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At least 757 records · Page 42Linked to original sources
PubMed2003

Genomic approaches to analyzing natural variation in Arabidopsis thaliana.

The genomics tools available for studying Arabidopsis thaliana are a great resource for researchers trying to characterize and understand the genetic basis of natural variation. Abundant polymorphic markers aid quantitative trait locus (QTL) mapping, the fully sequenced genome provides rapid identification of candidate loci, and extensive knockout collections allow those candidate loci to be tested. Combining QTL mapping of classic phenotypic traits with biochemical or expression analysis is providing mechanistic insight into the traits of interest. Conversely, natural variation studies are now being done on genomic traits such as methylation or chiasma frequency.

Arabidopsis↗
PubMed2004

Genome-wide linkage analysis of chromogranin B expression in the CEPH pedigrees: implications for exocytotic sympathochromaffin secretion in humans.

Chromogranin B (CgB), a major member of the chromogranin/secretogranin family of catecholamine storage vesicle secretory proteins, plays both intracellular (vesiculogenic) and extracellular (prohormone) roles in the neuroendocrine system, and its biosynthesis and release are under the control of efferent sympathetic nerve traffic ("stimulus-transcription coupling"). To explore the role of heredity in control of CgB, we conducted a genome-wide linkage analysis of CgB release in 12 extended CEPH (Centre d'Etude du Polymorphisme Humain) pedigrees. Region-specific radioimmunoassays were used to measure five CgB fragments in plasma: CgB1-16, CgB312-331, CgB439-451, CgB568-577, and CgB647-657. Substantial heritability, as measured by h2r, was observed for three of the fragment concentrations, CgB312-331, CgB439-451, and CgB568-577, which yielded h2r estimates ranging from 0.378 (P = 0.002) to 0.910 (P < 0.0000001). Variance-component genome-wide linkage analysis with 654 microsatellite markers at 5 cM spacing identified a major quantitative trait locus for CgB312-331 on chromosome 11q24-q25 with a maximum multipoint LOD score of 5.84. Significant allelic associations between markers in the region and CgB levels were also observed. Although the 2-LOD confidence interval for linkage did not include the CgB locus itself, known trans-activators of the CgB gene promoter, or prohormone cleaving proteases, examination of positional candidate loci within this region yielded novel and plausible physiological candidates for further exploration. Allelic variation in this region may thus influence effects of sympathetic outflow on target organs in humans.

Alleles↗
PubMed2006

Toward understanding the genetics of alcohol drinking through transcriptome meta-analysis.

Much evidence from studies in humans and animals supports the hypothesis that alcohol addiction is a complex disease with both hereditary and environmental influences. Molecular determinants of excessive alcohol consumption are difficult to study in humans. However, several rodent models show a high or low degree of alcohol preference, which provides a unique opportunity to approach the molecular complexities underlying the genetic predisposition to drink alcohol. Microarray analyses of brain gene expression in three selected lines, and six isogenic strains of mice known to differ markedly in voluntary alcohol consumption provided >4.5 million data points for a meta-analysis. A total of 107 arrays were obtained and arranged into six experimental data sets, allowing the identification of 3,800 unique genes significantly and consistently changed between all models of high or low amounts of alcohol consumption. Several functional groups, including mitogen-activated protein kinase signaling and transcription regulation pathways, were found to be significantly overrepresented and may play an important role in establishing a high level of voluntary alcohol drinking in these mouse models. Data from the general meta-analysis was further filtered by a congenic strain microarray set, from which cis-regulated candidate genes for an alcohol preference quantitative trait locus on chromosome 9 were identified: Arhgef12, Carm1, Cryab, Cox5a, Dlat, Fxyd6, Limd1, Nicn1, Nmnat3, Pknox2, Rbp1, Sc5d, Scn4b, Tcf12, Vps11, and Zfp291 and four ESTs. The present study demonstrates the use of (i) a microarray meta-analysis to analyze a behavioral phenotype (in this case, alcohol preference) and (ii) a congenic strain for identification of cis regulation.

Alcohol Drinking↗
PubMed1997

Secretory phospholipase Pla2g2a confers resistance to intestinal tumorigenesis.

