes for which the beta haplotypes were directly determined or derived from family studies. The haplotype distribution does not differ significantly among the five populations. The two most common haplotypes in all tribes were haplotypes 2 and 6, with average frequencies of 0.843 and 0.122, respectively. The genetic affinities between Brazilian Indians and other human populations were evaluated by estimates of genetic distance based on haplotype data. The lowest values were observed in relation to Asians, especially Chinese, Polynesians, and Micronesians.

Brazil↗

PubMed2006

Variant IRAK-1 haplotype is associated with increased nuclear factor-kappaB activation and worse outcomes in sepsis.

RATIONALE: The IL-1 receptor-associated kinase (IRAK-1) plays a central role in TLR2- and TLR4-induced activation of nuclear factor (NF)-kappaB, a critical event in the transcriptional regulation of many sepsis-associated proinflammatory mediators. There are two haplotypes for the IRAK-1 gene in Caucasians, with the variant haplotype consisting of five intron single-nucleotide polymorphisms (SNPs) and three exon SNPs. OBJECTIVES: To examine the functional significance of the IRAK-1 variant haplotype in modifying nuclear translocation of NF-kappaB and affecting outcomes from sepsis. MEASUREMENTS AND MAIN RESULTS: One hundred fifty-five Caucasian patients with sepsis were included. Twenty-one (14%) were homozygous for the IRAK-1 variant haplotype as determined by a SNP in which T is replaced with C at nucleotide 1,595 within exon 12 of the IRAK-1 gene. The IRAK-1 variant haplotype was associated with increased nuclear levels of NF-kappaB in LPS-stimulated peripheral blood neutrophils from patients with sepsis compared with that found in patients with wild-type IRAK-1 haplotype (p=0.0009). There was an increased incidence of shock (p=0.047) (odds ratio [OR], 2.9; 95% confidence interval [CI], 1.1-7.7), greater requirement for more prolonged mechanical ventilator support (p=0.04) (OR, 2.7; 95% CI, 1.05-6.9), and higher 60-d mortality (p=0.05) (OR, 2.7; 95% CI, 1.0-6.8) in patients with the IRAK-1 variant haplotype compared with wild type. CONCLUSIONS: These results indicate that the IRAK-1 variant haplotype is functionally significant in patients with sepsis, being associated with increased nuclear translocation of NF-kappaB, more severe organ dysfunction, and higher mortality.

Adolescent↗

PubMed2006

Globally, CYP1B1 mutations in primary congenital glaucoma are strongly structured by geographic and haplotype backgrounds.

PURPOSE: To obtain a global perspective on the distribution and evolution of CYP1B1 mutations in primary congenital glaucoma (PCG) worldwide. METHODS: Five intragenic single-nucleotide polymorphisms in CYP1B1-R48G, A119S, V432L, D449D, and N453S-were used to generate haplotype data from 138 Indian patients with PCG and 132 ethnically matched normal controls, which were then analyzed in conjunction with data from other populations. Maximum-likelihood estimates of haplotype frequencies were estimated from the genotype data. Subsets of patients and normal control subjects were also genotyped with respect to eight short tandem repeat (STR) markers around the CYP1B1 locus (D2S305, D2S165, D2S367, D2S2259, D2S391, D2S3337, D2S23678, and D2S286), to gain evolutionary insights. RESULTS: Common mutations in CYP1B1 that are causal of PCG occurred on a uniform haplotype background among Indian patients, which is completely distinct from the modal haplotype background found among unaffected control subjects. Comparison of these data with data from other global regions reveals strong clustering of CYP1B1 mutations by geographic and haplotype backgrounds. The two distinct modal haplotypes found among Indian patients with PCG and control subjects are both ancient with ages of similar magnitudes, as indicated by large variances in the number of repeats at eight STR loci. Together with data from chimpanzee and normal control subjects from India and other global regions, it was possible to make a parsimonious reconstruction of the evolution of these haplotypes. CONCLUSIONS: The strong association of specific haplotypes with some predominant CYP1B1 mutations underlying PCG and the observed geographical clustering, probably due to founder effects, may be useful for predictive testing.

