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PubMed2002

High resolution mapping of quantitative trait loci by linkage disequilibrium analysis.

Two methods, linkage analysis and linkage disequilibrium (LD) mapping or association study, are usually utilised for mapping quantitative trait loci (QTL). Linkage mapping is appropriate for low resolution mapping to localise trait loci to broad chromosome regions within a few cM (<10 cM), and is based on family data. Linkage disequilibrium mapping, on the other hand, is useful in high resolution or fine mapping, and is based on both population and family data. Using only one marker, one may carry out single-point linkage analysis and linkage disequilibrium mapping. Using two or more markers, it is possible to flank the QTL by multipoint analysis. The development and thus availability of dense marker maps, such as single nucleotide polymorphisms (SNP) in human genome, presents a tremendous opportunity for multipoint fine mapping. In this article, we propose a regression approach of mapping QTL by linkage disequilibrium mapping based on population data. Assuming that two marker loci flank one quantitative trait locus, a two-point linear regression is proposed to analyse population data. We derive analytical formulas of parameter estimations, and non-centrality parameters of appropriate tests of genetic effects and linkage disequilibrium coefficients. The merit of the method is shown by the power calculation and comparison. The two-point regression model can capture much more linkage and linkage disequilibrium information than that derived when only one marker is used. For a complex disease with heritability h(2)> or =0.15, a study with sample size of 250 can provide high power for QTL detection under moderate linkage disequilibria.

Chromosome Mapping↗
PubMed2003

Combined high resolution linkage and association mapping of quantitative trait loci.

In this paper, we investigate variance component models of both linkage analysis and high resolution linkage disequilibrium (LD) mapping for quantitative trait loci (QTL). The models are based on both family pedigree and population data. We consider likelihoods which utilize flanking marker information, and carry out an analysis of model building and parameter estimations. The likelihoods jointly include recombination fractions, LD coefficients, the average allele substitution effect and allele dominant effect as parameters. Hence, the model simultaneously takes care of the linkage, LD or association and the effects of the putative trait locus. The models clearly demonstrate that linkage analysis and LD mapping are complementary, not exclusive, methods for QTL mapping. By power calculations and comparisons, we show the advantages of the proposed method: (1) population data can provide information for LD mapping, and family pedigree data can provide information for both linkage analysis and LD mapping; (2) using family pedigree data and a sparse marker map, one may investigate the prior suggestive linkage between trait locus and markers to obtain low resolution of the trait loci, because linkage analysis can locate a broad candidate region; (3) with the prior knowledge of suggestive linkage from linkage analysis, both population and family pedigree data can be used simultaneously in high resolution LD mapping based on a dense marker map, since LD mapping can increase the resolution for candidate regions; (4) models of high resolution LD mappings using two flanking markers have higher power than that of models of using only one marker in the analysis; (5) excluding the dominant variance from the analysis when it does exist would lose power; (6) by performing linkage interval mappings, one may get higher power than by using only one marker in the analysis.

Chromosome Mapping↗
PubMed2002

An integrated comparative map of the porcine X chromosome.

The objectives of this study were to assign both microsatellite and gene-based markers on porcine chromosome X to two radiation hybrid (RH) panels and to develop a more extensive integrated map of SSC-X. Thirty-five microsatellite and 20 gene-based markers were assigned to T43RH, and 16 previously unreported microsatellite and 15 gene-based markers were added to IMpRH map. Of these, 30 microsatellite and 12 gene-based markers were common to both RH maps. Twenty-two gene-based markers were submitted to BLASTN analysis for identification of orthologues of genes on HSA-X. Single nucleotide polymorphisms (SNPs) were detected for 12 gene-based markers, and nine of these were placed on the genetic map. A total of 92 known loci are present on at least one porcine chromosome X map. Thirty-seven loci are present on all three maps; 31 loci are found on only one map. Location of 33 gene-based markers on the comprehensive map translates into an integrated comparative map that supports conservation of gene order between SSC-X and HSA-X. This integrated map will be valuable for selection of candidate genes for porcine quantitative trait loci (QTLs) that map to SSC-X.

Animals↗
PubMed2002

Consensus and comprehensive linkage maps of bovine chromosome 24.