Individuals inheriting the same mutation predisposing to cancer may show very different outcomes, ranging from early aggressive cancer to disease-free survival. Experimental mouse models can provide a powerful tool to identify factors in the environment and genetic background that account for such modifications. The Min mouse strain, in which the ApcMin mutation disrupts the mouse homologue of the human familial polyposis gene, develops intestinal neoplasms whose multiplicity is strongly affected by genetic background. We previously mapped a strong modifier locus, Mom1 (modifier of Min-1), to a 4-cM region on mouse chromosome 4 containing a candidate gene Pla2g2a encoding a secretory phospholipase. Here, we report that a cosmid transgene overexpressing Pla2g2a caused a reduction in tumour multiplicity and size, comparable to that conferred by a single copy of the resistance allele of Mom1. These results offer strong evidence that this secretory phospholipase can provide active tumour resistance. The association of Pla2g2a with Mom1 thus withstands a strong functional test and is likely to represent the successful identification of a polymorphic quantitative trait locus in mammals.

Adenomatous Polyposis Coli↗
PubMed2002

QTL Express: mapping quantitative trait loci in simple and complex pedigrees.

QTL Express is the first application for Quantitative Trait Locus (QTL) mapping in outbred populations with a web-based user interface. User input of three files containing a marker map, trait data and marker genotypes allows mapping of single or multiple QTL by the regression approach, with the option to perform permutation or bootstrap tests.

Chromosome Mapping↗
PubMed2001

Effects of Dmo1 on obesity, dyslipidaemia and hyperglycaemia in the Otsuka Long Evans Tokushima Fatty strain.

Whole-genome scans have identified Dmo1 as a major quantitative trait locus (QTL) for obesity and dyslipidaemia in the Otsuka Long Evans Tokushima Fatty (OLETF) rat. We have produced congenic rats for the Dmo1 locus, using marker-assisted speed congenic protocols, enforced by selective removal of other QTL regions (QTL-marker-assisted counterselection), to efficiently transfer chromosomal segments from non-diabetic Fischer 344 (F344) rats into the OLETF background. In the third generation of congenic animals, we observed a substantial therapeutic effect of the Dmo1 locus on lipid metabolism, obesity control and plasma glucose homeostasis. We conclude that single-allele correction of an impaired genetic pathway can generate a substantial therapeutic effect, despite the complex polygenic nature of type II diabetic syndromes.

Alleles↗
PubMed2005

Bioinformatics toolbox for narrowing rodent quantitative trait loci.

Quantitative trait locus (QTL) analysis is a powerful method for localizing disease genes, but identifying the causal gene remains difficult. Rodent models of disease facilitate QTL gene identification, and causal genes underlying rodent QTL are often associated with the corresponding human diseases. Recently developed bioinformatics methods, including comparative genomics, combined cross analysis, interval-specific and genome-wide haplotype analysis, followed by sequence and expression analysis, each facilitated by public databases, provide new tools for narrowing rodent QTLs. Here we discuss each tool, illustrate its application and generate a bioinformatics strategy for narrowing QTLs. Combining these bioinformatics tools with classical experimental methods should accelerate QTL gene identification.

Animals↗
PubMed2002

The genetics of phytate and phosphate accumulation in seeds and leaves of Arabidopsis thaliana, using natural variation.

Phytate (myo-inositol-1,2,3,4,5,6-hexakisphosphate, InsP6) is the most abundant P-containing compound in plants, and an important anti-nutritional factor, due to its ability to complex essential micro-nutrients, e.g. iron and zinc. Analysis of natural variation for InsP6 and Pi accumulation in seeds and leaves for a large number of accessions of Arabidopsis thaliana, using a novel method for InsP6 detection, revealed a wide range of variation in InsP6 and Pi levels, varying from 7.0 mg to 23.1 mg of InsP6 per gram of seed. Quantitative trait locus (QTL) analysis of InsP6 and Pi levels in seeds and leaves, using an existing recombinant inbred line population, was performed in order to identify a gene(s) that is (are) involved in the regulation of InsP6 accumulation. Five genomic regions affecting the quantity of the InsP6 and Pi in seeds and leaves were identified. One of them, located on top of chromosome 3, affects all four traits. This QTL appears as the major locus responsible for the observed variation in InsP6 and Pi contents in the L er/Cvi RIL population; the L er allele decreases the content of both InsP6 and Pi in seeds and in leaves. The InsP6/Pi locus was further fine-mapped to a 99-kb region, containing 13 open reading frames. The maternal inheritance of the QTL and the positive correlation between InsP6 and total Pi levels both in seeds and in leaves indicate that the difference in InsP6 level between L er and Cvi is likely to be caused by a difference in transport rather than by an alteration in the biosynthesis. Therefore, we consider the vacuolar membrane ATPase subunit G, located in the region of interest, as the most likely candidate gene for InsP6/Pi.

