Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Haplotype phasing”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 343 records · Page 19Linked to original sources
PubMed2006

Linkage disequilibrium on chromosome 6 in Australian Holstein-Friesian cattle.

We analysed linkage disequilibrium (LD) in Australian Holstein-Friesian cattle by genotyping a sample of 45 bulls for 15 closely-spaced microsatellites on two regions of BTA6 reported to carry important QTL for dairy traits. The order and distance of markers were based on the USDA-MARC linkage map. Frequencies of haplotypes were estimated using the E-M approach and a more computationally-intensive Bayesian approach as implemented in PHASE. LD was then estimated using the Hedrick multiallelic extension of Lewontin normalised coefficient D'. Estimates of D' from the two approaches were in close agreement (r = 0.91). The mean estimates of D' for marker pairs with an inter-marker distance of less than 5 cM (n = 13) are 0.57 and 0.51, and for distances more than 20 cM (n = 44) are 0.29 and 0.17, estimated from the E-M and Bayesian approaches, respectively. The Malecot model was fitted for the exponential decline of LD with map distance between markers. The swept radii (the distance at which LD has declined to 1/e ( approximately 37%) of its initial value) are 11.6 and 13.7 cM for the above two methods, respectively. The Malecot model was also fitted using map distance in Mb from the bovine integrated map (bovine location database, bLDB) in addition to cM from the MARC map. Overall, the results indicate a high level of LD on chromosome 6 in Australian dairy cattle.

Animals↗
PubMed1982

Acute autoimmune encephalomyelitis in mice. II. Susceptibility is controlled by the combination of H-2 and histamine sensitization genes.

The expression of acute experimental autoimmune encephalomyelitis (EAE) in mice is controlled by several dominant genes, H-2 and histamine sensitization genes. SJL/J and SWR/J, which are H-2s and H-2q, respectively, are susceptible to EAE and sensitive to Bordetella pertussis histamine-sensitizing factor (HSF), which produces a vasoactive amine hypersensitivity. Other H-2s or H-2q strains such as A.SW, B10.Q and several others do not develop acute EAE and are not sensitive to B. pertussis HSF. One strain tested, DDD (KsIsD?) is HSF sensitive but does not develop EAE (presumably because it lacks the appropriate responder H-2 haplotype). However, F1 hybrids between B10.S and DDD are sensitive to HSF and develop EAE. The induction and effector phases of acute EAE are apparently controlled by the combination of H-2 and HSF genes. A combination of the correct H-2 hapotype and histamine sensitivity is required for the development of acute EAE.

Acute Disease↗
PubMed2007

Chromosome 7p linkage and GPR154 gene association in Italian families with allergic asthma.

BACKGROUND: Several genome scans have reported linkage of markers on chromosome 7p with asthma and related phenotypes in different populations. A fine mapping in Finnish and French-Canadian populations has associated the GPR154 gene (also known as G-protein-coupled receptor for asthma susceptibility, GPRA) with elevated IgE or asthma. OBJECTIVE: To confirm chromosome 7p linkage and candidate gene association in Italian families with atopic asthma. METHODS: In a two-phase approach, we first performed a linkage analysis of chromosome 7, and then a family-based association study on the GPR154 gene for allergic asthma phenotypes in the Italian population. RESULTS: The screening of 117 families with 19 microsatellite markers showed potential linkage for elevated IgE (P<0.002 at 22 cM from p-ter), asthma (P<0.005 at 44 cM), or atopy (P<0.005 at 54 cM). In the second phase of the present study, candidate gene GPR154, which is located in the phase one-linked region, was investigated in 211 families with seven single nucleotide polymorphisms (SNPs) that tag most haplotype variability, by the pedigree disequilibrium test. Elevated IgE levels were associated with two GPR154 gene SNPs (SNP 546333, P=0.0046; rs740 347, P=0.006), and with haplotypes in the global test (P=0.013). Haplotype analysis performed in nuclear families having at least 1 asthmatic parent showed a significant association with asthma (P=0.0173), atopy (P=0.0058), SPT (P=0.0025), and bronchial hyper reactivity (P=0.0163). CONCLUSION: These results support a susceptibility locus for asthma and related phenotypes on chromosome 7, and are in agreement with recent reports suggesting that a common susceptibility factor for atopic manifestations in asthma is likely conferred by the locus containing the GPR154 gene.

