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Results for “Haplotype structures”

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PubMed2005

No association between microsomal triglyceride transfer protein (MTP) haplotype and longevity in humans.

Human longevity is a multifactorial condition with a significant genetic contribution. A recent association study in two independent samples of long-lived U.S. Caucasians [long-lived individuals (LLI)] identified a SNP haplotype of the microsomal triglyceride transfer protein (MTP, 4q25) that was underrepresented among LLI when compared with younger controls. This suggested that variation in the MTP gene might modify human longevity. Because of its function in lipid metabolism, the MTP gene product could plausibly play a pivotal role in the physiology of aging. However, the association observed in the U.S. samples could not be replicated by the same authors in a larger French LLI sample. We have therefore investigated the MTP "risk" haplotype in our own collection of 1,589 German nonagenarians, centenarians, and appropriately matched controls. No statistically significant differences were observed between LLI and controls at the allele, genotype, or haplotype level. This indicates that a noteworthy influence of the respective MTP haplotype on human longevity in the German population is unlikely. Furthermore, in comparison with all other U.S. and European samples analyzed, the MTP "risk" haplotype was found to be overrepresented only in the U.S. controls. This implies that the putative association is more likely to reflect recent changes in the genetic structure of the U.S. Caucasian population as a whole, rather than genetic effects upon survival to old age. In our view, the original study therefore highlights potential problems that arise when the case-control design is used as a means to map longevity genes in humans.

Aged↗

PubMed2005

Comparison of type I error for multiple test corrections in large single-nucleotide polymorphism studies using principal components versus haplotype blocking algorithms.

Although permutation testing has been the gold standard for assessing significance levels in studies using multiple markers, it is time-consuming. A Bonferroni correction to the nominal p-value that uses the underlying pair-wise linkage disequilibrium (LD) structure among the markers to determine the number of effectively independent tests has recently been proposed. We propose using the number of independent LD blocks plus the number of independent single-nucleotide polymorphisms for correction. Using the Collaborative Study on the Genetics of Alcoholism LD data for chromosome 21, we simulated 1,000 replicates of parent-child trio data under the null hypothesis with two levels of LD: moderate and high. Assuming haplotype blocks were independent, we calculated the number of independent statistical tests using 3 haplotype blocking algorithms. We then compared the type I error rates using a principal components-based method, the three blocking methods, a traditional Bonferroni correction, and the unadjusted p-values obtained from FBAT. Under high LD conditions, the PC method and one of the blocking methods were slightly conservative, whereas the 2 other blocking methods exceeded the target type I error rate. Under conditions of moderate LD, we show that the blocking algorithm corrections are closest to the desired type I error, although still slightly conservative, with the principal components-based method being almost as conservative as the traditional Bonferroni correction.

Algorithms↗

PubMed2000

The dynamics of natural selection and vicariance in the Dominican anole: patterns of within-island molecular and morphological divergence.

The larger islands of the Lesser Antilles are ecologically and geologically complex and are inhabited by single, but morphologically variable, Anolis species. Although earlier work has indicated that a large part of the morphological variation in Anolis oculatus from Dominica can be attributed to selection, a history of recurrent volcanic activity over the last few million years suggests that vicariance may have also played a significant role. We report a study of variation in the cytochrome b gene of mitochondrial DNA across the island to address this issue. We uncovered a very high degree of polymorphism, with an overall gene diversity of 0.97 and a nucleotide diversity of 0.04. Sequences, on average, differ by 3.82% and the maximum pairwise divergence (corrected for multiple hits) is 9.29%. Most haplotypes are restricted to single localities (a pattern not changed by increasing the sample size). Phylogenetic analysis revealed the presence of two distinct lineages on the island with strong phylogeographic structure. One of these is geographically restricted to a relatively small part of the central Caribbean coast. Sublineages were also discernible within the other more widely distributed lineage, but resolution within and support for these sublineages was poor. The phylogeographic pattern is not congruent with generalized body shape and scalation, but is significantly correlated with color pattern. Even when correcting for this lineage effect with partial Matrix correspondence tests, the relationship between color pattern and vegetation is reaffirmed, suggesting that although both vicariance and selection have played a role in the morphological differentiation of this species, selection for current environmental conditions has been more important. We discuss the causes of the phylogeographic structure in light of the volcanic history of the island and highlight the exceptional instance of congruence between all morphological character systems and lineage boundaries, which occurs at the transition between the northern and southern Caribbean ecotypes.

