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Results for “quantitative trait locus”

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PubMed2000

Power of selective genotyping in genetic association analyses of quantitative traits.

A power calculation is described in which the power of selective genotyping in genetic association studies of quantitative traits is evaluated. The method of selective genotyping implies the selection of the extremely high and low scoring individuals from the continuous distribution of a quantitative trait. The selected individuals are genotyped and association is tested. In the power calculation the following parameters are varied: total sample size of the phenotyped group (1000, 1500, 2000); selection of extremely high and low scoring individuals (2.5%, 5%, 10%); allele frequency of the risk increasing allele (0.10 to 0.90); mode of inheritance and proportion of variance explained by the quantitative trait locus (QTL) (omega 2 = 0.01, 0.05, 0.10). We conclude that the method of selective genotyping is a powerful method to detect association for a quantitative trait.

Chromosome Mapping↗

PubMed2002

Mice that are congenic for the char2 locus are susceptible to malaria.

A major advance has been made towards the positional cloning of char2 (a quantitative trait locus encoding resistance to Plasmodium chabaudi malaria). Mice congenic for the locus have been used to fine map the gene and to prove that char2 plays a significant role in the outcome of malarial infection, independently of other resistance loci.

Animals↗

PubMed2006

RMo1 confers blast resistance in barley and is located within the complex of resistance genes containing Mla, a powdery mildew resistance gene.

Isolates of Magnaporthe oryzae (the causal agent of rice blast disease) can infect a range of grass species, including barley. We report that barley Hordeum vulgare cv. Baronesse and an experimental line, BCD47, show a range of resistance reactions to infection with two rice blast isolates. The complete resistance of Baronesse to the isolate Ken 54-20 is controlled by a single dominant gene, designated RMo1. RMo1 mapped to the same linkage map position on chromosome 1H as the powdery mildew resistance locus Mla and an expressed sequence tag (k04320) that corresponds to the barley gene 711N16.16. A resistance quantitative trait locus (QTL), at which Baronesse contributed the resistance allele, to the isolate Ken 53-33 also mapped at the same position as RMo1. Synteny analysis revealed that a corresponding region on rice chromosome 5 includes the bacterial blight resistance gene xa5. These results indicate that a defined region on the short arm of barley chromosome 1H, including RMo1 and Mla, harbors genes conferring qualitative and quantitative resistance to multiple pathogens. The partial resistance of BCD47 to Ken53-33 is determined by alleles at three QTL, two of which coincide with the linkage map positions of the mildew resistance genes mlo and Mlf.

Chromosome Mapping↗

PubMed2003

Mapping cholesterol gallstone susceptibility (Lith) genes in inbred mice.

The individual risk for developing cholesterol gallstones in response to specific environmental factors is determined by complex genetics involving multiple genes. In this review, we introduce inbred mice as a model to localise and identify the murine genes that harbour cholesterol gallstone susceptibility alleles (Lith genes). These genes are associated with increased risk of gallstone formation when mice are fed a lithogenic diet containing cholesterol and cholic acid. We summarise the steps involved in localising the chromosomal regions that harbour Lith genes, focusing particularly on the initial step known as quantitative trait locus mapping, which employs breeding crosses of gallstone-susceptible and gallstone-resistant inbred mouse strains. Subsequent steps to narrow the chromosomal regions of the quantitative trait loci and identify the underlying Lith genes are outlined, with particular reference to the examples of Lith1 and Lith2, the first discovered quantitative trait loci associated with murine cholesterol cholelithiasis. We have now reported five quantitative trait loci for murine cholelithogenesis, which are officially named Lith1 through Lith5. Once the genes underlying these quantitative trait loci and other chromosomal loci from ongoing mouse crosses are identified and confirmed, the 'road-map' for discovery of orthologous human LITH genes will be available and, thereafter, their putative roles in cholesterol gallstone formation can be tested in selected human populations.

Animals↗

PubMed2005

EgMYB2, a new transcriptional activator from Eucalyptus xylem, regulates secondary cell wall formation and lignin biosynthesis.

