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Results for “Haplotype structures”

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PubMed2005

X-chromosome as a marker for population history: linkage disequilibrium and haplotype study in Eurasian populations.

Linkage disequilibrium (LD) structure is still unpredictable because the interplay of regional recombination rate and demographic history is poorly understood. We have compared the distribution of LD across two genomic regions differing in crossing-over activity -- Xq13 (0.166 cM/Mb) and Xp22 (1.3 cM/Mb) -- in 15 Eurasian populations. Demographic events predicted to increase the LD level -- genetic drift, bottleneck and admixture - had a very strong impact on extent and patterns of regional LD across Xq13 compared to Xp22. The haplotype distribution of the DXS1225-DXS8082 microsatellites from Xq13 exhibiting strong association in all populations was remarkably influenced by population history. European populations shared one common haplotype with a frequency of 25-40%. The Volga-Ural populations studied, living at the geographic borderline of Europe, showed elevated LD as well as harboring a significant fraction of haplotypes originating from East Asia, thus reflecting their past migrations and admixture. In the young Kuusamo isolate from Finland, a bottleneck has led to allelic associations between loci and shifted the haplotype distribution, but has much less affected single microsatellite allele frequencies compared to the main Finnish population. The data show that the footprint of a demographic event is longer preserved in haplotype distribution within a region of low crossing-over rate, than in the information content of a single marker, or between actively recombining markers. As the knowledge of LD patterns is often chosen to assist association mapping of common disease, our conclusions emphasize the importance of understanding the history, structure and variation of a study population.

Asia↗

PubMedDate not supplied

[The molecular basis of dominantly inherited beta-thalassemia].

In this study, we sought to clarity the molecular basis of a dominant inherited beta-thalassemia, found in heterozygosity in a northern Portuguese family with thalassemia intermedia. We characterized: i) the alpha-globin gene cluster structure; ii) the beta-globin gene cluster haplotype; and iii) the beta-thalassemia mutation. The alpha-globin gene cluster was structurally normal. The G-->T transversion at codon 121 of the beta-globin gene was found in the affected individuals in association with Orkin's haplotype V. This is an uncommon, though ubiquitous, mutation. Which has also been found, in association with different haplotypes, in several distant populations. It has only been observed in this three-generation family, in the Portuguese population. We suggest a mechanism to explain the genotype/phenotype correlation.

Adult↗

PubMed2006

Evolutionary patterns in the antR-Cor gene in the dwarf dogwood complex (Cornus, Cornaceae).

The evolutionary pattern of the myc-like anthocyanin regulatory gene antR-Cor was examined in the dwarf dogwood species complex (Cornus Subgenus Arctocrania) that contains two diploid species (C. canadensis and C. suecica), their putative hybrids with intermediate phenotypes, and a tetraploid derivative (C. unalaschkensis). Full-length sequences of this gene ( approximately 4 kb) were sequenced and characterized for 47 dwarf dogwood samples representing all taxa categories from 43 sites in the Pacific Northwest. Analysis of nucleotide diversity indicated departures from neutral evolution, due most likely to local population structure. Neighbor-joining and haplotype network analyses show that sequences from the tetraploid and diploid intermediates are much more strongly diverged from C. suecica than from C. canadensis, and that the intermediate phenotypes may represent an ancestral group to C. canadensis rather than interspecific hybrids. Seven amino acid mutations that are potentially linked to myc-like anthocyanin regulatory gene function correlate with petal colors differences that characterize the divergence between two diploid species and the tetraploid species in this complex. The evidence provides a working hypothesis for testing the role of the gene in speciation and its link to the petal coloration. Sequencing and analysis of additional nuclear genes will be necessary to resolve questions about the evolution of the dwarf dogwood complex.

Alaska↗

PubMed2004

Corn and humans: recombination and linkage disequilibrium in two genomes of similar size.