This study describes development of a consensus genetic linkage map of bovine chromosome 24 (BTA24). Eight participating laboratories contributed data for 58 unique markers including a total of 25 409 meioses. Eighteen markers, which were typed in more than one reference population, were used as potential anchors to generate a consensus framework map. The framework map contained 16 loci ordered with odds greater than 1000:1 and spanned 79.3 cM. Remaining markers were included in a comprehensive map relative to these anchors. The resulting BTA24 comprehensive map was 98.3 cM in length. Average marker intervals were 6.1 and 2.5 cM for framework and comprehensive maps, respectively. Marker order was generally consistent with previously reported BTA24 linkage maps. Only one discrepancy was found when comparing the comprehensive map with the published USDA-MARC linkage map. Integration of genetic information from different maps provides a high-resolution BTA24 linkage map.

Animals↗
PubMed2000

Hippocampal participation in navigational map learning in young homing pigeons is dependent on training experience.

The homing pigeon navigational map is perhaps one of the most striking examples of a naturally occurring spatial representation of the environment used to guide navigation. In a previous study, it was found that hippocampal lesions thoroughly disrupt the ability of young homing pigeons held in an outdoor aviary to learn a navigational map. However, since that study an accumulation of anecdotal data has hinted that hippocampal-lesioned young pigeons allowed to fly during their first summer could learn a navigational map. In the present study, young control and hippocampal-lesioned homing pigeons were either held in an outdoor aviary or allowed to fly during the time of navigational map learning. At the end of their first summer, the birds were experimentally released to test for navigational map learning. Independent of training experience, control pigeons oriented homeward during the experimental releases demonstrating that they learned a navigational map. Surprisingly, while the aviary-held hippocampal-lesioned pigeons failed to learn a navigational map as reported previously, hippocampal-lesioned birds allowed flight experience learned a navigational map indistinguishable from the two control groups. A subsequent experiment revealed that the navigational map learned by the three groups was based on atmospheric odours. The results demonstrate that hippocampal participation in navigational map learning depends on the type of experience a young bird pigeon has, and presumably, the type of navigational map learned.

Animals↗
PubMed1994

Genome structure and evolution in Drosophila: applications of the framework P1 map.

Physical maps showing the relative locations of cloned DNA fragments in the genome are important resources for research in molecular genetics, genome analysis, and evolutionary biology. In addition to affording a common frame of reference for organizing diverse types of genetic data, physical maps also provide ready access to clones containing DNA sequences from any defined region of the genome. In this paper, we present a physical map of the genome of Drosophila melanogaster based on in situ hybridization with 2461 DNA fragments, averaging approximately 80 kilobase pairs each, cloned in bacteriophage P1. The map is a framework map in the sense that most putative overlaps between clones have not yet been demonstrated at the molecular level. Nevertheless, the framework map includes approximately 85% of all genes in the euchromatic genome. A continuous physical map composed of sets of overlapping P1 clones (contigs), which together span most of the euchromatic genome, is currently being assembled by screening a library of 9216 P1 clones with single-copy genetic markers as well as with the ends of the P1 clones already assigned positions in the framework map. Because most P1 clones from D. melanogaster hybridize in situ with chromosomes from related species, the framework map also makes it possible to determine the genome maps of D. pseudoobscura and other species in the subgenus Sophophora. Likewise, a P1 framework map of D. virilis affords potential access to genome organization and evolution in the subgenus Drosophila.

Animals↗
PubMed2003

A 3.9-centimorgan-resolution human single-nucleotide polymorphism linkage map and screening set.

Recent advances in technologies for high-throughout single-nucleotide polymorphism (SNP)-based genotyping have improved efficiency and cost so that it is now becoming reasonable to consider the use of SNPs for genomewide linkage analysis. However, a suitable screening set of SNPs and a corresponding linkage map have yet to be described. The SNP maps described here fill this void and provide a resource for fast genome scanning for disease genes. We have evaluated 6,297 SNPs in a diversity panel composed of European Americans, African Americans, and Asians. The markers were assessed for assay robustness, suitable allele frequencies, and informativeness of multi-SNP clusters. Individuals from 56 Centre d'Etude du Polymorphisme Humain pedigrees, with >770 potentially informative meioses altogether, were genotyped with a subset of 2,988 SNPs, for map construction. Extensive genotyping-error analysis was performed, and the resulting SNP linkage map has an average map resolution of 3.9 cM, with map positions containing either a single SNP or several tightly linked SNPs. The order of markers on this map compares favorably with several other linkage and physical maps. We compared map distances between the SNP linkage map and the interpolated SNP linkage map constructed by the deCode Genetics group. We also evaluated cM/Mb distance ratios in females and males, along each chromosome, showing broadly defined regions of increased and decreased rates of recombination. Evaluations indicate that this SNP screening set is more informative than the Marshfield Clinic's commonly used microsatellite-based screening set.

