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Results for “QTL mapping”

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PubMed2006

Mouse bone marrow and peripheral blood erythroid cell counts are regulated by different autosomal genetic loci.

Erythropoiesis is under fine control and genetic loci that affect it are likely to be important in a range of conditions. To assess the relative contributions of different genetic loci to parameters of erythropoiesis, we have measured RBC counts in the peripheral circulation and committed erythroid cells (RBC and small normoblasts) in the bone marrow in a cohort of (CBA/H x C57BL/6) F2 mice to map quantitative trait loci (QTL). Candidate genes were assessed using bioinformatics and DNA sequencing. Different autosomal loci affect bone marrow (chromosomes 5, 11 and 19) and peripheral blood (chromosome 4) erythroid cell counts but there may be a common chromosome X locus. Spleen weight QTL were found on chromosomes 3, 15 and 17. Surprisingly, erythropoietin (Epo) is the best candidate quantitative trait gene (QTG) in the chromosome 5 locus that affects bone marrow but not peripheral blood erythroid cell counts. Epo gene expression is known to be genetically regulated in mice, but our data suggest a tissue-specific role for epo in mouse erythropoiesis that is also genetically determined. The identity of the other QTG will be important both to further knowledge of the control of erythropoiesis and as potential modifier genes for haematological disorders.

Animals↗
PubMed1996

Genetic models in the study of anesthetic drug action.

This chapter reviews the use of genetic models in the study of anesthetic drug action. Genetic model systems provide a novel approach to understanding mechanisms of anesthetic drug action. Many models have been derived using selection processes that emphasize differential drug sensitivity, producing animal lines that differ in their CNS drug response. Studies of vertebrate (rodent) and invertebrate (Drosophila, Caenorhabditis elegans) animal model systems are covered. The review discusses studies employing lines derived from spontaneous and induced mutagenic processes, selectively bred lines, and inbred lines possessing inherent differential drug sensitivities. The primary focus of included studies is the general anesthetic drugs that are commonly used in the clinical setting. These are drugs such as the inhalational agents (halothane, enflurane, isoflurane, nitrous oxide) and the intravenous induction agents (propofol and diazepam). Rodent lines with differential sensitivity to opiates are also discussed. Finally, an approach to identifying and isolating the genes that control anesthetic sensitivity is discussed in a section on mapping quantitative trait loci (QTL) in recombinant inbred lines.

Anesthetics↗
PubMed2003

Identification of QTLs for differential capsaicin sensitivity between mouse strains KJR and C57BL/6.

Capsaicin (8-methyl-N-vanillyl-6-nonenamide) is the main compound of hot chili peppers that causes both a pungent sensation and physiological pain. Capsaicin activates vanilloid receptor 1, a multi-functional receptor for pain sensation. In our previous report, it was found that sensitivity for capsaicin varies among mouse strains. In the present study, we conducted a quantitative trait loci (QTL) analysis to characterize the genetic loci involved in the different sensitivities to capsaicin between C57BL/6 and KJR mouse strains. In the study, we generated F2 progeny from the intercross of F1 mice obtained from a cross of C57BL/6 and KJR. We applied a fluid intake test of a capsaicin solution to the F2 progeny and conducted a QTL analysis. In this mapping study, four QTLs for capsaicin sensitivity were detected. Each of these loci contributed to 18.7-27.87% of strain difference of capsaicin consumption between C57BL/6 and KJR at each concentration. Because the sensation for capsaicin is associated with perception of pain, this genetic study on different capsaicin sensitivities will help future analyses of endogenous analgesic pathway.

Animals↗
PubMed2002

Mutation rate at swine microsatellite loci.