Arabidopsis↗
PubMed2005

SNPAnalyzer: a web-based integrated workbench for single-nucleotide polymorphism analysis.

SNPAnalyzer is a software that performs four essential statistical analyses of SNPs in a common computational environment. It is composed of three main modules: (i) data manipulation, (ii) analysis and (iii) visualization. The data manipulation module is responsible for data input and output, and handles genotype, phenotype and genetic distance data. To ensure user convenience, the data format is simple. The analysis module performs statistical calculations and consists of four subcomponents: (i) Hardy-Weinberg equilibrium, (ii) Haplotype Estimation, (iii) linkage disequilibrium (LD) and (iv) quantitative trait locus analysis. The main feature of the analysis module is multiple implementations of different algorithms and indices for haplotype estimation and for LD analysis. This enables users to compare separate results generated by different algorithms, which help to avoid biased results acquired by applying a single statistical algorithm. The performance of all implemented algorithms has been validated using experimentally proven datasets. The visualization module presents most of the analyzed results as figures, rather than as simple text, which aids in the intuitive understanding of complex data. The SNPAnalyzer has been developed using C and C++ and is available at http://www.istech.info/istech/board/login_form.jsp.

Algorithms↗
PubMed2002

A haplotypic approach to founder-origin probabilities and outbred QTL analysis.

Founder-origin probability methods are used to trace specific chromosomal segments in individual offspring. A haplotypic method was developed for calculating founder-origin probabilities in three-generation outbred pedigrees suited to quantitative trait locus (QTL) analysis. Estimators for expected founder-origin proportions were derived for a linkage group segment, an entire linkage group and a complete haplotype. If the founders are truly outbred, the haplotypic method gives a close approximation when compared with the Haley et al. (1994) method that simultaneously uses all marker information for QTL analysis, and it is less computationally demanding. The chief limitation of the haplotypic method is that some information in two-allele intercross marker-type configurations is ignored. Informativeness of marker arrays is discussed in the framework of founder-origin probabilities and proportions. The haplotypic method can be extended to more complex pedigrees with additional generations.

Founder Effect↗
PubMed2003

Studies of natural allele effects in mice can be used to identify genes causing common human obesity.

Although genes causing rare Mendelian forms of human obesity have provided much useful information about underlying causes of obesity, these genes do not explain significant proportions of common obesity. This review presents evidence that animal models can be used to uncover subtle genetic effects on obesity and can provide a powerful rigorous compliment to human association studies. We discuss the advantages of animal models of obesity, various approaches to discovering obesity genes, and the future of mapping and isolating naturally occurring alleles of obesity genes. We review evidence that it is important to map naturally occurring obesity genes using quantitative trait locus (QTL) mapping, instead of mutagenesis and knockout models because the latter do not allow study of interactions and because naturally occurring obesity alleles can interfere with cloning from mutagenesis projects. Because a substantial percentage of human obesity results from complex interactions, the underlying genes can only be identified by direct studies in humans, which are still very difficult, or by studies in mice that begin with QTL mapping. Finally, we emphasize that animal model studies can be used to prove that a specific gene, only associated with obesity in humans, can indeed be the underlying cause of obesity in mammals.

Animals↗
PubMed2004

Hyplip2, a new gene for combined hyperlipidemia and increased atherosclerosis.