Africa↗

PubMed2005

Sequential analysis of tacrolimus dosing in adult lung transplant patients with ABCB1 haplotypes.

The genetic polymorphisms in the ABCB1 gene, which encodes for the membrane pump, P-glycoprotein, have been previously demonstrated to have an association with tacrolimus dosing in organ transplant patients. This study associated the haplotype and genotype for ABCB1 G2677T and C3435T variants with a sequential analysis of tacrolimus blood level (ng/mL) per mg/day dosage ([L/D]) administered to 91 adult lung transplant patients at 1, 3, 6, 9, and 12 months after transplantation. Haplotype 22 carriers had a significantly higher tacrolimus [L/D] value in comparison with nonhaplotype 22 carriers (P = .04) only at 1 month after transplant. Sequential analysis demonstrated that ABCB1 genotypes 00 and 01 had low tacrolimus [L/D] values at 1 and 3 months, but these values increased substantially at 6, 9, and 12 months after transplantation. This was not true of the other genotypes with the exception of genotypes 10 and 21, which had small numbers of patients but had consistently low tacrolimus [L/D]. Haplotype analysis also suggested that the homozygous for ABCB1 2677 variant allele had more of an impact on tacrolimus [L/D] in haplotype analysis than that of ABCB1 3435. In conclusion, sequential analysis of tacrolimus [L/D] with haplotypes can explain previous clinical observations of changes in tacrolimus dosage over time but suggests that this effect is limited to individual patient haplotypes. Sequential analysis of drug dosing and haplotypes relationships can provide important information about the induction or inhibition of drug-drug and disease-drug interactions among specific haplotypes.

ATP-Binding Cassette Transporters↗

PubMed1996

TNF microsatellites in systemic lupus erythematosus-a high frequency of the TNFabc 2-3-1 haplotype in multicase SLE families.

TNFa, TNFb and TNFc microsatellites were analyzed in 102 SLE patients recruited from a defined area in Southern Sweden. Furthermore we studied 27 SLE patients belonging to 10 multiplex families in which a majority of the members were living within the same area in Southern Sweden. As a control population 98 healthy blood donors from the same region was used. The TNFa2 allele was found more often in the SLE patients (48%) than in the normal controls (33%) (P < 0.01). A low frequency of the TNFa4 allele (10%) vs 16% in controls was observed. The family study showed that the TNFabc haplotype 2-3-1 was more common in SLE associated haplotypes than in non-SLE haplotypes (P < 0.001). The 2-3-1 haplotype was associated with the extended haplotype MHC haplotype [HLA-B8,SC01,DR17]. The results suggest that TNF haplotypes do not constitute special markers of susceptibility to SLE but reflect the increased frequencies of specific intact haplotypes already known to be associated with the disease.

Adolescent↗

PubMed2006

HaploRec: efficient and accurate large-scale reconstruction of haplotypes.

BACKGROUND: Haplotypes extracted from human DNA can be used for gene mapping and other analysis of genetic patterns within and across populations. A fundamental problem is, however, that current practical laboratory methods do not give haplotype information. Estimation of phased haplotypes of unrelated individuals given their unphased genotypes is known as the haplotype reconstruction or phasing problem. RESULTS: We define three novel statistical models and give an efficient algorithm for haplotype reconstruction, jointly called HaploRec. HaploRec is based on exploiting local regularities conserved in haplotypes: it reconstructs haplotypes so that they have maximal local coherence. This approach--not assuming statistical dependence for remotely located markers--has two useful properties: it is well-suited for sparse marker maps, such as those used in gene mapping, and it can actually take advantage of long maps. CONCLUSION: Our experimental results with simulated and real data show that HaploRec is a powerful method for the large scale haplotyping needed in association studies. With sample sizes large enough for gene mapping it appeared to be the best compared to all other tested methods (Phase, fastPhase, PL-EM, Snphap, Gerbil; simulated data), with small samples it was competitive with the best available methods (real data). HaploRec is several orders of magnitude faster than Phase and comparable to the other methods; the running times are roughly linear in the number of subjects and the number of markers. HaploRec is publicly available at http://www.cs.helsinki.fi/group/genetics/haplotyping.html.

Chromosome Mapping↗