During genotyping of 38 microsatellites for QTL (quantitative trait loci) mapping in three F2 swine populations, five mutant alleles were detected in a total of 66,436 parent-offspring transfers of microsatellite alleles, which gives an overall mutation rate of 7.52 x 10(-5) per locus per generation. No significant (P > 0.05) association between mutation rates and other factors (i.e., GC contents in the flanking regions, heterozygosity, and repeat number) was revealed. Detailed sequencing showed that four out of five mutant alleles were caused by insertions of one to five repeats, respectively. The other mutant allele was produced by either an insertion of three repeats or a change of 30 base pairs (a deletion of 16 CT repeats and an insertion of one CA repeat). An insertion of one base pair in the flanking region of a microsatellite was also detected. Together, these data indicate that expansions are more common than contractions among microsatellites and that the mutation processes are very complicated, do not fit with the strict stepwise mutation model and may vary from locus to locus.

Animals↗
PubMed2005

Amazing grass: developmental genetics of maize domestication.

Crop plants were domesticated by prehistoric farmers through artificial selection to provide a means of feeding the human population. This article discusses the developmental genetics of crop domestication and improvement, including the historical framework and recent approaches in maize and other grasses. In many cases, selecting for a plant form that correlates with productivity involves controlling meristem activity. In the domestication of modern maize from its progenitor Zea mays ssp. parviglumis, QTL (quantitative trait loci) mapping, genetics and population genomics approaches have identified several genes that contain signatures of selection. Only a few genes involved in the derivation of the highly productive maize ear have been identified, including teosinte glume architecture1 and ramosa1. Future prospects hinge on forward and reverse genetics, as well as on other approaches from the developing discipline of evo-devo (evolutionary developmental biology).

Animals↗
PubMed2000

A recombination hotspot delimits a wild-species quantitative trait locus for tomato sugar content to 484 bp within an invertase gene.

In nature, genetic variation usually takes the form of a continuous phenotypic range rather than discrete classes. The genetic variation underlying quantitative traits results from the segregation of numerous interacting quantitative trait loci (QTLs), whose expression is modified by the environment. To uncover the molecular basis of this variation, we characterized a QTL (Brix9-2-5) derived from the green-fruited tomato species Lycopersicon pennellii. The wild-species allele increased glucose and fructose contents in cultivated tomato fruits in various genetic backgrounds and environments. Using nearly isogenic lines for the QTL, high-resolution mapping analysis delimited Brix9-2-5 to a single nucleotide polymorphism-defined recombination hotspot of 484 bp spanning an exon and intron of a fruit-specific apoplastic invertase. We suggest that the differences between the Brix9-2-5 alleles of the two species are associated with a polymorphic intronic element that modulates sink strength of tomato fruits. Our results demonstrate a link between naturally occurring DNA variation and a Mendelian determinant of a complex phenotype for a yield-associated trait.

Alleles↗
PubMed2002

A genomewide linkage screen for relative hand skill in sibling pairs.

Genomewide quantitative-trait locus (QTL) linkage analysis was performed using a continuous measure of relative hand skill (PegQ) in a sample of 195 reading-disabled sibling pairs from the United Kingdom. This was the first genomewide screen for any measure related to handedness. The mean PegQ in the sample was equivalent to that of normative data, and PegQ was not correlated with tests of reading ability (correlations between minus sign0.13 and 0.05). Relative hand skill could therefore be considered normal within the sample. A QTL on chromosome 2p11.2-12 yielded strong evidence for linkage to PegQ (empirical P=.00007), and another suggestive QTL on 17p11-q23 was also identified (empirical P=.002). The 2p11.2-12 locus was further analyzed in an independent sample of 143 reading-disabled sibling pairs, and this analysis yielded an empirical P=.13. Relative hand skill therefore is probably a complex multifactorial phenotype with a heterogeneous background, but nevertheless is amenable to QTL-based gene-mapping approaches.

Chromosome Mapping↗
PubMed2003

Positional candidate gene selection from livestock EST databases using Gene Ontology.