Animals↗

PubMed1999

Assessment of linkage disequilibrium by the decay of haplotype sharing, with application to fine-scale genetic mapping.

Linkage disequilibrium (LD) is of great interest for gene mapping and the study of population history. We propose a multilocus model for LD, based on the decay of haplotype sharing (DHS). The DHS model is most appropriate when the LD in which one is interested is due to the introduction of a variant on an ancestral haplotype, with recombinations in succeeding generations resulting in preservation of only a small region of the ancestral haplotype around the variant. This is generally the scenario of interest for gene mapping by LD. The DHS parameter is a measure of LD that can be interpreted as the expected genetic distance to which the ancestral haplotype is preserved, or, equivalently, 1/(time in generations to the ancestral haplotype). The method allows for multiple origins of alleles and for mutations, and it takes into account missing observations and ambiguities in haplotype determination, via a hidden Markov model. Whereas most commonly used measures of LD apply to pairs of loci, the DHS measure is designed for application to the densely mapped haplotype data that are increasingly available. The DHS method explicitly models the dependence among multiple tightly linked loci on a chromosome. When the assumptions about population structure are sufficiently tractable, the estimate of LD is obtained by maximum likelihood. For more-complicated models of population history, we find means and covariances based on the model and solve a quasi-score estimating equation. Simulations show that this approach works extremely well both for estimation of LD and for fine mapping. We apply the DHS method to published data sets for cystic fibrosis and progressive myoclonus epilepsy.

Algorithms↗

PubMed2026

Comparative genomics reveals lineage-associated structural variation and diversification in a barley fungal pathogen.

Leaf rust, caused by Puccinia hordei, is a major barley disease worldwide. Despite repeated shifts in virulence, contrasting reproductive histories, and emerging fungicide insensitivity, the genomic basis of its diversification and adaptation remains poorly understood. In this study, we generated haplotype-resolved, chromosome-level genome assemblies for two isolates with contrasting virulence and analyzed 41 Australian isolates collected over 54 yr (1966-2020), integrating comparative and population genomics, mating-type gene phylogenies, chromosome-specific k-mer profiling, genome-wide copy-number variation (CNV) analysis, and gene-expression analysis. We identified a structurally dynamic chromosome characterized by repeat-associated rearrangements, structural variation, and lineage-associated CNV, representing the first evidence in a rust fungus of chromosome-scale structural diversification of this extent. Population analyses distinguished clonally expanded lineages from recombination-associated lineages, with mating-type gene phylogenies providing further support for lineage differentiation. More recently collected isolates showed increased duplication-associated variation, and CNV boundaries were associated with structural-variant breakpoints. We also identified lineage-associated amplification of Cyp51, with increased copy number associated with higher transcript abundance, supporting a potential role in fungicide adaptation. Overall, our findings highlight structural variation, contrasting reproductive histories, and lineage-associated CNV as important contributors to diversification in P. hordei, providing insights for future rust pathogen surveillance and management strategies.

Cyp51 gene↗

PubMed2004

Limited phylogeographical structure across Eurasia in two red wood ant species Formica pratensis and F. lugubris (Hymenoptera, Formicidae).