Summary EgMYB2, a member of a new subgroup of the R2R3 MYB family of transcription factors, was cloned from a library consisting of RNA from differentiating Eucalyptus xylem. EgMYB2 maps to a unique locus on the Eucalyptus grandis linkage map and co-localizes with a quantitative trait locus (QTL) for lignin content. Recombinant EgMYB2 protein was able to bind specifically the cis-regulatory regions of the promoters of two lignin biosynthetic genes, cinnamoyl-coenzyme A reductase (CCR) and cinnamyl alcohol dehydrogenase (CAD), which contain MYB consensus binding sites. EgMYB2 was also able to regulate their transcription in both transient and stable expression assays. Transgenic tobacco plants over-expressing EgMYB2 displayed phenotypic changes relative to wild-type plants, among which were a dramatic increase in secondary cell wall thickness, and an alteration of the lignin profiles. Transcript abundance of genes encoding enzymes specific to lignin biosynthesis was increased to varying extents according to the position of individual genes in the pathway, whereas core phenylpropanoid genes were not significantly affected. Together these results suggest a role for EgMYB2 in the co-ordinated control of genes belonging to the monolignol-specific pathway, and therefore in the biosynthesis of lignin and the regulation of secondary cell wall formation.

Amino Acid Sequence↗

PubMed2006

Two-stage two-locus models in genome-wide association.

Studies in model organisms suggest that epistasis may play an important role in the etiology of complex diseases and traits in humans. With the era of large-scale genome-wide association studies fast approaching, it is important to quantify whether it will be possible to detect interacting loci using realistic sample sizes in humans and to what extent undetected epistasis will adversely affect power to detect association when single-locus approaches are employed. We therefore investigated the power to detect association for an extensive range of two-locus quantitative trait models that incorporated varying degrees of epistasis. We compared the power to detect association using a single-locus model that ignored interaction effects, a full two-locus model that allowed for interactions, and, most important, two two-stage strategies whereby a subset of loci initially identified using single-locus tests were analyzed using the full two-locus model. Despite the penalty introduced by multiple testing, fitting the full two-locus model performed better than single-locus tests for many of the situations considered, particularly when compared with attempts to detect both individual loci. Using a two-stage strategy reduced the computational burden associated with performing an exhaustive two-locus search across the genome but was not as powerful as the exhaustive search when loci interacted. Two-stage approaches also increased the risk of missing interacting loci that contributed little effect at the margins. Based on our extensive simulations, our results suggest that an exhaustive search involving all pairwise combinations of markers across the genome might provide a useful complement to single-locus scans in identifying interacting loci that contribute to moderate proportions of the phenotypic variance.

Alleles↗

PubMed1992

On the use of the moments method of estimation to obtain approximate maximum likelihood estimates of linkage between a genetic marker and a quantitative locus.

The approximate maximum likelihood method of Luo & Kearsey (1989) to determine the parameters of a segregating quantitative trait locus (QTL) in an F2 population by linkage to a genetic marker is compared to the 'true' maximum likelihood estimates derived by scanning the seven parameter likelihood space. The two methods did not yield identical results, and diverged markedly for a dominant QTL loosely linked to the genetic marker. Further study is suggested to evaluate other methods that do not simultaneously maximize the likelihood for all parameters.

Genetic Linkage↗

PubMed1996

Cytochrome P4504A genotype cosegregates with hypertension in Dahl S rats.

Recent studies indicate that the production of 20-HETE by a P4504A2 enzyme in the outer medulla of the kidney is reduced in Dahl salt-sensitive (SS/Jr) rats, but the contribution of this abnormality to the elevation in loop Cl- transport and development of hypertension in this model is unknown. THe present study found that alleles at the locus for the P4504A2 gene cosegregate with blood pressure in an F2 population (n=151) derived from a cross between SS/Jr and Lewis rats (P < .0001). The P4504A2 locus is located in a region on rat chromosome 5 where a blood pressure quantitative trait locus was previously detected. Systolic blood pressure averaged 201 +/- 6 mm Hg in rats with the SS genotype (n=36), 192 +/- 4 mm Hg in SL genotype rats (n=77), and 169 +/- 3 mm Hg in LL genotype rats (n=38). In further studies, we confirmed that there are phenotypic differences in the expression of the P4504A2 gene in the kidneys of SS/Jr and Lewis rats. Although the production of 20-HETE from 14C-arachidonic acid was similar in microsomes prepared from the renal cortex of SS/Jr and Lewis rats (54 +/- 3 versus 55 +/- 3 pmol/min/mg protein), the production of 20-HETE in microsomes prepared from the outer medulla (OM) was markedly reduced in SS/Jr rats (2.8 +/- 0.8 versus 6.7 +/- 1 pmol/min/mg protein). The diminished production of 20-HETE in the OM was due to a threefold reduction in the level of P4504A2 protein. These results suggest that an altered expression of the P4504A2 enzyme in the OM may contribute to the development of hypertension in SS/Jr rats.