OBJECTIVE: We previously reported the mapping of a quantitative trait locus (QTL) on chromosome 15 contributing to hyperlipidemia in a cross between inbred strains MRL/MpJ (MRL) and BALB/cJ (BALB). Using marker-assisted breeding, we constructed a congenic strain in which chromosome 15 interval from MRL is placed on the genetic background of BALB. The congenic allowed us to confirm the QTL result and to further characterize the properties and location of the underlying gene. METHODS AND RESULTS: On chow and high-fat (atherogenic) diets, the congenic mice exhibited higher levels of plasma triglycerides and cholesterol than BALB mice. In response to the atherogenic diet, the congenic mice but not BALB mice exhibited a dramatic approximately 30-fold increase in atherogenic lesions accompanied by approximately 2-fold decrease in high-density lipoprotein cholesterol levels. With respect to atherosclerotic lesions and some lipid parameters, this chromosome 15 gene, designated Hyplip2, exhibited dominant inheritance. Expression array analyses suggested that Hyplip2 may influence inflammatory and bile acid synthesis pathways. Finally, we demonstrated the usefulness of subcongenic strains to narrow the locus (50 Mbp) with the goal of positionally cloning Hyplip2. CONCLUSIONS: Our data demonstrate that the Hyplip2 gene significantly contributes to combined hyperlipidemia and increased atherosclerosis in mice.

Animals↗
PubMed2004

Genetic control of branching in foxtail millet.

Reduction in vegetative branching is commonplace when crops are domesticated from their wild progenitors. We have identified genetic loci responsible for these changes in foxtail millet (Setaria italica), a crop closely related to maize but whose genetics are little known. Quantitative trait locus (QTL) analysis and comparative genomics reveal that basal branching (tillering) and axillary branching are partially controlled by separate loci, and that the orthologue of teosinte branched1, the major gene controlling branching phenotype in maize, has only a minor and variable effect. We identify other candidate genes for control of branching, including a number of hormone biosynthesis pathway genes. These results suggest that similar phenotypic effects may not be produced by orthologous loci, even in closely related species, and that results from well characterized model systems such as maize must be reviewed critically before being applied to other species.

Analysis of Variance↗
PubMed2003

Genetic modulation of tau phosphorylation in the mouse.

The axonal microtubule stabilizing protein tau is hyperphosphorylated in several neurodegenerative conditions, including Alzheimer's disease, yet the genes that regulate tau phosphorylation are largely unknown. Disabled-1 (Dab1) is a cytoplasmic adapter protein that interacts with apolipoprotein E (ApoE) receptors and controls neuronal positioning during embryonic brain development. We have investigated the role of Dab1 in tau phosphorylation. We found that wild-type Dab1, but not a mutant lacking tyrosine phosphorylation sites, protects mice from the hyperphosphorylation of tau. However, the absence of Dab1 is not sufficient to cause tau hyperphosphorylation, because hyperphosphorylation is manifested only when Dab1 is mutated in specific mouse strain backgrounds. Tau hyperphosphorylation correlates with early death in susceptible mouse strains, and it occurs in the neurons of the hippocampus and dentate gyrus. By quantitative trait locus (QTL) analysis of Dab1-deficient mice on a hybrid strain background, we uncovered one significant and three suggestive chromosomal loci that modulate tau phosphorylation. Two of these QTL regions contain genes that are defective in early onset Alzheimer's disease. Our findings suggest that Dab1 gene disruption sensitizes mice to tau hyperphosphorylation contingent on specific haplotypes that are linked to Alzheimer's disease loci. Dab1 mutant mice provide an animal model for studying the relationships between ApoE receptors, tau hyperphosphorylation, and Alzheimer's disease.

Alzheimer Disease↗
PubMed2004

Genetic analysis of X-linked hybrid sterility in the house mouse.