Alleles↗
PubMed1994

ODS_BOOTSTRAP: assessing the statistical reliability of physical maps by bootstrap resampling.

In the program ODS_BOOTSTRAP we provide a methodology for quickly ordering clones in a genomic library into a physical map and for applying a statistical tool known as the bootstrap to assess the statistical reliability of a clonal ordering. Each clone is assigned a binary fingerprint by one of a variety of experimental approaches to physical mapping. For example, the binary fingerprints might be generated by hybridizing a panel of m probes to a library of n clones. The resulting n x m binary data matrix, X, is input to ODS_BOOTSTRAP, which utilizes the similarity in binary fingerprints of clones to construct a physical map. Under this particular implementation of bootstrap resampling, the m probes (or columns of the data matrix) are sampled randomly with replacement in the computer to generate a new n x m data matrix, X*, from which a second physical map is constructed. The resampling process is repeated 100 or more times to generate 100 or more X* matrices. The resulting 100 or more physical maps are compared with the original physical map based on the original data matrix X by counting how often links in the original physical map reappear. Three confidence statistics are introduced for each link in a physical map. The statistic C1 is defined as the percentage of time two neighboring clones on the original map reappear as neighbors under resampling. The statistic C2 is defined as the percentage of time that two neighboring clones i and j on the original map reappear as neighbors or that a clone with an identical binary fingerprint to clone i reappears as a neighbor to clone j. The statistic C3 is defined as the percentage of time that two neighboring clones on the original map reappear in the same contig under resampling.

Algorithms↗
PubMed1998

Interferon-gamma expression by Th1 effector T cells mediated by the p38 MAP kinase signaling pathway.

Signal transduction via MAP kinase pathways plays a key role in a variety of cellular responses, including growth factor-induced proliferation, differentiation and cell death. In mammalian cells, p38 MAP kinase can be activated by multiple stimuli, such as pro-inflammatory cytokines and environmental stress. Although p38 MAP kinase is implicated in the control of inflammatory responses, the molecular mechanisms remain unclear. Upon activation, CD4+ T cells differentiate into Th2 cells, which potentiate the humoral immune response or pro-inflammatory Th1 cells. Here, we show that pyridinyl imidazole compounds (specific inhibitors of p38 MAP kinase) block the production of interferon-gamma (IFNgamma) by Th1 cells without affecting IL-4 production by Th2 cells. These drugs also inhibit transcription driven by the IFNgamma promoter. In transgenic mice, inhibition of the p38 MAP kinase pathway by the expression of dominant-negative p38 MAP kinase results in selective impairment of Th1 responses. In contrast, activation of the p38 MAP kinase pathway by the expression of constitutivelyactivated MAP kinase kinase 6 in transgenic mice caused increased production of IFNgamma during the differentiation and activation of Th1 cells. Together, these data demonstrate that the p38 MAP kinase is relevant for Th1 cells, not Th2 cells, and that inhibition of p38 MAP kinase represents a possible site of therapeutic intervention in diseases where a predominant Th1 immune response leads to a pathological outcome. Moreover, our study provides an additional mechanism by which the p38 MAP kinase pathway controls inflammatory responses.

Animals↗
PubMed1988

Mapping of Escherichia coli chromosomal Tn5 and F insertions by pulsed field gel electrophoresis.

A low resolution Not I physical map of Escherichia coli was recently constructed. In this report we demonstrated that this map can be used to map Tn5 and F insertions physically. The transposon, Tn5, contains Not I recognition sequences in its IS50 sequences. F plasmid contains an unmapped Not I site. Hence, the location of Tn5 and F in the chromosome can be mapped by identifying the location of the introduced Not I sites using pulsed field gel electrophoresis. The physical mapping of genetically mapped Tn5 insertions confirm the previously constructed Not I map and helps align the E. coli physical and genetic maps. The use of Tn5 can assist the construction of both physical and genetic maps for microorganisms lacking such maps. Variations on this approach will facilitate physical mapping with a wide variety of organisms, enzymes, and genetic elements.

Alleles↗
PubMed1994

Precision mapping of quantitative trait loci.