Alleles↗

PubMed2004

Fine mapping and SNP analysis of positional candidates at the preeclampsia susceptibility locus (PREG1) on chromosome 2.

Genome scans in Icelandic, Australian and New Zealand, and Finnish families have localized putative susceptibility loci for preeclampsia/ eclampsia to chromosome 2. The locus mapped in the Australian and New Zealand study (designated PREG1) was thought to be the same locus as that identified in the Icelandic study. In both these studies, two distinct quantitative trait locus (QTL) regions were evident on chromosome 2. Here, we describe our fine mapping of the PREG1 locus and a genetic analysis of two positional candidate genes. Twenty-five additional microsatellite markers were genotyped within the 74-cM linkage region defined by the combined Icelandic and Australian and New Zealand genome scans. The overall position and shape of the localization evidence obtained using nonparametric multipoint analysis did not change from that seen previously in our 10-cM resolution genome scan; two peaks were displayed, one on chromosome 2p at marker D2S388 (107.46 cM) and the other on chromosome 2q at 151.5 cM at marker D2S2313. Using the robust two-point linkage analysis implemented in the Analyze program, all 25 markers gave positive LOD scores with significant evidence of linkage being seen at marker D2S2313 (151.5 cM), achieving a LOD score of 3.37 under a strict diagnostic model. Suggestive evidence of linkage was seen at marker D2S388 (107.46 cM) with a LOD score of 2.22 under the general diagnostic model. Two candidate genes beneath the peak on chromosome 2p were selected for further analysis using public single nucleotide polymorphisms (SNPs) within these genes. Maximum LOD scores were obtained for an SNP in TACR1 (LOD = 3.5) and for an SNP in TCF7L1 (LOD = 3.33), both achieving genome-wide significance. However, no evidence of association was seen with any of the markers tested. These data strongly support the presence of a susceptibility gene on chromosome 2p11-12 and substantiate the possibility of a second locus on chromosome 2q23.

Australia↗

PubMed2002

Unified sampling approach for multipoint linkage disequilibrium mapping of qualitative and quantitative traits.

Rapid development in biotechnology has enhanced the opportunity to deal with multipoint gene mapping for complex diseases, and association studies using quantitative traits have recently generated much attention. Unlike the conventional hypothesis-testing approach for fine mapping, we propose a unified multipoint method to localize a gene controlling a quantitative trait. We first calculate the sample size needed to detect linkage and linkage disequilibrium (LD) for a quantitative trait, categorized by decile, under three different modes of inheritance. Our results show that sampling trios of offspring and their parents from either extremely low (EL) or extremely high (EH) probands provides greater statistical power than sampling in the intermediate range. We next propose a unified sampling approach for multipoint LD mapping, where the goal is to estimate the map position (tau) of a trait locus and to calculate a confidence interval along with its sampling uncertainty. Our method builds upon a model for an expected preferential transmission statistic at an arbitrary locus conditional on the sampling scheme, such as sampling from EL and EH probands. This approach is valid regardless of the underlying genetic model. The one major assumption for this model is that no more than one quantitative trait locus (QTL) is linked to the region being mapped. Finally we illustrate the proposed method using family data on total serum IgE levels collected in multiplex asthmatic families from Barbados. An unobserved QTL appears to be located at tau; = 41.93 cM with 95% confidence interval of (40.84, 43.02) through the 20-cM region framed by markers D12S1052 and D12S1064 on chromosome 12. The test statistic shows strong evidence of linkage and LD (chi-square statistic = 18.39 with 2 df, P-value = 0.0001).

Asthma↗

PubMed1996

Evaluation of potential genetic associations between ethanol tolerance and sensitization in BXD/Ty recombinant inbred mice.