Hybrid sterility is a common postzygotic reproductive isolation mechanism that appears in the early stages of speciation of various organisms. Mus musculus musculus and Mus musculus domesticus represent two recently separated mouse subspecies particularly suitable for genetic studies of hybrid sterility. Here we show that the introgression of Chr X of M. m. musculus origin (PWD/Ph inbred strain, henceforth PWD) into the genetic background of the C57BL/6J (henceforth B6) inbred strain (predominantly of M. m. domesticus origin) causes male sterility. The X-linked hybrid sterility is associated with reduced testes weight, lower sperm count, and morphological abnormalities of sperm heads. The analysis of recombinant Chr Xs in sterile and fertile males as well as quantitative trait locus (QTL) analysis of several fertility parameters revealed an oligogenic nature of the X-linked hybrid sterility. The Hstx1 locus responsible for male sterility was mapped near DXMit119 in the central part of Chr X. To ensure full sterility, the PWD allele of Hstx1 has to be supported with the PWD allelic form of loci in at least one proximal and/or one distal region of Chr X. Mapping and cloning of Hstx1 and other genes responsible for sterility of B6-X PWD Y B6 males could help to elucidate the special role of Chr X in hybrid sterility and consequently in speciation.

Acrosome Reaction↗
PubMed2005

Robust estimation of experimentwise P values applied to a genome scan of multiple asthma traits identifies a new region of significant linkage on chromosome 20q13.

Over 30 genomic regions show linkage to asthma traits. Six asthma genes have been cloned, but the putative loci in many linked regions have not been identified. To search for asthma susceptibility loci, we performed genomewide univariate linkage analyses of seven asthma traits, using 202 Australian families ascertained through a twin proband. House-dust mite sensitivity (Dpter) exceeded the empirical threshold for significant linkage at 102 cM on chromosome 20q13, near marker D20S173 (empirical pointwise P = .00001 and genomewide P = .005, both uncorrected for multiple-trait testing). Atopy, bronchial hyperresponsiveness (BHR), and forced expiratory volume in 1 s (FEV1) were also linked to this region. In addition, 16 regions were linked to at least one trait at the suggestive level, including 12q24, which has consistently shown linkage to asthma traits in other studies. Some regions were expected to be false-positives arising from multiple-trait testing. To address this, we developed a new approach to estimate genomewide significance that accounts for multiple-trait testing and for correlation between traits and that does not require a Bonferroni correction. With this approach, Dpter remained significantly linked to 20q13 (empirical genomewide P = .042), and airway obstruction remained linked to 12q24 at the suggestive level. Finally, we extended this method to show that the linkage of Dpter, atopy, BHR, FEV1, asthma, and airway obstruction to chromosome 20q13 is unlikely to be due to chance and may result from a quantitative trait locus in this region that affects several of these traits.

Adult↗
PubMed2000

Epistatic quantitative trait loci for alcohol preference in mice.

Alcohol consumption is a complex trait, responding to the influence of various genes and environmental influences acting in a quantitative fashion. Various studies in alcohol consumption processes have identified quantitative trait locus (QTL) regions across the mouse genome that appear to contribute to this phenotype. The purpose of this study was to examine the influence of interactions between alleles at different loci, a phenomenon known as epistasis, on previously identified QTLs for alcohol consumption in mice. A multiple regression model was developed and applied to test for the significance of the interaction between two QTLs and to quantify this interaction. Our results indicate the presence of epistasis between loci on mouse chromosomes 2 and 3 accounting for 7-8% of the variation in alcohol preference, respectively.

Alcohol Drinking↗
PubMed2000

Quantitative trait loci mapping for cholesterol gallstones in AKR/J and C57L/J strains of mice.

Quantitative trait locus (QTL) mapping was used to locate genes that determine the difference in cholesterol gallstone disease between the gallstone-susceptible strain C57L/J and the gallstone-resistant strain AKR/J. Gallstone weight was determined in 231 male (AKR x C57L) F(1) x AKR backcross mice fed a lithogenic diet containing 1% cholesterol, 0.5% cholic acid, and 15% butterfat for 8 wk. Mice having no stones and mice having the largest stones were genotyped at approximately 20-cM intervals to find the loci determining cholesterol gallstone formation. The major locus, Lith1, mapped near D2Mit56 and was confirmed by constructing a congenic strain, AK. L-Lith1(s). Another locus, Lith2, mapped near D19Mit58 and was also confirmed by constructing a congenic strain AK.L-Lith2(s). Other suggestive, but not statistically significant, loci mapped to chromosomes 6, 7, 8, 10, and X. The identification of these Lith genes will elucidate the pathophysiology of cholesterol gallstone formation.

Animals↗