MOTIVATION: The number of expressed sequence tags (ESTs) in GenBank has now surpassed 200,000 for cattle and 100,000 for swine. The Institute of Genome Research (TIGR) has organized these sequences into approximately 60,000 non-redundant consensus sequences (identified by TIGR Gene Indices) for cattle and 40,000 for swine. Anonymous ESTs are of limited value unless they are connected to function. Functional information is difficult to manage electronically because of heterogeneity of meaning and form among databases. The Gene Ontology (GO) Consortium has produced ontologies for gene function with consistent meaning and form across species. Linking livestock EST to gene function through similarity with sequences from other annotation-rich mammals could accelerate: (1) the discovery of positional candidate genes underlying a livestock quantitative trait locus (QTL) and (2) comparative mapping between livestock and other mammals (e.g. humans, mouse and rat). We initiated this investigation to determine if incorporation of the GO into the annotation process could accelerate livestock positional candidate gene discovery. RESULTS: We have associated livestock ESTs with GO nodes through sequence similarity to the NCBI Reference Sequences (RefSeq). Positional candidate genes are identified within minutes that otherwise required days. The schema described here accommodates queries that return GO nodes from terms familiar to biologists, such as gene name, alternate/alias symbol, and OMIM phenotype. AVAILABILITY: Scripts and schema are available on request from the authors.

Animals↗
PubMed2001

Quantitative trait loci for the monoamine-related traits heart rate and headless behavior in Drosophila melanogaster.

Drosophila melanogaster appears to be well suited as a model organism for quantitative pharmacogenetic analysis. A genome-wide deficiency screen for haploinsufficient effects on prepupal heart rate identified nine regions of the genome that significantly reduce (five deficiencies) or increase (four deficiencies) heart rate across a range of genetic backgrounds. Candidate genes include several neurotransmitter receptor loci, particularly monoamine receptors, consistent with results of prior pharmacological manipulations of heart rate, as well as genes associated with paralytic phenotypes. Significant genetic variation is also shown to exist for a suite of four autonomic behaviors that are exhibited spontaneously upon decapitation, namely, grooming, grasping, righting, and quivering. Overall activity levels are increased by application of particular concentrations of the drugs octopamine and nicotine, but due to high environmental variance both within and among replicate vials, the significance of genetic variation among wild-type lines for response to the drugs is difficult to establish. An interval mapping design was also used to map two or three QTL for each behavioral trait in a set of recombinant inbred lines derived from the laboratory stocks Oregon-R and 2b.

Animals↗
PubMed2003

Candidate gene analysis for quantitative traits using the transmission disequilibrium test: the example of the melanocortin 4-receptor in pigs.

Population-wide associations between loci due to linkage disequilibrium can be used to map quantitative trait loci (QTL) with high resolution. However, spurious associations between markers and QTL can also arise as a consequence of population stratification. Statistical methods that cannot differentiate between loci associations due to linkage disequilibria from those caused in other ways can render false-positive results. The transmission-disequilibrium test (TDT) is a robust test for detecting QTL. The TDT exploits within-family associations that are not affected by population stratification. However, some TDTs are formulated in a rigid form, with reduced potential applications. In this study we generalize TDT using mixed linear models to allow greater statistical flexibility. Allelic effects are estimated with two independent parameters: one exploiting the robust within-family information and the other the potentially biased between-family information. A significant difference between these two parameters can be used as evidence for spurious association. This methodology was then used to test the effects of the fourth melanocortin receptor (MC4R) on production traits in the pig. The new analyses supported the previously reported results; i.e., the studied polymorphism is either causal or in very strong linkage disequilibrium with the causal mutation, and provided no evidence for spurious association.

Alleles↗
PubMed2004

Candidate defense genes as predictors of quantitative blast resistance in rice.

Although quantitative trait loci (QTL) underpin many desirable agronomic traits, their incorporation into crop plants through marker-assisted selection is limited by the low predictive value of markers on phenotypic performance. Here we used candidate defense response (DR) genes to dissect quantitative resistance in rice using recombinant inbred (RI) and advanced backcross (BC) populations derived from a blast-resistant cultivar, Sanhuangzhan 2 (SHZ-2). Based on DNA profiles of DR genes, RI lines were clustered into two groups corresponding to level of resistance. Five DR genes, encoding putative oxalate oxidase, dehydrin, PR-1, chitinase, and 14-3-3 protein, accounted for 30.0, 23.0, 15.8, 6.7, and 5.5% of diseased leaf area (DLA) variation, respectively. Together, they accounted for 60.3% of the DLA variation and co-localized with resistance QTL identified by interval mapping. Average phenotypic contributions of oxalate oxidase, dehydrin, PR-1, chitinase, and 14-3-3 protein in BC lines were 26.1, 19.0, 18.0, 11.5, and 10.6%, respectively, across environments. Advanced BC lines with four to five effective DR genes showed enhanced resistance under high disease pressure in field tests. Our results demonstrate that the use of natural variation in a few candidate genes can solve a long-standing problem in rice production and has the potential to address other problems involving complex traits.