Asthma↗
PubMed1989

Idiotypic and anti-idiotypic B-B cell interaction is controlled by major histocompatibility complex-restricted regulation.

We have previously reported that the immunization of BALB/c mice with MOPC-104E myeloma protein (M104E) induced idiotype-specific Ly 1-negative B lymphocytes that had an ability to enhance idiotype-positive anti-dextran antibody production. It was also shown that the cell interaction between idiotypic and anti-idiotypic B lymphocytes was observed in a class II-restricted manner. The effect of monoclonal anti-class II antibody on the B-B cell interaction is investigated in this report. The addition of anti-I-A or anti-I-E monoclonal antibody into the B-B cell interaction system, from both BALB/c (H-2d) and BALB.K (H-2k), inhibited the enhanced antibody production mediated by idiotype-immune B lymphocytes. Interestingly, however, it was revealed that the anti-I-A and anti-I-E antibodies acted differently on each B-lymphocyte population. Pretreatment of an anti-idiotypic (idiotype-immune) enhancing B-lymphocyte population with anti-I-A antibody diminished its enhancing activity, while anti-I-E did not. On the other hand, pretreatment of dextran-immune antibody producing B cells with anti-I-A antibody showed no effect, while anti-I-E inhibited anti-dextran antibody production. When the enhancing B-lymphocyte population of F1 mice was treated with anti-I-A antibody specific for one of their parents' haplotypes, co-operation with the respective haplotype B cells was inhibited, but the other haplotype was not. The inhibitory effect of anti-class II antibodies could only be seen at the early phase of culture period. Taken together, the results of these experiments suggest that the class II antigens are concerned with the self-recognitive cell interaction among B lymphocytes in the frame of idiotype network systems.

Animals↗
PubMed2003

A comparison of bayesian methods for haplotype reconstruction from population genotype data.

In this report, we compare and contrast three previously published Bayesian methods for inferring haplotypes from genotype data in a population sample. We review the methods, emphasizing the differences between them in terms of both the models ("priors") they use and the computational strategies they employ. We introduce a new algorithm that combines the modeling strategy of one method with the computational strategies of another. In comparisons using real and simulated data, this new algorithm outperforms all three existing methods. The new algorithm is included in the software package PHASE, version 2.0, available online (http://www.stat.washington.edu/stephens/software.html).

Algorithms↗
PubMed2005

Accounting for decay of linkage disequilibrium in haplotype inference and missing-data imputation.

Although many algorithms exist for estimating haplotypes from genotype data, none of them take full account of both the decay of linkage disequilibrium (LD) with distance and the order and spacing of genotyped markers. Here, we describe an algorithm that does take these factors into account, using a flexible model for the decay of LD with distance that can handle both "blocklike" and "nonblocklike" patterns of LD. We compare the accuracy of this approach with a range of other available algorithms in three ways: for reconstruction of randomly paired, molecularly determined male X chromosome haplotypes; for reconstruction of haplotypes obtained from trios in an autosomal region; and for estimation of missing genotypes in 50 autosomal genes that have been completely resequenced in 24 African Americans and 23 individuals of European descent. For the autosomal data sets, our new approach clearly outperforms the best available methods, whereas its accuracy in inferring the X chromosome haplotypes is only slightly superior. For estimation of missing genotypes, our method performed slightly better when the two subsamples were combined than when they were analyzed separately, which illustrates its robustness to population stratification. Our method is implemented in the software package PHASE (v2.1.1), available from the Stephens Lab Web site.

Algorithms↗
PubMed2005

Haplotype reconstruction for diploid populations.

