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PubMed1998

Genetic association of a GABA(A) receptor gamma2 subunit variant with severity of acute physiological dependence on alcohol.

The ultimate goal of quantitative trait locus (QTL) mapping is to identify the genes affecting complex traits. Using animal models, we recently identified QTLs on mouse Chromosomes (Chrs) 1, 4, and 11 affecting genetic predisposition to acute alcohol withdrawal. Among mice derived from the C57BL/6J (B6) and DBA/2J (D2) inbred strains, the locus identified on Chr 11 ( approximately 20 cM) accounted for 12% of the genetic variability in withdrawal liability. Candidate genes in proximity to this QTL encode the gamma2, alpha1, and alpha6 subunits of GABAA receptors. The present studies identify a polymorphism between the B6 and D2 strains in the gamma2 subunit gene, Gabrg2, and expand genotypic analysis to their BXD recombinant inbred strains. This polymorphism predicts a difference in amino acid sequence (Ala-11 vs. Thr-11) within the extracellular amino-terminal region of the gamma2 subunit. Analysis using BXD strain means for acute alcohol withdrawal severity suggests that the gamma2 subunit polymorphism is genetically correlated with alcohol withdrawal severity. This is the first report that QTL mapping for an alcohol-related trait has successfully led to the identification of a polymorphic candidate gene product that is genetically associated with the trait.

Animals↗
PubMedDate not supplied

Mapping of QTL for Body Conformation and Behavior in Cattle.

Genome scans for quantitative trait loci (QTL) in farm animals have concentrated on primary production and health traits, and information on QTL for other important traits is rare. We performed a whole genome scan in a granddaughter design to detect QTL affecting body conformation and behavior in dairy cattle. The analysis included 16 paternal half-sib families of the Holstein breed with 872 sons and 264 genetic markers. The markers were distributed across all 29 autosomes and the pseudoautosomal region of the sex chromosomes with average intervals of 13.9 cM and covering an estimated 3155.5 cM. All families were analyzed jointly for 22 traits using multimarker regression and significance thresholds determined empirically by permutation. QTL that exceeded the experiment-wise significance threshold (5% level) were detected on chromosome 6 for foot angle, teat placement, and udder depth, and on chromosome 29 for temperament. QTL approaching experiment-wise significance (10% level) were located on chromosome 6 for general quality of feet and legs and general quality of udder, on chromosome 13 for teat length, on chromosome 23 for general quality of feet and legs, and on chromosome 29 for milking speed. An additional 51 QTL significant at the 5% chromosome-wise level were distributed over 21 chromosomes. This study provides the first evidence for QTL involved in behavior of dairy cattle and identifies QTL for udder conformation on chromosome 6 that could form the basis of recently reported QTL for clinical mastitis.

Animals↗
PubMed2000

Confirmation of contextual fear conditioning QTLs by short-term selection.

A short-term selection study for contextual fear conditioning was conducted as a confirmational strategy to analyze the chromosomal locations of five previously mapped contextual fear conditioning quantitative trait loci (QTLs). The founding population was a C57BL/6 (B6) x DBA/2 (D2) F2 intercross. High and low lines were selected for three generations based on contextual fear conditioning scores. Fear conditioning was quantified as the percentage of time spent in a "frozen" posture when placed back into the chamber, where a mild footshock and a tone had been paired with exposure to the context 24 h earlier. Allele frequencies of at least three SSLP DNA markers linked to each of the five QTLs were determined in each generation. As the selection progressed, the frequency of D2 alleles decreased in the low line and increased in the high line for chromosomes 1 and 16, while the opposite was observed in chromosomes 2, 3, and 10. The direction of divergence for alleles on these five chromosomes is consistent with the original QTL mapping study. Differences between the lines in D2 allele frequencies were found to be significant for markers on chromosomes 2, 3, and 16 but did not reach significance on chromosomes 1 or 10. In general, the results are in good agreement with our original fear conditioning QTL mapping study and provide further evidence that these QTLs regulate variation in contextual fear conditioning in crosses of B6 and D2 mice.

Animals↗
PubMed2002

Mapping of QTL influencing saccharin consumption in the selectively bred alcohol-preferring and -nonpreferring rat lines.