DNA, Plant↗
PubMed2001

Genetic survival analysis of age-at-onset of bipolar disorder: evidence for anticipation or cohort effect in families.

Age-at-onset (AAO) in a number of extended families ascertained for bipolar disorder was analysed using survival analysis techniques, fitting proportional hazards models to estimate the fixed effects of sex, year of birth, and generation, and a random polygenic genetic effect. Data comprised the AAO (for 171 affecteds) or age when last seen (ALS) for 327 unaffecteds, on 498 individuals in 27 families. ALS was treated as the censored time in the statistical analyses. The majority of individuals classified as affected were diagnosed with bipolar I and II (n = 103) or recurrent major depressive disorder (n = 68). In addition to the significant effects of sex and year of birth, a fitted 'generation' effect was highly significant, which could be interpreted as evidence for an anticipation effect. The risk of developing bipolar or unipolar disorder increased twofold with each generation descended from the oldest founder. However, although information from both affected and unaffected individuals was used to estimate the relative risk of subsequent generations, it is possible that the results are biased because of the 'Penrose effect'. Females had a twofold increased risk in developing depressive disorder relative to males. The risk of developing bipolar or unipolar disorder increased by approximately 4% per year of birth. A polygenic component of variance was estimated, resulting in a 'heritability' of AAO of approximately 0.52. In a family showing strong evidence of linkage to chromosome 4p (family 22), the 'affected haplotype' increased the relative risk of being affected by a factor of 46. In this family, there was strong evidence of a time trend in the AAO. When either year of birth or generation was fitted in the model, these effects were highly significant, but neither was significant in the presence of the other. For this family, there was no increase in trinucleotide repeats measured by the repeat expansion detection method in affected individuals compared with control subjects. Proportional hazard models appear appropriate to analyse AAO data, and the methodology will be extended to map quantitative trait loci (QTL) for AAO.

Adult↗
PubMed2006

Statistical power of association using the extreme discordant phenotype design.

BACKGROUND: Selective genotyping has been proven to be an effective design for mapping quantitative trait loci (QTL), either by linkage or by allelic association, wherein the individual trait values can be used as the indices for phenotype selection. It has also been proposed that association studies of dichotomous traits can benefit from such design. When there is no quantitative measurement for phenotype available, cases and/or controls having extreme discordant phenotypes (EDP) can still be selected, based on their exposure status to a drug toxicity or environmental risk factor. The advantage of EDP design is intuitive and it has been successfully used in a number of studies. METHODS: In this report, we developed a statistical method to calculate the power of EDP methodology, using a mixture model of genotype-specific distributions of a single biallelic susceptibility locus. We also compared the power of three statistical tests commonly used in association studies - including the chi test of allelic frequencies, the chi test of genotype frequencies, and the Armitage trend test. The power of two different EDP designs was evaluated under a range of scenarios. RESULTS AND CONCLUSION: Our results indicate that the chi test of genotype frequency is a robust, though less powerful, test for single-locus association, and that EDP methodology is a powerful design for genetic association studies - especially those of common diseases caused by quantifiable drug toxicity or environmental risk factors.

Alleles↗
PubMed2006

Microarray analysis reveals differential gene expression in hybrid sunflower species.