Ethanol (EtOH) has both locomotor stimulant and locomotor ataxic effects. Repeated EtOH treatment can result in the development of behavioral sensitization (increased sensitivity) similar to that seen with the classical stimulant drugs amphetamine and cocaine. However, it has been suggested for EtOH that sensitization may be a by-product of the development of tolerance to the sedative/ataxic effects of EtOH. It is also possible that the converse is true: that tolerance develops as the result of sensitization development. We examined this notion by measuring EtOH sensitization and tolerance in the BXD/Ty recombinant inbred strains. Changes in locomotor activation and grid test ataxia were used as the measures of sensitization and tolerance, respectively. If a genetic relationship exists between sensitization and tolerance, then those strains most susceptible to sensitization should also develop the most robust tolerance. Genetic correlations did not support the presence of this relationship. In addition, the use of the BXD/Ty recombinant inbred strains enabled us to perform gene mapping by quantitative trait locus analysis for activity and ataxia measures. We found that 28% to 79% of the genetic variation in the various activity and ataxia responses could be explained by the identified quantitative trait loci associations. However, when associations of gene markers with behavioral phenotypes were compared, we obtained no strong evidence for common genes determining magnitude of sensitization and tolerance. Thus the results of this study do not support the hypothesis that sensitization results from development of tolerance to the sedative/ataxic effects of EtOH or, conversely, that tolerance is a by-product of sensitization.

Animals↗

PubMed2005

The quantitative trait linkage disequilibrium test: a more powerful alternative to the quantitative transmission disequilibrium test for use in the absence of population stratification.

Linkage analysis based on identity-by-descent allele-sharing can be used to identify a chromosomal region harboring a quantitative trait locus (QTL), but lacks the resolution required for gene identification. Consequently, linkage disequilibrium (association) analysis is often employed for fine-mapping. Variance-components based combined linkage and association analysis for quantitative traits in sib pairs, in which association is modeled as a mean effect and linkage is modeled in the covariance structure has been extended to general pedigrees (quantitative transmission disequilibrium test, QTDT). The QTDT approach accommodates data not only from parents and siblings, but also from all available relatives. QTDT is also robust to population stratification. However, when population stratification is absent, it is possible to utilize even more information, namely the additional information contained in the founder genotypes. In this paper, we introduce a simple modification of the allelic transmission scoring method used in the QTDT that results in a more powerful test of linkage disequilibrium, but is only applicable in the absence of population stratification. This test, the quantitative trait linkage disequilibrium (QTLD) test, has been incorporated into a new procedure in the statistical genetics computer package SOLAR. We apply this procedure in a linkage/association analysis of an electrophysiological measurement previously shown to be related to alcoholism. We also demonstrate by simulation the increase in power obtained with the QTLD test, relative to the QTDT, when a true association exists between a marker and a QTL.

Genetic Predisposition to Disease↗

PubMed2002

Variance components models for gene-environment interaction in twin analysis.

Gene-environment interaction is likely to be a common and important source of variation for complex behavioral traits. Often conceptualized as the genetic control of sensitivity to the environment, it can be incorporated in variance components twin analyses by partitioning genetic effects into a mean part, which is independent of the environment, and a part that is a linear function of the environment. The model allows for one or more environmental moderator variables (that possibly interact with each other) that may i). be continuous or binary ii). differ between twins within a pair iii). interact with residual environmental as well as genetic effects iv) have nonlinear moderating properties v). show scalar (different magnitudes) or qualitative (different genes) interactions vi). be correlated with genetic effects acting upon the trait, to allow for a test of gene-environment interaction in the presence of gene-environment correlation. Aspects and applications of a class of models are explored by simulation, in the context of both individual differences twin analysis and, in a companion paper (Purcell & Sham, 2002) sibpair quantitative trait locus linkage analysis. As well as elucidating environmental pathways, consideration of gene-environment interaction in quantitative and molecular studies will potentially direct and enhance gene-mapping efforts.

Computer Simulation↗

PubMed2004

IGF2 antisense transcript expression in porcine postnatal muscle is affected by a quantitative trait nucleotide in intron 3.

A paternally expressed quantitative trait locus (QTL) for muscle mass was mapped to the insulin-like growth factor II (IGF2) locus at the distal end of pig chromosome 2p. It was recently demonstrated that a G to A transition at position intron 3-nt 3072 is the quantitative trait nucleotide (QTN) underlying this QTL. In this study we report for the first time the existence of imprinted porcine IGF2 antisense transcripts (IGF2-AS) and demonstrate that their expression in postnatal muscle is also affected by the QTN. A coregulated expression of IGF2 and IGF2-AS RNAs in muscle and liver with decreasing transcription from fetal to adult age was demonstrated. Further, the significant difference found in expression of IGF2-AS in postnatal muscle between individuals with different QTL genotypes and the lack of significant differences in fetal muscle and liver reflect completely what has been found for IGF2 sense transcripts.