The inference of haplotype pairs directly from unphased genotype data is a key step in the analysis of genetic variation in relation to disease and pharmacogenetically relevant traits. Most popular methods such as Phase and PL do require either the coalescence assumption or the assumption of linkage between the single-nucleotide polymorphisms (SNPs). We have now developed novel approaches that are independent of these assumptions. First, we introduce a new optimization criterion in combination with a block-wise evolutionary Monte Carlo algorithm. Based on this criterion, the 'haplotype likelihood', we develop two kinds of estimators, the maximum haplotype-likelihood (MHL) estimator and its empirical Bayesian (EB) version. Using both real and simulated data sets, we demonstrate that our proposed estimators allow substantial improvements over both the expectation-maximization (EM) algorithm and Clark's procedure in terms of capacity/scalability and error rate. Thus, hundreds and more ambiguous loci and potentially very large sample sizes can be processed. Moreover, applying our proposed EB estimator can result in significant reductions of error rate in the case of unlinked or only weakly linked SNPs.

Algorithms↗
PubMed2004

Little loss of information due to unknown phase for fine-scale linkage-disequilibrium mapping with single-nucleotide-polymorphism genotype data.

We present the results of a simulation study that indicate that true haplotypes at multiple, tightly linked loci often provide little extra information for linkage-disequilibrium fine mapping, compared with the information provided by corresponding genotypes, provided that an appropriate statistical analysis method is used. In contrast, a two-stage approach to analyzing genotype data, in which haplotypes are inferred and then analyzed as if they were true haplotypes, can lead to a substantial loss of information. The study uses our COLDMAP software for fine mapping, which implements a Markov chain-Monte Carlo algorithm that is based on the shattered coalescent model of genetic heterogeneity at a disease locus. We applied COLDMAP to 100 replicate data sets simulated under each of 18 disease models. Each data set consists of haplotype pairs (diplotypes) for 20 SNPs typed at equal 50-kb intervals in a 950-kb candidate region that includes a single disease locus located at random. The data sets were analyzed in three formats: (1). as true haplotypes; (2). as haplotypes inferred from genotypes using an expectation-maximization algorithm; and (3). as unphased genotypes. On average, true haplotypes gave a 6% gain in efficiency compared with the unphased genotypes, whereas inferring haplotypes from genotypes led to a 20% loss of efficiency, where efficiency is defined in terms of root mean integrated square error of the location of the disease locus. Furthermore, treating inferred haplotypes as if they were true haplotypes leads to considerable overconfidence in estimates, with nominal 50% credibility intervals achieving, on average, only 19% coverage. We conclude that (1). given appropriate statistical analyses, the costs of directly measuring haplotypes will rarely be justified by a gain in the efficiency of fine mapping and that (2). a two-stage approach of inferring haplotypes followed by a haplotype-based analysis can be very inefficient for fine mapping, compared with an analysis based directly on the genotypes.

Algorithms↗
PubMed2001

Association between the ancestral haplotype HLA A30B18DR3 and multiple sclerosis in central Sardinia.

Association and linkage studies have established the importance of the major histocompatibility complex (MHC) in the susceptibility for multiple sclerosis (MS). We carried out a case-control study to investigate the ancestral haplotype A30B18DR3 and MS in the Nuoro population of Sardinia, which is isolated and genetically distinct from other populations in the Mediterranean basin and characterized by genetic homogeneity, high level of inbreeding, low migration, high prevalence of MS, high frequency of the relevant haplotype, and high past malaria prevalence. Cases and controls were serologically typed for the currently recognized HLA-A, B, and DR antigens. We used a log-linear approach to fit a wide class of models. We tested our hypothesis comparing different models via a likelihood ratio test. We overcame the complication due to unknown gametic phase using expectation-maximization (EM) algorithm as the estimation method. We estimated confidence intervals for odds ratio by using a profile likelihood approach. We found that: (1) the ancestral haplotype A30B18DR3 was associated to MS after allowing for a possible stratification in cases and controls; (2) DR3 allele was conditional independent on disease status, given A30B18 haplotype; (3) there was a tendency for ORs for the high-risk haplotypes to be higher in the high malaria strata; however, this indication did not achieve statistical significance (P = 0.11).