This paper describes the creation of a cDNA microarray for annual sunflowers and its use to elucidate patterns of gene expression in Helianthus annuus, Helianthus petiolaris, and the homoploid hybrid species Helianthus deserticola. The array comprises 3743 ESTs (expressed sequence tags) representing approximately 2897 unique genes. It has an average clone/EST identity rate of 91%, is applicable across species boundaries within the annual sunflowers, and shows patterns of gene expression that are highly reproducible according to real-time RT-PCR (reverse transcription-polymerase chain reaction) results. Overall, 12.8% of genes on the array showed statistically significant differential expression across the three species. Helianthus deserticola displayed transgressive, or extreme, expression for 58 genes, with roughly equal numbers exhibiting up- or down-regulation relative to both parental species. Transport-related proteins were strongly over-represented among the transgressively expressed genes, which makes functional sense given the extreme desert floor habitat of H. deserticola. The potential adaptive value of differential gene expression was evaluated for five genes in two populations of early generation (BC2) hybrids between the parental species grown in the H. deserticola habitat. One gene (a G protein-coupled receptor) had a significant association with fitness and maps close to a QTL controlling traits that may be adaptive in the desert habitat.

Base Sequence↗
PubMed2004

Susceptibility to neoplastic and non-neoplastic pulmonary diseases in mice: genetic similarities.

Chronic inflammation predisposes toward many types of cancer. Chronic bronchitis and asthma, for example, heighten the risk of lung cancer. Exactly which inflammatory mediators (e.g., oxidant species and growth factors) and lung wound repair processes (e.g., proangiogenic factors) enhance pulmonary neoplastic development is not clear. One approach to uncover the most relevant biochemical and physiological pathways is to identify genes underlying susceptibilities to inflammation and to cancer development at the same anatomic site. Mice develop lung adenocarcinomas similar in histology, molecular characteristics, and histogenesis to this most common human lung cancer subtype. Over two dozen loci, called Pas or pulmonary adenoma susceptibility, Par or pulmonary adenoma resistance, and Sluc or susceptibility to lung cancer genes, regulate differential lung tumor susceptibility among inbred mouse strains as assigned by QTL (quantitative trait locus) mapping. Chromosomal sites that determine responsiveness to proinflammatory pneumotoxicants such as ozone (O3), particulates, and hyperoxia have also been mapped in mice. For example, susceptibility QTLs have been identified on chromosomes 17 and 11 for O3-induced inflammation (Inf1, Inf2), O3-induced acute lung injury (Aliq3, Aliq1), and sulfate-associated particulates. Sites within the human and mouse genomes for asthma and COPD phenotypes have also been delineated. It is of great interest that several susceptibility loci for mouse lung neoplasia also contain susceptibility genes for toxicant-induced lung injury and inflammation and are homologous to several human asthma loci. These QTLs are described herein, candidate genes are suggested within these sites, and experimental evidence that inflammation enhances lung tumor development is provided.

Animals↗
PubMed2000

Microsatellite marker panels for use in high-throughput genotyping of mouse crosses.

Several microsatellite genotyping panel sets have been developed that are polymorphic between C57BL/6J and CAST/Ei mice, or C57BL/6J and DBA/2J. One set of markers for each strain pair has an intermarker distance of approximately 20 cM, and a second set has an intermarker distance of 5 cM. The 20-cM set contains 105 markers for C57BL/6J x DBA/2J and 108 for C57BL/6J x CAST/Ei, divided into 13 panels. Each 5-cM set includes 350 markers arranged into 45 panels. A panel contains a number of primer pairs whose fluorescently labeled PCR products can be pooled together and separated on one lane of a polyacrylamide gel. The sets are arranged by the size of the PCR product and by the type of fluorescent dye; 5-cM sets are also arranged by chromosomal region. The 20-cM sets are most useful for full-genome scans, the 5-cM sets are useful for full-genome and/or for region-specific chromosome screens. Both sets were proven as useful tools for speed congenic development, quantitative trait loci (QTL) analysis and physical mapping. These panel sets provide a throughput of 1,536-2,304 mouse genotypes daily per one gel-based system. Whole genome scans of one animal require 13 or 48 gel lanes, with 20 cM or 5 cM density, respectively.

Animals↗