Animals↗

PubMed2006

A distant upstream enhancer at the maize domestication gene tb1 has pleiotropic effects on plant and inflorescent architecture.

Although quantitative trait locus (QTL) mapping has been successful in describing the genetic architecture of complex traits, the molecular basis of quantitative variation is less well understood, especially in plants such as maize that have large genome sizes. Regulatory changes at the teosinte branched1 (tb1) gene have been proposed to underlie QTLs of large effect for morphological differences that distinguish maize (Zea mays ssp. mays) from its wild ancestors, the teosintes (Z. mays ssp. parviglumis and mexicana). We used a fine mapping approach to show that intergenic sequences approximately 58-69 kb 5' to the tb1 cDNA confer pleiotropic effects on Z. mays morphology. Moreover, using an allele-specific expression assay, we found that sequences >41 kb upstream of tb1 act in cis to alter tb1 transcription. Our findings show that the large stretches of noncoding DNA that comprise the majority of many plant genomes can be a source of variation affecting gene expression and quantitative phenotypes.

Genes, Plant↗

PubMed2005

Using progenitor strain information to identify quantitative trait nucleotides in outbred mice.

We have developed a fast and economical strategy for dissecting the genetic architecture of quantitative trait loci at a molecular level. The method uses two pieces of information: mapping data from crosses that involve more than two inbred strains and sequence variants in the progenitor strains within the interval containing a quantitative trait locus (QTL). By testing whether the strain distribution pattern in the progenitor strains is consistent with the observed genetic effect of the QTL we can assign a probability that any sequence variant is a quantitative trait nucleotide (QTN). It is not necessary to genotype the animals except at a skeleton of markers; the genotypes at all other polymorphisms are estimated by a multipoint analysis. We apply the method to a 4.8-Mb region on mouse chromosome 1 that contains a QTL influencing anxiety segregating in a heterogeneous stock and show that, under the assumption that a single QTN is present and lies in a region conserved between the human and mouse genomes, it is possible to reduce the number of variants likely to be the quantitative trait nucleotide from many thousands to <20.

Animals↗

PubMed2006

Mapping novel traits by array-assisted bulk segregant analysis in Saccharomyces cerevisiae.

We demonstrate a new method, microarray-assisted bulk segregant analysis, for mapping traits in yeast by genotyping pooled segregants. We apply a probabilistic model to the progeny of a single cross and as little as two microarray hybridizations to reliably map an auxotrophic marker, a Mendelian trait, and a major-effect quantitative trait locus.

Chromosome Mapping↗

PubMed2005

Fine mapping of the FT1 locus for soybean flowering time using a residual heterozygous line derived from a recombinant inbred line.

Fine-mapping of loci related to complex quantitative traits is essential for map-based cloning. A residual heterozygous line (RHL) of soybean (Glycine max) derived from a recombinant inbred line (RIL) was used for fine-mapping FT1, which is a major quantitative trait locus (QTL) responsible for soybean flowering time. The residual heterozygous line RHL1-156 was selected from the RILs that were derived from two distantly related varieties, Misuzudaizu and Moshidou Gong 503. The genome of RHL1-156 contains a heterozygous segment (approximately 17 cM) surrounding the FT1 locus but is homozygous in other regions, including three other loci affecting flowering time. A large segregating population of 1,006 individuals derived by selfing of RHL1-156 included two homozygous genotypes for the nearest marker of FT1 whose flowering time differed by 26 days. No continuous range of phenotypes was observed, in contrast to the F2 population, suggesting that a single FT1 locus affected the flowering time in the RHL1-156 line. Linkage analysis revealed that the FT1 locus mapped as a single Mendelian factor between two tightly linked DNA markers, Satt365 and GM169, at distances of approximately 0.1 cM and 0.4 cM, respectively. Our results show that a RHL derived from RILs can be used to fine-map a QTL and that RHLs can be an efficient tool for a systematic fine-mapping of QTLs.

Breeding↗