The phylogeography and demographic history of two closely related species of the red wood ant (Formica pratensis and F. lugubris) were examined across Eurasia. The phylogeny based on a 1.5-kilobase mitochondrial DNA fragment, including the cytochrome b gene and part of the ND6 gene, showed one phylogeographical division in F. pratensis. This division (0.7% of nucleotide divergence) suggests postglacial colonization of western Europe and of a wide area ranging from Sweden on the west to Lake Baikal on the east from separate forest refugia. In two localities, mitochondrial DNA has been transferred from F. lugubris to F. pratensis and all the individuals of F. pratensis sampled from the Pyrenees had haplotypes clustering in the lugubris clade. No phylogeographical divisions were detected in F. lugubris. Comparison of species-wide phylogeography between the two sympatrically distributed species of ant demonstrates a difference in phylogeographical structure that implies different vicariant histories. However, over most of the species' distribution ranges, similar signs of demographic expansion predating the last glaciation and the lack of phylogeographical structure were found in both the eastern phylogroup of F. pratensis and F. lugubris. This finding is highly consistent with the results reported for all other boreal forest animal species studied to date in Eurasia. Contraction of the distribution range of each species to a single refugial area at different times during the late Pleistocene and a subsequent population expansion seem to be an explanation for the lack of phylogeographical structure across most of Eurasia in species that are ecologically associated with the boreal forest.

Animals↗

PubMed2005

Allelic series of four powdery mildew resistance genes at the Pm3 locus in hexaploid bread wheat.

At the Pm3 locus in hexaploid wheat (Triticum aestivum), 10 alleles conferring race-specific resistance to powdery mildew (Blumeria graminis f. sp. tritici) are known. A cluster of genes encoding coiled-coil-nucleotide-binding site-leucine-rich repeat proteins spans the Pm3 locus on wheat chromosome 1A, and one member of this gene family has recently been identified as the Pm3b resistance gene. Using molecular markers closely linked to Pm3b, we performed haplotype analysis of 10 lines carrying different Pm3 alleles. All these lines have a conserved genomic region delimited by markers cosegregating with Pm3b and including a structurally conserved Pm3b-like gene. A polymerase chain reaction-based strategy allowed the amplification of one Pm3b-like sequence from lines carrying Pm3a, Pm3d, and Pm3f alleles. These candidate genes for Pm3a, Pm3d, and Pm3f conferred AvrPm3a-, AvrPm3d-, and AvrPm3f-dependent resistance, respectively, to wheat powdery mildew in a single cell transient transformation assay. A high level of amino acid similarity (97.8%) was found between the PM3A, PM3B, PM3D, and PM3F proteins. The coiled-coil domain was 100% conserved, whereas, in the nucleotide binding site region, sequence exchange was detected, indicating intragenic recombination or gene conversion between alleles. All these results indicate that Pm3a, Pm3b, Pm3d, and Pm3f form a true allelic series. The low level of sequence divergence between the four characterized alleles as well as the finding of a conserved Pm3 haplotype are in agreement with the hypothesis of a recent evolution of Pm3-based resistance, suggesting that some or most of the diversity found at the Pm3 locus in modern wheat has evolved after wheat domestication.

Alleles↗

PubMed2004

Linkage disequilibrium mapping via cladistic analysis of single-nucleotide polymorphism haplotypes.

We present a novel approach to disease-gene mapping via cladistic analysis of single-nucleotide polymorphism (SNP) haplotypes obtained from large-scale, population-based association studies, applicable to whole-genome screens, candidate-gene studies, or fine-scale mapping. Clades of haplotypes are tested for association with disease, exploiting the expected similarity of chromosomes with recent shared ancestry in the region flanking the disease gene. The method is developed in a logistic-regression framework and can easily incorporate covariates such as environmental risk factors or additional unlinked loci to allow for population structure. To evaluate the power of this approach to detect disease-marker association, we have developed a simulation algorithm to generate high-density SNP data with short-range linkage disequilibrium based on empirical patterns of haplotype diversity. The results of the simulation study highlight substantial gains in power over single-locus tests for a wide range of disease models, despite overcorrection for multiple testing.

Chromosome Mapping↗

PubMed1996

Measuring and testing genetic differentiation with ordered versus unordered alleles.

Estimates and variances of diversity and differentiation measures in subdivided populations are proposed that can be applied to haplotypes (ordered alleles such as DNA sequences, which may contain a record of their own histories). Hence, two measures of differentiation can be compared for a single data set: one (GST) that makes use only of the allelic frequencies and the other (NST) for which similarities between the haplotypes are taken into account in addition. Tests are proposed to compare NST and GST with zero and with each other. The difference between NST and GST can be caused by several factors, including sampling artefacts, unequal effect of mutation rates and phylogeographic structure. The method presented is applied to a published data set where a nuclear DNA sequence had been determined from individuals of a grasshopper distributed in 24 regions of Europe. Additional insights into the genetic subdivision of these populations are obtained by progressively combining related haplotypes and reanalyzing the data each time.