Alleles↗
PubMed1980

Genetic regulation of delayed-type hypersensitivity responses to poly(LTyr,LGu)-poly(DLAla)--poly(LLys). I. Expression of the genetic defect at two phases of the immune process.

Delayed-type hypersensitivity (DTH) responses served in this study as an experimental model for the analysis of genetic regulations of T-cell responses. Educated irradiated cells from H-2b mice mediated responses in syngeneic recipients, whereas mice of the a, d, f, k, and s haplotypes were nonresponders to poly(LTyr,LGlu)-poly(DLAla)--poly(LLys)[(T,G)-A--L]. These results suggest that cell-mediated immune responsiveness to (T,G)-A--L is linked to the H-2 complex, as was shown for humoral responses. Educated irradiated T cells of F1 hybrids between high and low responders mediated DTH responses, which indicates that the gene(s) controlling the DTH responses is dominant. To analyze the genetic defect in DTH responses to (T,G)-A--L, we separated the T-cell activation phase from the effector phase that was determined in recipient mice. Two types of nonresponders were observed: (a) When lymphocytes of the a or k haplotypes were educated in a syngeneic environment and then transferred into hybrids between the parental (nonresponder x responder) F1 recipients, DTH responses could have been manifested. (b) On the other hand, no DTH responses could be mediated by transferring educated cells of the H-2s or H-2f origin into the appropriate F1 recipients. In addition, irradiated F1 cells that had been activated to (T,G)-A--L could not mediate DTH responses in both types of nonresponder recipients. These results suggest that T cells of H-2k or H-2a mice can be activated to generate DTH responses to (T,G)-A--L and that the defect in these mouse strains is expressed in another cell population needed for the manifestation of the DTH reaction in the recipient mice. In contrast, T cells of H-2s and H-2f origin cannot be activated to (T,G)-A--L and, thus, fail to manifest DTH responses.

Animals↗
PubMed1999

Different manifestations of Toxoplasma gondii infection in F344 and LEW rats.

There is evidence that not only the immune status, but also the genetic predisposition of certain hosts influence the clinical outcome of Toxoplasma gondii infection. By far the majority of our knowledge on genetic and immunological mechanisms involved in control of T. gondii infection has been obtained by studying mouse models, which in terms of clinical outcome of infection differ considerably from humans. Rats which show a rather similar course of infection in comparison to humans have not so far been investigated for effects of genetic differences on course of the infection. In this study we show that, like mice, different strains of rats exhibit a remarkable variation in the number of brain cysts arising from chronic infection. LEW rats seem to be highly resistant to cyst formation, in contrast to F344 rats that are susceptible. In addition, F344 rats express high numbers of gammadelta T cells during the acute phase of infection, whereas LEW rats express elevated but comparably low numbers of gammadelta T cells. The RT1 (rat MHC) haplotypes of both strains are identical in the RT1A and RT1B/D regions, which encode the restriction elements for conventional peptide antigens. Consequently, rat strain-specific differences may be useful to define MHC-independent mechanisms of resistance against T. gondii, which may also act in humans.

Animals↗
PubMed2000

Biogeography of a southern hemisphere freshwater fish: how important is marine dispersal?

Galaxias maculatus is one of the world's most widely distributed freshwater fish. This species has a marine-tolerant juvenile phase, and a geographical range extending through much of the southern hemisphere. We conducted phylogeographic analyses of 163 control region haplotypes of G. maculatus, including samples from New Zealand (five locations), Tasmania (one location) and Chile (one location). A lack of genetic structure among New Zealand samples suggests that marine dispersal facilitates considerable gene flow on an intra-continental scale. The discovery of a Tasmanian-like haplotype in one of 144 New Zealand samples indicates that inter-continental marine dispersal occurs but is insufficient to prevent mitochondrial DNA differentiation among continents. The sister relationship of Tasmanian and New Zealand clades implies that marine dispersal is an important biogeographical mechanism for this species. However, a vicariant role in the divergence of eastern and western Pacific G. maculatus cannot be rejected.

Animals↗
PubMed2001

Paraoxonase genotype modifies the effect of pravastatin on high-density lipoprotein cholesterol.