The inbred preferring (iP) and nonpreferring (iNP) rat strains were derived from the selectively bred alcohol-preferring (P) and alcohol-nonpreferring (NP) lines. Previously, 381 iP x iNP F2 progeny were generated to identify quantitative trait loci (QTLs) influencing alcohol consumption and preference. Saccharin consumption (ml/48 h) and saccharin intake (ml/kg/day) were also measured in the F2 sample and were significantly correlated with both alcohol consumption and preference (all r > or = .20, p < .0001), suggesting that there might be some QTLs influencing both saccharin and alcohol phenotypes. We have performed a genome screen using F2 animals with extreme saccharin or alcohol consumption to identify QTLs contributing to saccharin-related phenotypes. Lod scores greater than 2.0 were found on chromosomes 3, 16 and 18 in this sample. Additional genotyping was performed in these regions in the full sample of 381 F2 progeny to further characterize these putative QTLs. On chromosome 3, the maximum lod score in the full sample was 2.7 with saccharin consumption. This QTL appears to overlap with a QTL identified for alcohol consumption in the iP and iNP lines and has pleiotropic effects on both phenotypes. Interestingly, this region of rat chromosome 3 is syntenic with mouse chromosome 2, where a QTL influencing alcohol preference has been previously reported. The QTL on chromosome 16 has a maximum lod score of 4.0 with saccharin intake and 2.6 with saccharin consumption. The QTL on chromosome 18 has a maximum lod score of 2.7 with saccharin consumption. Taken together, these data provide the first results of a genome screen for QTLs contributing to saccharin phenotypes in the rat.

Alcohol Drinking↗
PubMed2004

Quantitative trait loci controlling phenotypes related to the perennial versus annual habit in wild relatives of maize.

We used quantitative trait locus/loci (QTL) mapping to study the inheritance of traits associated with perennialism in a cross between an annual (Zea mays ssp. parviglumis) and a perennial (Z. diploperennis) species of teosinte. The most striking difference between these species is that Z. diploperennis forms rhizomes, whereas Z. mays ssp. parviglumis lacks these over-wintering underground stems. An F2 population of 425 individuals was genotyped at 95 restriction fragment length polymorphism marker loci and the association between phenotype and genotype was analyzed by composite interval mapping. We detected a total of 38 QTL for eight traits. The number of QTL found for each trait ranged from two for rhizome formation to nine for tillering. QTL for six of the traits mapped near each other on chromosome 2, and QTL for four traits mapped near each other on chromosome 6, suggesting that these regions play an important role in the evolution of the perennial habit in teosinte. Most of the 38 QTL had small effects, and no single QTL showed a strikingly large effect. The map positions that we determined for rhizome formation and other traits in teosinte may help to locate corresponding QTL in pasture and turf grasses used as forage for cattle and for erosion control in agro-ecosystems.

Chromosome Mapping↗
PubMed2004

Refined histopathologic scoring system improves power to detect colitis QTL in mice.

Induction of colitis in mice by a targeted mutation in the I110 gene is inbred strain dependent. C3H/ HeJBir (C3H) mice are colitis susceptible while C57BL/6J (B6) mice are resistant. Identification of quantitative trait loci (QTL) determining the differential strain responsiveness requires histopathologic scoring of multiple lesion subphenotypes in both cecum and colon. Here we show that ability to detect a major C3H-derived QTL on Chr 3 (cytokine deficiency-induced colitis susceptibility 1, Cdcs1) was critically dependent upon the degree of refinement of the histopathologic scoring system. QTL mapping was performed using a first-back-cross population of interleukin-10-deficient mice and applying two different grading systems to assess lesion subphenotypes. The same histological specimens were scored by two independent pathologists using either a very detailed scoring system for four subphenotypes developed at The Jackson Laboratory (TJL) or a simpler scoring system developed at the Hannover Medical School (MHH). The more detailed TJL subphenotyping protocol increased power to identify Cdcs1 (a maximum LOD score of 4.28 versus a LOD score of 1.77 when using the abbreviated MHH subphenotyping scoring system). This study shows that for QTL mapping in a mouse model of colitis, in which histology represents the gold standard for phenotyping, ability to detect linkage is critically dependent upon the degree of refinement adopted for separately scoring the multiple histopathologic lesions comprising this complex phenotype.

Animals↗
PubMed2004

QTL analysis for discovery of genes involved in drug responses.