Alleles↗

PubMed2026

Genetic (Genomic) and Morphological Evidence Suggest That the Korean Endemic Fat Minnow (Rhynchocypris kumgangensis) and the Deogyu Population Represent Distinct Species.

Geographically disconnected populations of freshwater fishes often show ecological and genetic divergence in response to opposing selection differentials in different habitat environments, sometimes leading to the formation of ecotypes and even speciation. Nevertheless, evidence for the speciation through allopatric processes in freshwater fish systems remains scarce. Kumkang fat minnow (Rhynchocypris kumgangensis), a Korean endemic coldwater fish, has recently been suggested to diverge into a separate species (Rhynchocypris deogyuensis). However, the level of their genetic and ecological divergence remains largely unknown. We analyzed population genetic structure of R. kumgangensis together with R. deogyuensis using mitochondrial DNA (mtDNA) and eight newly developed microsatellite markers. Genetic divergence at mitogenome level was further assessed between the presumed two species. Moreover, we examined morphology between two groups by analyzing morphometric traits and also conducted geometric morphometrics on body shape. We found distinct population structure between R. kumgangensis and R. deogyuensis at both mtDNA and microsatellites. One remnant population of R. deogyuensis harbored only a single haplotype and showed a very high level of inbreeding. Comparative analysis of the mitogenomes showed approximately 2.9% divergence between R. kumgangensis and R. deogyuensis, supporting the species-level divergence. The analyses of both morphometric traits and geometric morphometrics indicated significant morphological divergence between the two species. The observed low values of length-weight relationship and condition factor for R. deogyuensis are likely to be attributed to effects of the elevated level of inbreeding and depleted genetic diversity. Overall, our combined genetic/genomic and morphological analyses suggest the considerable divergence between R. kumgangensis and R. deogyuensis, supporting the hypothesis that they are distinct species. The mechanisms underpinning how they speciate still need to be studied further in detail.

Deogyu fat minnow↗

PubMed2005

Correlations between genotype and pharmacological, histological, functional, and clinical phenotypes in malignant hyperthermia susceptibility.

Malignant hyperthermia susceptibility (MHS) is a subclinical pharmacogenetic disorder caused by an impairment of skeletal muscle calcium homeostasis in response to triggering agents. While in vitro contracture testing (IVCT) is the gold standard for defining MHS, molecular analysis is increasingly used to diagnosis MHS. Mutations associated with MHS have been reported in two genes: RYR1 and CACNA1S. Mutations in RYR1 are also responsible for central core disease (CCD), a myopathy that can be associated with a positive IVCT response. We report here the results of correlation studies performed with molecular, pharmacological, histological, and functional data obtained in 175 families (referred to as confirmed (129) or potential (46) MHS families). Extensive molecular analysis allowed us to identify a variant in 60% of the confirmed MHS families, and resulted in the characterization of 11 new variants in the RYR1 gene. Most mutations clustered to MH1 and MH2 domains of RYR1. Functional analysis allowed us to assign a causative role for seven MHS mutations that we propose to add to the panel of MHS mutations used for genetic testing. The use of genetic data to determine MHS status led to a 99.5% sensitivity for IVCT. IVCT-positive/mutation-negative diagnoses were analyzed not only in terms of specificity for IVCT, but also to assess the presence of a second MHS trait in families, and the genetic heterogeneity of the disease. Histological analyses revealed the presence of cores in more than 20% of muscle biopsies originating from 242 genotyped and tested MHS patients who did not present with clinical symptoms. This indicates that these patients must be considered as MHS patients with cores, and are clearly differentiated from CCD patients who have been tested positive for MHS.

Calcium↗

PubMed1981

Fine specificity of cytotoxic T lymphocytes directed against H-2Ld.