Paraoxonase (PON) is an enzyme carried by high-density lipoprotein cholesterol (HDL-C). Two gene polymorphisms leading to amino acid substitutions of methionine for leucine at position 55 (M/L55) and arginine for glutamine at position 192 (R/Q192) modulate the activity of the enzyme and possibly also lipid and apolipoprotein concentrations. Our purpose was to examine the effect of the PON genotype on HDL-C and apolipoprotein AI (apo AI) responses to pravastatin treatment. Fifty-one mildly hypercholesterolemic male subjects (mean age 35 +/- 4 years) were enrolled by this prospective, randomized, double-blind study. Lipid concentrations were measured at baseline and after 6 months of pravastatin (n = 25) or placebo (n = 26) therapy. Low active (MM, ML or QQ) and high active (LL or RQ, RR) PON genotype groups were related to lipid and apolipoprotein concentration changes. Pravastatin increased the apo AI concentration 12% (P = 0.017, RANOVA) and tended to increase the HDL-C concentration (P = 0.095, RANOVA) in R allele carriers but not in QQ homozygotes. Significant predictors of the change in apo AI concentration during pravastatin treatment were R/Q192 genotype (P = 0.002), apo AI concentration at baseline (P = 0.002) and M/L55 genotype (P = 0.042). Correspondingly, R/Q192 (P = 0.009) and M/L55 (P = 0.050) genotypes were the statistically significant determinants of HDL-C concentration change. The PON genotype thus modifies the effect of pravastatin on serum HDL-C and apo AI concentrations. This could partly explain the contradictory results obtained from previous studies on the effects of statins on the serum HDL-C concentration.

Adult↗
PubMed2026

A chromosome-level, haplotype-resolved genome assembly for the barn owl, Tyto alba.

Recent advances in long-read sequencing have enabled near telomere-to-telomere (T2T) assemblies across diverse taxa. However, avian genomes remain challenging due to numerous microchromosomes, small, typically < 20Mb, DNA molecules that are gene-, GC-, and repeat-rich. As a consequence, microchromosomes are often missing from genome assemblies. Here, we present a chromosome-level, haplotype-resolved genome assembly for the Western barn owl (Tyto alba). Using a trio-binning strategy with Illumina parental reads combined with PacBio HiFi and Oxford Nanopore Technologies data, we generated two phased contig sets. These were scaffolded into 40 linkage groups using a linkage map. Comparative analyses identified unplaced HiFi scaffolds corresponding to microchromosomes, which we integrated into six additional microchromosomes using long reads information. The two assemblies present 46 chromosomes, matching the karyotype of the species. They exhibit strong synteny between parental haplotypes, except for a &#x223c;38 Mb complex region on chromosome 7 containing nested inversions. This high-quality reference provides a haplotype-resolved and chromosome-level genome for Strigiformes, enabling fine-scale studies of structural variation and avian genome evolution.

Tyto alba↗
PubMed2002

Influence of vascular endothelial growth factor single nucleotide polymorphisms on tumour development in cutaneous malignant melanoma.

Vascular endothelial growth factor (VEGF) is a potent regulator of vasculogenesis and tumour angiogenesis. We have investigated whether the VEGF -2578, -1154, +405 and +936 SNPs and associated haplotypes confer susceptibility to and/or influence prognosis in cutaneous malignant melanoma (CMM) skin cancer. A total of 152 CMM patients and 266 controls were genotyped for VEGF promoter SNPs by ARMS-PCR. Strong linkage disequilibrium between the -2578, -1154 and +405 SNPs was detected (association, rho = 0.488-0.965), but not between these SNPs and SNP +936 (association, rho = 0.004-0.130). No SNPs or three SNP haplotypes (-2578, -1154, +405) were significantly associated with CMM, although a number of non-significant trends were observed. However, the VEGF -1154 AA genotype and -2578, -1154, +405 CAC haplotype were both significantly associated with less advanced (Stage 1) disease (P = 0.03). In addition, the VEGF -1154 AA genotype was associated with thinner primary vertical growth phase tumours (P = 0.002), while VEGF -1154 GG was associated with thicker primary tumours (P = 0.02). These preliminary results indicate that VEGF genotype may influence tumour growth in CMM, possibly via the effects of differential VEGF expression on tumour angiogenesis.