The completed Plasmodium falciparum genome sequence poses a significant challenge: how do we bring this wealth of data to bear against the steady march of malaria parasites towards multiple-drug resistance? Studies of parasite drug resistance have until now focused on a qualitative, single-gene concept of resistance determination; however, the emergence of powerful genomics tools insists that these questions be rephrased. It is now possible to address the true genetic complexity underlying quantitative drug sensitivities. Quantitative trait loci (QTL) mapping is an effective tool for tracking multi-gene traits by partitioning genetic effects that influence these traits into specific genomic regions. A cross between two parasite clones captures allele combinations that have segregated into progeny clones that display varying sensitivity to drugs. The specific allele forms and their combinations contributed by each parent are, in effect, genetic signatures of their unique evolutionary histories. In addition to resistance genes, per se, a drug resistant parasite carries co-evolved gene combinations comprising a genetic background of drug resistance. Research into drug resistance necessarily has been directed at specific genes and mechanisms favored by a priori knowledge and assumptions about how resistance works. QTL mapping, by superimposing real biological phenotypes on genome sequence, structural polymorphisms, and gene expression data, can provide an alternative, unbiased view of the network of gene actions that build a complex phenotype. Through an integrated approach, studies can move beyond the search for markers of resistance to instead characterize the predisposition of parasites to develop new resistances and cross-resistances.

Alleles↗
PubMed2003

Mapping of QTL associated with nitrogen storage and remobilization in barley (Hordeum vulgare L.) leaves.

Nitrogen uptake and metabolism are central for vegetative and reproductive plant growth. This is reflected by the fact that nitrogen can be remobilized and reused within a plant, and this process is crucial for yield in most annual crops. A population of 146 recombinant inbred barley lines (F(8) and F(9) plants, grown in 2000 and 2001), derived from a cross between two varieties differing markedly in grain protein concentration, was used to compare the location of QTL associated with nitrogen uptake, storage and remobilization in flag leaves relative to QTL controlling developmental parameters and grain protein accumulation. Overlaps of support intervals for such QTL were found on several chromosomes, with chromosomes 3 and 6 being especially important. For QTL on these chromosomes, alleles associated with inefficient N remobilization were associated with depressed yield and higher levels of total or soluble organic nitrogen during grain filling and vice versa; therefore, genes directly involved in N recycling or genes regulating N recycling may be located on these chromosomes. Interestingly, the most prominent QTL for grain protein concentration (on chromosome 6) did not co-localize with QTL for nitrogen remobilization. However, QTL peaks for nitrate and soluble organic nitrogen were detected at this locus for plants grown in 2001 (but not in 2000). For these, alleles associated with low grain protein concentration were associated with higher soluble nitrogen levels in leaves during grain filling; therefore, gene(s) found at this locus might influence the nitrogen sink strength of developing barley grains.

Algorithms↗
PubMedDate not supplied

Genetic structure of susceptibility traits for hip dysplasia and microsatellite informativeness of an outcrossed canine pedigree.

An outcrossed canine pedigree was developed for quantitative trait locus (QTL) mapping of hip dysplasia by breeding dysplastic Labrador retrievers to trait-free greyhounds. Measured susceptibility traits included age at onset of femoral capital chondroepiphyseal ossification (OSS), maximum hip distraction (laxity) index (DI), and the dorsolateral subluxation (DLS) score. The pedigrees consisted of 147 dogs representing four generations. For 59 dogs genotyped with 65 microsatellites, the median heterozygosity and polymorphic information content (PIC) values of the F(1) generation were 0.82 and 0.68, respectively. Seventy-seven percent of microsatellites had a PIC greater than 0.59 in the F(1)s. Ninety-six percent of alleles showed Mendelian inheritance. Based on marker informativeness, approximately 350 randomly selected markers would be required for genome-wide screening to obtain an average interval between informative markers of 10 cM. Heritability was estimated as 0.43, 0.5, and 0.61 for OSS, DI, and the DLS score, respectively. Biometric estimates of the mean (+/- variance) effective number of segregating QTLs was 1.2 (+/- 0.05), 0.8 (+/- 0.02), and 1.0 (+/- 0.03) for OSS, DI, and the DLS score, respectively. The distributions of simulated backcross trait data suggested that the loci controlling these traits acted additively and that the DI may be controlled by a major locus. When combined with previous power and quantitative genetic analyses, these estimates indicate that this pedigree is informative for QTL mapping of hip dysplasia traits.

Animals↗
PubMed2004

A unified Markov chain Monte Carlo framework for mapping multiple quantitative trait loci.