Adequate separation of effects of possible multiple linked quantitative trait loci (QTLs) on mapping QTLs is the key to increasing the precision of QTL mapping. A new method of QTL mapping is proposed and analyzed in this paper by combining interval mapping with multiple regression. The basis of the proposed method is an interval test in which the test statistic on a marker interval is made to be unaffected by QTLs located outside a defined interval. This is achieved by fitting other genetic markers in the statistical model as a control when performing interval mapping. Compared with the current QTL mapping method (i.e., the interval mapping method which uses a pair or two pairs of markers for mapping QTLs), this method has several advantages. (1) By confining the test to one region at a time, it reduces a multiple dimensional search problem (for multiple QTLs) to a one dimensional search problem. (2) By conditioning linked markers in the test, the sensitivity of the test statistic to the position of individual QTLs is increased, and the precision of QTL mapping can be improved. (3) By selectively and simultaneously using other markers in the analysis, the efficiency of QTL mapping can be also improved. The behavior of the test statistic under the null hypothesis and appropriate critical value of the test statistic for an overall test in a genome are discussed and analyzed. A simulation study of QTL mapping is also presented which illustrates the utility, properties, advantages and disadvantages of the method.

Chromosome Mapping↗
PubMed2002

Precision and high-resolution mapping of quantitative trait loci by use of recurrent selection, backcross or intercross schemes.

Dissecting quantitative genetic variation into genes at the molecular level has been recognized as the greatest challenge facing geneticists in the twenty-first century. Tremendous efforts in the last two decades were invested to map a wide spectrum of quantitative genetic variation in nearly all important organisms onto their genome regions that may contain genes underlying the variation, but the candidate regions predicted so far are too coarse for accurate gene targeting. In this article, the recurrent selection and backcross (RSB) schemes were investigated theoretically and by simulation for their potential in mapping quantitative trait loci (QTL). In the RSB schemes, selection plays the role of maintaining the recipient genome in the vicinity of the QTL, which, at the same time, are rapidly narrowed down over multiple generations of backcrossing. With a high-density linkage map of DNA polymorphisms, the RSB approach has the potential of dissecting the complex genetic architecture of quantitative traits and enabling the underlying QTL to be mapped with the precision and resolution needed for their map-based cloning to be attempted. The factors affecting efficiency of the mapping method were investigated, suggesting guidelines under which experimental designs of the RSB schemes can be optimized. Comparison was made between the RSB schemes and the two popular QTL mapping methods, interval mapping and composite interval mapping, and showed that the scenario of genomic distribution of QTL that was unlocked by the RSB-based mapping method is qualitatively distinguished from those unlocked by the interval mapping-based methods.

Animals↗
PubMed2002

Excess heterozygosity contributes to genetic map expansion in pea recombinant inbred populations.

Several plant genetic maps presented in the literature are longer than expected from cytogenetic data. Here we compare F(2) and RI maps derived from a cross between the same two parental lines and show that excess heterozygosity contributes to map inflation. These maps have been constructed using a common set of dominant markers. Although not generally regarded as informative for F(2) mapping, these allowed rapid map construction, and the resulting data analysis has provided information not otherwise obvious when examining a population from only one generation. Segregation distortion, a common feature of most populations and marker systems, found in the F(2) but not the RI, has identified excess heterozygosity. A few markers with a deficiency of heterozygotes were found to map to linkage group V (chromosome 3), which is known to form rod bivalents in this cross. Although the final map length was longer for the F(2) population, the mapped order of markers was generally the same in the F(2) and RI maps. The data presented in this analysis reconcile much of the inconsistency between map length estimates from chiasma counts and genetic data.

Chromosome Mapping↗
PubMed2003

Female site-specific transposase-induced recombination: a high-efficiency method for fine mapping mutations on the X chromosome in Drosophila.

P-element transposons in the Drosophila germline mobilize only in the presence of the appropriate transposase enzyme. Sometimes, instead of mobilizing completely, P elements will undergo site-specific recombination with the homologous chromosome. Site-specific recombination is the basis for male recombination mapping, since the male germline does not normally undergo recombination. Site-specific recombination also takes place in females, but this has been difficult to study because of the obscuring effects of meiotic recombination. Using map functions, I demonstrate that it is possible to employ female site-specific transposase-induced recombination (FaSSTIR) to map loci on the X chromosome and predict that FaSSTIR mapping should be more efficient than meiotic mapping over short genetic intervals. Both FaSSTIR mapping and meiotic mapping were used to fine map the crossveinless locus on the X chromosome. Both techniques identified the same 10-kb interval as the probable location of the crossveinless mutation. Over short intervals (< approximately 7.6 cM), FaSSTIR produces more informative recombination events than does meiotic recombination. Over longer intervals, FaSSTIR is not always more efficient than meiotic mapping, but it produces the correct gene order. FaSSTIR matches the expectations suggested by the map functions and promises to be a useful technique, particularly for mapping X-linked loci.