Two species with genomes of almost identical size, maize and human, have different evolutionary histories, and as a result their genomes differ greatly in their content of retroelements, average size of the genes and amount of genetic diversity. However, there are also significant similarities: they both have undergone bottlenecks during their recent history and seem to have non-uniform distribution of recombination events. The human genome has been shown to contain large linkage blocks characterized by a limited number of haplotypes. A similar linkage block structure is likely to exist in maize. Although highly diverse maize populations show rapid decline of linkage disequilibrium, as in humans, it is possible to define populations with strong linkage disequilibrium, suitable for whole-genome scan association mapping. The genetic diversity and lack of sequence homology found in maize influences recombinational properties and local linkage disequilibrium levels but also challenges our understanding of the relationship between the genome sequence and species definition.

Alleles↗

PubMed2000

Chloroplast DNA variation in a rainforest tree (Aucoumea klaineana, burseraceae) in Gabon.

One of the dominant savannah colonists in Gabon is Aucoumea klaineana or Okoumé (Burseraceae), an endemic species which belongs to a monotypic genus. Chloroplast DNA (cpDNA) variation was studied in this species by means of PCR amplification of 40 kb of cpDNA sequences, followed by restriction analysis of the resulting fragments. No insertion/deletion events were noted, and a single point mutation was found. The level of differentiation among the 19 populations studied was relatively low (GST = 0.54) compared to other plant species (mean of 0.76), in agreement with the pioneer status of the species. However, cpDNA diversity was geographically structured, with the less frequent haplotype occurring only in populations from southern Gabon. This distribution might suggest either that there were two ancient source populations of Okoumé, one in the north and the other in the south, from which the colonizing process of the savannah began after the last ice age, or alternatively that there was one polymorphic source in the south. The low level of cpDNA diversity could indicate that Okoumé populations in these refugia were quite small.

DNA, Chloroplast↗

PubMed2006

Green turtle (Chelonia mydas) foraging and nesting aggregations in the Caribbean and Atlantic: impact of currents and behavior on dispersal.

Although significant amounts of research have been dedicated to increasing the knowledge of the life history of green turtles (Chelonia mydas), large gaps exist in our understanding of juvenile migratory behavior. These gaps can be filled by genetic studies of foraging ground aggregations. Using mitochondrial DNA markers and Bayesian analyses, samples (n = 106) from a foraging aggregation in North Carolina indicated that animals from the east coast of the United States (54%) and Mexico (27%) dominate the composition with the remainder coming from other Caribbean and Atlantic nesting aggregations. These findings prompted a reanalysis of 4 regional foraging aggregations using Bayesian mixed stock analysis, analysis of molecular variance, and diversity measures. Significant regional population structure between northern and southern foraging aggregations in the Caribbean was detected (phiST = 0.27, P = 0.000) in addition to significant nesting aggregation structure (phiST = 0.87, P = 0.000). Haplotype diversity levels were highest at foraging aggregations located within the confluence of major current systems. These findings indicate that both currents and behavior have strong influences on the composition of foraging aggregations. In addition, our results provide evidence of juvenile homing to regional foraging grounds and highlight the difficulties of separating historical and current effects on recruitment patterns at foraging locations.

Animal Population Groups↗

PubMed2006

HUMHOT: a database of human meiotic recombination hot spots.

Meiotic recombination occurs preferentially at certain regions in the genome referred to as hot spots. The number of hot spots known in humans has increased manifold in recent years. The identification of these hot spots in humans is of great interest to population and medical geneticists since they influence the structure of Linkage Disequilibrium and Haplotype blocks in human populations, whose patterns have applications in mapping disease genes. HUMHOT is a web-based database of Human Meiotic Recombination Hot Spots. The database comprises DNA sequences corresponding to the hot spot regions from the literature that have been mapped to a high resolution (<4 kb) in humans. It also provides flanking sequence information for the hot spot region along with references describing the hot spot. The database can be queried based on hot spot identity, chromosome position or by homology to user-defined sequences. It is also updated with new hot spot sequences as they are discovered and provides hyperlinks to commonly used tools for estimating recombination rates, performing genetic analysis and new advances in our understanding of meiotic hot spots. Public access to the HUMHOT database is available at http://www.jncasr.ac.in/humhot.