Endothelial Growth Factors↗
PubMed1998

Haplotype construction of sires with progeny genotypes based on an exact likelihood.

A maximum likelihood method is presented that can be used to construct parental haplotypes based on their progeny genotypes. The exact error rate and choice of family size in haplotype construction were evaluated through mathematical expressions and numerical examples. Numerical results suggest that, if two markers are tightly linked (< or = 10 cM) and each has intermediate allele frequencies, a difference of one between progeny receiving parental and recombinant gametes is sufficient for constructing sire linkage phase; a difference of two or more progeny is required with two markers 30 cM apart. When each of two adjacent markers has two alleles with equal allelic frequencies, genotyping 10 and 50 progeny are needed to achieve a power of 0.85 for constructing a sire linkage phase of two tightly (10 cM) and moderately tightly linked (30 cM) markers, respectively. The family size is reduced by approximately half when both markers have three alleles with equal frequencies. Results suggest that, when an experiment requiring haplotype determination of a parent is being designed, researches should choose the appropriate threshold and family size in the context of marker allelic frequencies and recombination fractions.

Alleles↗
PubMed1994

Toward fully automated genotyping: allele assignment, pedigree construction, phase determination, and recombination detection in Duchenne muscular dystrophy.

Human genetic maps have made quantum leaps in the past few years, because of the characterization of > 2,000 CA dinucleotide repeat loci: these PCR-based markers offer extraordinarily high PIC, and within the next year their density is expected to reach intervals of a few centimorgans per marker. These new genetic maps open new avenues for disease gene research, including large-scale genotyping for both simple and complex disease loci. However, the allele patterns of many dinucleotide repeat loci can be complex and difficult to interpret, with genotyping errors a recognized problem. Furthermore, the possibility of genotyping individuals at hundreds or thousands of polymorphic loci requires improvements in data handling and analysis. The automation of genotyping and analysis of computer-derived haplotypes would remove many of the barriers preventing optimal use of dense and informative dinucleotide genetic maps. Toward this end, we have automated the allele identification, genotyping, phase determinations, and inheritance consistency checks generated by four CA repeats within the 2.5-Mbp, 10-cM X-linked dystrophin gene, using fluorescein-labeled multiplexed PCR products analyzed on automated sequencers. The described algorithms can deconvolute and resolve closely spaced alleles, despite interfering stutter noise; set phase in females; propagate the phase through the family; and identify recombination events. We show the implementation of these algorithms for the completely automated interpretation of allele data and risk assessment for five Duchenne/Becker muscular dystrophy families. The described approach can be scaled up to perform genome-based analyses with hundreds or thousands of CA-repeat loci, using multiple fluorophors on automated sequencers.

Alleles↗
PubMed1999

Fine-mapping of quantitative trait loci by identity by descent in outbred populations: application to milk production in dairy cattle.

We previously mapped a quantitative trait locus (QTL) affecting milk production to bovine chromosome 14. To refine the map position of this QTL, we have increased the density of the genetic map of BTA14q11-16 by addition of nine microsatellites and three single nucleotide polymorphisms. Fine-mapping of the QTL was accomplished by a two-tiered approach. In the first phase, we identified seven sires heterozygous "Qq" for the QTL by marker-assisted segregation analysis in a Holstein-Friesian pedigree comprising 1,158 individuals. In a second phase, we genotyped the seven selected sires for the newly developed high-density marker map and searched for a shared haplotype flanking an hypothetical, identical-by-descent QTL allele with large substitution effect. The seven chromosomes increasing milk fat percentage were indeed shown to carry a common chromosome segment with an estimated size of 5 cM predicted to contain the studied QTL. The same haplotype was shown to be associated with increased fat percentage in the general population as well, providing additional support in favor of the location of the QTL within the corresponding interval.

Animals↗