The fine specificity of cytotoxic T lymphocytes (CTL) directed against H-2Ld was analyzed by studying the lytic activity of BALB/c H-2dm2 (H-2Ld loss mutant) anti-BALB/c-H-2d CTL, generated in secondary mixed lymphocyte culture (MLC) against a panel of target cells of different H-2 haplotypes. Target cells of all H-2 haplotypes tested, except that of the MLC responder, were lysed by anti-Ld CTL, although to a widely varying extent. The genes coding for antigens detected by anti-Ld CTL were mapped to distinct regions in the H-2d, H-2dm1, H-2q, H-2k, and H-2b haplotypes. The sequence of lysis intensity against the various H-2 haplotypes and the H-2 regions involved were as follows: Ld, DqLq, Ddm1 Ldm1, Kk, DbLb, r, p, f, s, C3h.OH (KdDkLk), strong lysis occurring against Ld and weak lysis against H-2s and C3H.OH. By monolayer adsorption and cold target inhibition experiments, it was shown that anti-Ld CTL contained a CTL subset directed against a private Ld specificity, hitherto undetected by anti-Ld antibodies. This subset a CTL was separate from the CTL subsets reacting against H-2q and against the mutant haplotype H-2dm1. The reactions against the latter two haplotypes were also mediated by separate CTL subsets. It is concluded that the Ld molecule, to a varying extent, shares target antigens for CTL and K- and/or D-end H-2 molecules of all haplotypes tested. These antigens are detected by multiple subsets of anti-Ld CTL. One CTL subset is directed against a target structure unique for Ld (Ld private specificity).

Adsorption↗

PubMed1999

Mitochondrial DNA Diversity in Three Populations of the Giant Tiger Shrimp Penaeus monodon.

: Mitochondrial DNA restriction fragment length polymorphism (mtDNA-RFLP) was utilized for determination of genetic variation and population structure in Penaeus monodon collected from Satun (the Andaman Sea) and Surat and Trat (the Gulf of Thailand). Twenty-eight composite haplotypes were generated from 52 restriction profiles of P. monodon mtDNA digested with 11 restriction endonucleases. The size of the entire P. monodon mitochondrial genome was estimated to be 15.913 +/- 0.177 kb. The average haplotype diversity in P. monodon was 0.864, whereas the mean nucleotide diversity within populations was 2.51%, 2.22%, and 1.91% for Satun, Trat, and Surat, respectively. Geographic heterogeneity analysis indicated population differentiation between P. monodon from the Andaman Sea and P. monodon from the Gulf of Thailand (p <.0001). On the basis of the high genetic diversity level of P. monodon in Thailand, the Satun and Trat P. monodon populations from the west and east of the pennisula were selected to be founder stocks in our selective breeding program.

Journal Article↗

PubMed2000

HLA-B*4012: a new allele with unique serological features.

We have defined the new allele HLA-B*4012, which had been isolated from a black individual. It was initially recognized as a serologically unique allele when typing her father for renal transplantation. The HLA class I phenotype was A*0201,*6602; B*4001,*4012; Bw6; Cw*0304,*1505. Sequencing from exon 1 through intron 3 of B*4012 was performed. B*4012 is identical to B*4001 and B*4010 in exon 3, and in the 3' part of exon 2, but it is unique in that exon 1 and the 5' part of exon 2 are identical to B*1503, B*1509, B*1510, B*1518, B*1523, and B*1529. The generation of this allele is best explained by a recombination event in exon 2 (break point between nucleotides 205 and 222 from the beginning of the coding region) of B*4001 or B*4010 with one of these B*15 variants as a donor allele. Its unique serological feature (B48, B60, B70, and B72 reactivity) is consistent with the sequence data of its donor alleles.

Alleles↗

PubMed1992

Delineation of a 50 kilobase DNA segment containing the recombination site in a sporadic case of Huntington's disease.

No detectable rearrangements involving chromosome 4p16.3 have been observed in patients with Huntington's disease (HD). New mutations for HD could involve structural alterations which might aid the localization of the defective gene. We have reinvestigated a well documented sporadic case of HD. DNA haplotyping with markers between D4S10 and the telomeric locus D4S141 reveals a recombination event in one chromosome of the sporadic HD patient. The site of recombination maps within a 50 kilobase (kb) region, about 700 kb from the 4p telomere. Based on the extremely low HD mutation rate and significantly decreased recombination in the distal region of 4p, we hypothesize a direct link between the site of the recombination and HD in this patient.