Base Sequence↗

PubMed2025

Defining and cataloging variants in pangenome graphs.

Structural variation causes some human haplotypes to align poorly with the linear reference genome, leading to 'reference bias'. A pangenome reference graph could ameliorate this bias by relating a sample to multiple reference assemblies. However, this approach requires a new definition of a 'genetic variant.' We introduce a definition of pangenome variants and a method, pantree, to identify them. Our approach involves a pangenome reference tree which includes all nodes (sequences) of the pangenome graph, but only a subset of its edges; non-reference edges are variant edges. Our variants are biallelic and have well-defined positions. Analyzing the Minigraph-Cactus draft human pangenome reference graph, we identified 29.6 million genetic variants. Most variants (99.2%) are small, and most small variants (73.9%) are SNPs. 3.5 million variants (11.7%) have a reference allele which is not on GRCh38; these variants are difficult to detect without a pangenome reference, or with existing pangenome-based approaches. They tend to be embedded within tangled, multiallelic regions. We analyze two medically relevant regions, around the HLA-A and RHD genes, identifying thousands of small variants embedded within several large insertions, deletions, and inversions. We release an open-source software tool together with a VCF variant catalogue.

Journal Article↗

PubMed1987

Deletion and duplication of DNA sequences is associated with the embryonic lethal phenotype of the t9 complementation group of the mouse t complex.

We have analyzed the genomic structure of three mouse t haplotypes of the t9 complementation group. Each of these t haplotypes, tw18, t4, and tks1, is known to have resulted from a rare recombination event between a complete t haplotype and a wild-type chromosome. Using molecular probes that identify sequences in the distal portion of the t complex, we have shown that each of these t haplotypes contains a similar (perhaps identical) deletion of one group of t complex sequences, and duplication of another group. These data suggest that the recombination events that produced these three t haplotypes involved similar unequal crossovers within the distal inversion. The deletion and duplication of genetic material associated with all members of the t9 complementation group tested provides a molecular explanation for the recessive lethal mutation associated with these t haplotypes.

Animals↗

PubMed2005

Multiple sclerosis.

Multiple sclerosis (MS) is a complex genetic disease associated with inflammation in the central nervous system (CNS) white matter and is thought to be mediated by autoimmune processes. Clonal expansion of B cells, their antibody products, and T cells, hallmarks of inflammation in the CNS, are found in MS. The association of the disease with major histocompatibility complex genes, the inflammatory white matter infiltrates, similarities with animal models, and the observation that MS can be treated with immunomodulatory and immunosuppressive therapies support the hypothesis that autoimmunity plays a major role in the disease pathology. This review discusses the immunopathology of MS with particular focus given to regulatory T cells and the role of B cells and antibodies, immunomodulatory therapeutics, and finally new directions in MS research, particularly new methods to define the molecular pathology of human disease with high-throughput examination of germline DNA haplotypes, RNA expression, and protein structures that will allow the generation of a new series of hypotheses that can be tested to develop better understandings and therapies for this disease.

Animals↗

PubMed2004

Multiple sclerosis.

Multiple sclerosis is a complex genetic disease associated with inflammation in the CNS white matter thought to be mediated by autoreactive T cells. Clonal expansion of B cells, their antibody products, and T cells, hallmarks of inflammation in the CNS, are found in MS. This review discusses new methods to define the molecular pathology of human disease with high-throughput examination of germline DNA haplotypes, RNA expression, and protein structures that will allow the generation of a new series of hypotheses that can be tested to develop better understanding of and therapies for this disease.

Humans↗

PubMed2005

Cis-effects on meiotic recombination across distinct a1-sh2 intervals in a common Zea genetic background.