Animals↗
PubMed1986

Structural differences of microtubule associated proteins from brain probed by tryptic peptide mapping.

Microtubules were purified from porcine brain by two cycles of temperature-dependent assembly and disassembly, then microtubule associated proteins, MAP-1, MAP-2, and tau, were separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Two-dimensional tryptic peptide maps of radioiodinated polypeptides were compared with each other by means of mixed sample experiments, and the following results were obtained. Subspecies of MAP-1 (355-345 and 325 kDa) showed about 33% homology in the tryptic peptide maps. Structural homology of MAP-1 and MAP-2 was very low; only 3 out of 40 peptide spots of MAP-2 were identical with those of MAP-1-C. Subspecies of tau proteins (65 and 60 kDa) were very closely related. Structural similarity between MAP-2 and tau was very low. MAP-1 from porcine brain and rat brain showed very high structural homology.

Animals↗
PubMed2000

A consensus linkage map of the chicken genome.

A consensus linkage map has been developed in the chicken that combines all of the genotyping data from the three available chicken mapping populations. Genotyping data were contributed by the laboratories that have been using the East Lansing and Compton reference populations and from the Animal Breeding and Genetics Group of the Wageningen University using the Wageningen/Euribrid population. The resulting linkage map of the chicken genome contains 1889 loci. A framework map is presented that contains 480 loci ordered on 50 linkage groups. Framework loci are defined as loci whose order relative to one another is supported by odds greater then 3. The possible positions of the remaining 1409 loci are indicated relative to these framework loci. The total map spans 3800 cM, which is considerably larger than previous estimates for the chicken genome. Furthermore, although the physical size of the chicken genome is threefold smaller then that of mammals, its genetic map is comparable in size to that of most mammals. The map contains 350 markers within expressed sequences, 235 of which represent identified genes or sequences that have significant sequence identity to known genes. This improves the contribution of the chicken linkage map to comparative gene mapping considerably and clearly shows the conservation of large syntenic regions between the human and chicken genomes. The compact physical size of the chicken genome, combined with the large size of its genetic map and the observed degree of conserved synteny, makes the chicken a valuable model organism in the genomics as well as the postgenomics era. The linkage maps, the two-point lod scores, and additional information about the loci are available at web sites in Wageningen (http://www.zod.wau.nl/vf/ research/chicken/frame_chicken.html) and East Lansing (http://poultry.mph.msu.edu/).

Animals↗
PubMed1998

Parallel radiation hybrid mapping: a powerful tool for high-resolution genomic comparison.

Comparative gene mapping in mammals typically involves identification of segments of conserved synteny in diverse genomes. The development of maps that permit comparison of gene order within conserved synteny has not advanced beyond the mouse map that takes advantage of linkage analysis in interspecific backcrosses. Radiation hybrid (RH) mapping provides a powerful tool for determining order of genes in genomes for which gene-based linkage mapping is impractical. Comparative RH mapping of 24 orthologous genes in this study revealed internal structural rearrangements between human chromosome 17 (HSA17) and bovine chromosome 19 (BTA19), two chromosomes known previously to be conserved completely and exclusively at level of synteny. Only six of the 24 genes had been previously ordered on the human G3 RH map. The use of the G3 panel to map the other 18, however, produced parallel RH maps for comparison of gene order at a resolution of <5 Mb on the bovine linkage map and from 1 to 3 Mb in the human physical map.

Animals↗
PubMed2004

A linkage map of Atlantic salmon (Salmo salar) reveals an uncommonly large difference in recombination rate between the sexes.

A genetic linkage map of the Atlantic salmon (Salmo salar) was constructed, using 54 microsatellites and 473 amplified fragment length polymorphism (AFLP) markers. The mapping population consisted of two full-sib families within one paternal half-sib family from the Norwegian breeding population. A mapping strategy was developed that facilitated the construction of separate male and female maps, while retaining all the information contributed by the dominant AFLP markers. By using this strategy, we were able to map a significant number of the AFLP markers for which all informative offspring had two heterozygous parents; these markers then served as bridges between the male and female maps. The female map spanned 901 cM and had 33 linkage groups, while the male spanned 103 cM and had 31 linkage groups. Twenty-five linkage groups were common between the two maps. The construction of the genetic map revealed a large difference in recombination rate between females and males. The ratio of female recombination rate vs. male recombination rate was 8.26, the highest ratio reported for any vertebrate. This map constitutes the first linkage map of Atlantic salmon, one of the most important aquaculture species worldwide.

Animals↗