Adult↗

PubMed2003

Patterns of spatial genetic structuring in a hydropsychid caddisfly (Cheumatopsyche sp. AV1) from southeastern Australia.

We assessed levels of mitochondrial genetic spatial structuring in the hydropsychid caddisfly Cheumatopsyche sp. AV1 in southeastern New South Wales, Australia. No significant spatial structuring was detected within or between catchments using analysis of molecular variance, and nested clade contingency analysis suggested no strong relationship between haplotypes and geographical location, at any clade level. However, tests for association among haplotypes incorporating geographical distance in the nested clade analysis, revealed patterns of historical range expansion and recent restricted gene flow. Most likely, population fragmentation preceded range expansion, although subsequent recontact and gene flow among the previously sundered populations has apparently obscured the geographical signature of the former fragmentation. Taken together, our analyses suggest that a number of populations fragmented during the Pleistocene evolved in isolation for a time and subsequently expanded into secondary contact. Since expansion, there has apparently been substantial (albeit somewhat restricted) dispersal and gene flow of adult female Cheumatopsyche sp. AV1, throughout the study area.

Analysis of Variance↗

PubMed1998

Both allelic variation and expression of nuclear and cytoplasmic transcripts of Hsr-omega are closely associated with thermal phenotype in Drosophila.

Inducible heat shock genes are considered a major component of the molecular mechanisms that confer cellular protection against a variety of environmental stresses, in particular high temperature extremes. We have tested the association between expression of the heat shock RNA gene hsr-omega and thermoresistance by generating thermoresistant lines of Drosophila melanogaster after application of two distinct regimes of laboratory selection. One set of lines was selected for resistance to knockdown by heat stress and the other was similarly selected but before selection a mild heat exposure known to increase resistance (heat hardening) was applied. A cross between resistant and susceptible lines confirmed our earlier observation that increased thermal tolerance cosegregates with allelic variation in the hsr-omega gene. This cosegregating variation is attributed largely to two haplotype groups. Using quantitative reverse transcription-PCR, we find evidence for divergent phenotypic responses in the two selection regimes, involving both structural and regulatory changes in hsr-omega. Lines selected after hardening showed increased levels of the cytoplasmic transcript but decreased levels of the nuclear transcript. Lines selected without hardening showed decreased levels of the cytoplasmic transcript. The allelic frequency changes at hsr-omega could not by themselves account for the altered transcription patterns. Our results support the idea that the functional RNA molecules transcribed from hsr-omega are an important and polymorphic regulatory component of an insect thermoresistance phenotype.

Alleles↗

PubMedDate not supplied

Molecular cloning of steroid 21-hydroxylase.

Congenital adrenal hyperplasia due to 21-hydroxylase (21-OH) deficiency is HLA-linked. The haplotype HLA-(A3);Bw47;DR7 is strongly associated with 21-OH deficiency and always carries a null allele at the complement C4A (Rodgers) locus. It seemed likely that this haplotype carries a deletion encompassing both the C4A and 21-OH loci. We hypothesized that the HLA-linked defect involved a structural gene for the adrenal microsomal cytochrome P-450 specific for steroid 21-hydroxylation. We isolated a plasmid with a 520 bp bovine adrenal cDNA insert encoding the middle third of the P-450 peptide. When human DNA was digested with Taq I restriction endonuclease and hybridized with the cDNA probe, DNA from 13 unrelated normal individuals yielded two hybridizing bands of equal intensity at 3.7 and 3.2 kb. The upper band was not present in DNA from a patient homozygous for Bw47. DNA from six unrelated patients heterozygous for Bw47 yielded, in five, diminished relative intensity of the upper band consistent with a heterozygous deletion, and complete disappearance of the upper band in one. Thus 21-OH deficiency sometimes results from the deletion of a gene and sometimes, presumably, from smaller mutations. This gene is probably located very near the C4A gene encoding the 4th component of complement.

Adrenal Cortex↗