Genetic distances across the a1-sh2 interval varied threefold in three near-isogenic stocks that carry structurally distinct teosinte A1 Sh2 haplotypes (from Z. mays spp. mexicana Chalco, Z. mays spp. parviglumis, and Z. luxurians) and a common maize a1::rdt sh2 haplotype. In each haplotype >85% of recombination events resolved in the proximal 10% of the approximately 130-kb a1-sh2 interval. Even so, significant differences in the distributions of recombination breakpoints were observed across subintervals among haplotypes. Each of the three previously detected recombination hot spots was detected in at least one of the three teosinte haplotypes and two of these hot spots were not detected in at least one teosinte haplotype. Moreover, novel hot spots were detected in two teosinte haplotypes. Due to the near-isogenic nature of the three stocks, the observed variation in the distribution of recombination events is the consequence of cis-modifications. Although generally negatively correlated with rates of recombination per megabase, levels of sequence polymorphisms do not fully account for the nonrandom distribution of recombination breakpoints. This study also suggests that estimates of linkage disequilibrium must be interpreted with caution when considering whether a gene has been under selection.

Chi-Square Distribution↗

PubMed1994

T cell receptor alpha-chain repertoire of pathogenic autoantibody-inducing T cells in lupus mice.

The production of pathogenic anti-DNA autoantibodies in mice with lupus nephritis is dependent on special autoimmune Th cells that can also transfer the disease into preautoimmune mice. In previous work, these pathogenic Th cells were cloned and their TCR beta-chains were sequenced to reveal a recurrent motif of anionic residues in their CDR3 loops. Accordingly, approximately half of the Th clones were found to be specific for nucleosomal Ag that contain cationic residues. Herein, we analyzed the TCR alpha-chain repertoire of 15 of these pathogenic Th clones and found them to be heterogeneous, even among the nucleosome-specific Th clones. Most of these autoimmune TCR alpha-chains contained anionic residues in their CDR3 in addition to cationic residues. Therefore, these pathogenic Th clones of lupus probably recognize epitopes with mixed charge runs that are derived from autoantigens, such as histone-DNA complexes. Interestingly, the V alpha gene segments used by 10 of these Th clones derived from the (SWR x NZB)F1 lupus mice differed from previously reported sequences indicating that they were new members or alleles of the respective V alpha gene family. One of the Th clones used a gene from an entirely new murine V alpha gene family, identified here as V alpha 23, which consisted of approximately two members that were conserved among strains with different V alpha haplotypes. Knowledge of the primary structure of the TCR expressed by these pathogenic Th clones of lupus would help in the analysis of their antigenic specificities and also would be essential for studying their regulation in transgenic mice carrying these autoimmune TCR genes.

Amino Acid Sequence↗

PubMed2005

A statistical framework for haplotype block inference.

The existence of haplotype blocks transmitted from parents to offspring has been suggested recently. This has created an interest in the inference of the block structure and length. The motivation is that haplotype blocks that are characterized well will make it relatively easier to quickly map all the genes carrying human diseases. To study the inference of haplotype block systematically, we propose a statistical framework. In this framework, the optimal haplotype block partitioning is formulated as the problem of statistical model selection; missing data can be handled in a standard statistical way; population strata can be implemented; block structure inference/hypothesis testing can be performed; prior knowledge, if present, can be incorporated to perform a Bayesian inference. The algorithm is linear in the number of loci, instead of NP-hard for many such algorithms. We illustrate the applications of our method to both simulated and real data sets.

Algorithms↗

PubMed2006

The APL test: extension to general nuclear families and haplotypes and examination of its robustness.

OBJECTIVE: The Association in the Presence of Linkage test (APL) is a powerful statistical method that allows for missing parental genotypes in nuclear families. However, in its original form, the statistic does not easily extend to mixed nuclear family structures nor to multiple-marker haplotypes. Furthermore, the robustness of APL in practice has not been examined. Here we present a generalization of the APL model and examination of its robustness under a variety of non-standard scenarios. METHODS: The generalization is made possible by incorporating a bootstrap variance estimator instead of the original robust variance estimator. This allows for use of more than two affected siblings. Haplotype analysis was accomplished by combining estimation of haplotype phase into the EM algorithm. Computer simulation was used to examine robustness of the APL to departures from test assumptions. RESULTS: The extended APL tests both single-marker and multiple-marker haplotypes and shows more power than other association methods. Simulation results showed that the single-marker APL test is robust to the departure from HWE. For the haplotype test, violation of the HWE assumption can inflate type I error. We also evaluated general guidelines for the validity of APL with rare alleles and rare haplotypes. Software for the APL test is available from http://www.chg.duke.edu/research/apl.html.

Computer Simulation↗

PubMed2002

Testing for candidate gene linkage disequilibrium using a dense array of single nucleotide polymorphisms in case-parents studies.

The future of genetic studies of complex human diseases will rely more and more on the epidemiologic association paradigm, in particular the use of the transmission/disequilibrium test to detect linkage disequilibrium in a case-parents study. With the rapid progress in genomic studies, many single nucleotide polymorphisms will be identified and genotyped within a very short physical distance. Analyzing multiple single nucleotide polymorphisms within a candidate gene/region with Bonferroni correction for multiple transmission/disequilibrium tests will lead to a conservative test, and hence a power loss. I propose a new method, the "Adaptive PRIncipal COmponent Test" (APRICOT). The method has the following properties: (1) it does not need haplotype information; (2) it is nonparametric-it does not make specific assumptions about the population history or population structure; and (3) the calculation of the test statistic and the determination of its significance level are simple and straightforward. Monte-Carlo simulation reveals that adaptive principal component test maintains the nominal significance level under the null hypothesis of no linkage disequilibrium, even under complex situations of multiple ancestral haplotypes and structured populations. It provides a substantial power advantage over the conventional Bonferroni approach. The adaptive principal component test is a promising method for candidate gene testing using single nucleotide polymorphisms.

Genetic Markers↗

PubMed2005

A haplotype map of the human genome.

Inherited genetic variation has a critical but as yet largely uncharacterized role in human disease. Here we report a public database of common variation in the human genome: more than one million single nucleotide polymorphisms (SNPs) for which accurate and complete genotypes have been obtained in 269 DNA samples from four populations, including ten 500-kilobase regions in which essentially all information about common DNA variation has been extracted. These data document the generality of recombination hotspots, a block-like structure of linkage disequilibrium and low haplotype diversity, leading to substantial correlations of SNPs with many of their neighbours. We show how the HapMap resource can guide the design and analysis of genetic association studies, shed light on structural variation and recombination, and identify loci that may have been subject to natural selection during human evolution.

Chromosomes, Human, Y↗

PubMed1986

Biochemistry of HLA-DRw6: evidence for seven distinct haplotypes.

The DRw6 specificity, which has a frequency of 11% in the Caucasian population, cannot be positively defined, since no monospecific allo-antiserum is available. This particular status among DR specificities led us to study the DRw6 haplotypes at the molecular level. We performed 2D-PAGE analysis of HLA-DR molecules in 44 different DRw6 haplotypes. The data were obtained from six homozygous typing cells, eight families informative for the segregation of the DRw6 haplotype, and 15 unrelated donors. Five unique beta-chain electrophoretic patterns were detected, indicating the existence of five structurally distinct DRw6 beta-chains. Each haplotype expresses one or two beta-chains. The different combinations of the DR beta-chains present in a single haplotype allow to characterize seven unique DRw6 haplotypes. In contrast to what has been previously found for DR2 and DR4, there is no DR beta-chain common to all the DRw6 cells. Correlation of the biochemical data with the recent serologic (DRw13 vs DRw14) and cellular (Dw9, Dw18, Dw19) splits of the DRw6 specificity will be discussed.

Antibodies, Monoclonal↗