In this article, a unified Markov chain Monte Carlo (MCMC) framework is proposed to identify multiple quantitative trait loci (QTL) for complex traits in experimental designs, based on a composite space representation of the problem that has fixed dimension. The proposed unified approach includes the existing Bayesian QTL mapping methods using reversible jump MCMC algorithm as special cases. We also show that a variety of Bayesian variable selection methods using Gibbs sampling can be applied to the composite model space for mapping multiple QTL. The unified framework not only results in some new algorithms, but also gives useful insight into some of the important factors governing the performance of Gibbs sampling and reversible jump for mapping multiple QTL. Finally, we develop strategies to improve the performance of MCMC algorithms.

Chromosome Mapping↗
PubMed2006

Genetics of flower size and nectar volume in Petunia pollination syndromes.

The two related Petunia species, P. axillaris and P. integrifolia, are sympatric at various locations in South America but do not hybridise. Divergent pollinator preferences are believed to be in part responsible for their reproductive isolation. The volume of nectar produced and several components of flower morphology might contribute to pollinator-dependant reproductive isolation. In this study, we aimed to identify the genetic changes underlying the quantitative differences observed between these two Petunia species in flower size and nectar volume. We mapped quantitative trait loci (QTL) responsible for the different phenotypes of P. axillaris and P. integrifolia in an inter-specific backcross population. QTL of small to moderate effect control the differences in flower size and volume of nectar. In addition, we observed strong suppression of meiotic recombination in Petunia, even between closely related species, which precluded a fine resolution of QTL mapping. Thus, our data suggest that flower size and nectar volume are highly polygenic. They are likely to have evolved gradually through pollinator-mediated adaptation or reinforcement, and are not likely to have been primary factors in early steps of pollinator isolation of P. axillaris and P. integrifolia.

Crosses, Genetic↗
PubMed2005

Bayesian mapping of QTL in outbred F2 families allowing inference about whether F0 grandparents are homozygous or heterozygous at QTL.

In this paper, we propose a new Bayesian method for QTL analysis in outbred F2 families based on Markov chain Monte Carlo (MCMC) estimation allowing inference about whether each of F0 founders (grandparents) is homozygous or heterozygous at QTL. This, in turn, allows us to select a model accurately explaining observations of phenotypes for F2 individuals. The proposed method performs the fitting a statistical model of the two possible QTL states in each F0 grandparent, that is, homozygous and heterozygous at QTL, and gives a posterior distribution for the QTL states in each F0 grandparent. We confine ourselves to the discrimination of two QTL states, homozygous or heterozygous, for each of the F0 grandparents without taking into consideration whether common alleles are shared by F0 grandparents. The statistical model includes allelic effects and dominance effects for each QTL. The number of parameters representing allelic effects and dominance effects is therefore changed depending on the QTL states. A Reversible Jump MCMC technique is used for transition between the models of different dimensions. The effectiveness of the proposed method was investigated using simulation experiments. It was practicable to estimate the QTL states of F0 grandparents as well as the number, the locations and the effects of QTL segregating in an outbred F2 family.

Alleles↗
PubMed1998

Further investigation on the regression method of mapping quantitative trait loci.

The simple regression method of mapping quantitative trait loci (QTL) is further investigated in comparison with the mixture model maximum likelihood method under high heritabilities, dominant and missing markers. No significant difference between the two methods is detected in terms of errors of parameter estimation and statistical powers, with the exception that the estimation of residual variance provided by the regression method is confounded with part of the QTL variance. The test statistic profiles show some difference between the two methods, but the difference is only detectable at the micro level. An alternative method, referred to as iteratively reweighted least squares, is proposed, which can correct the deficiency of parameter confounding in the regression method yet retains the properties of simplicity and rapidity of the ordinary regression method. Like the existing regression method, the weighted least squares method can be useful in QTL mapping in conjunction with the permutation tests and construction of confidence intervals by bootstrapping.

Chromosome Mapping↗
PubMed2004

Unexpected complexity in the haplotypes of commonly used inbred strains of laboratory mice.

Investigation of sequence variation in common inbred mouse strains has revealed a segmented pattern in which regions of high and low variant density are intermixed. Furthermore, it has been suggested that allelic strain distribution patterns also occur in well defined blocks and consequently could be used to map quantitative trait loci (QTL) in comparisons between inbred strains. We report a detailed analysis of polymorphism distribution in multiple inbred mouse strains over a 4.8-megabase region containing a QTL influencing anxiety. Our analysis indicates that it is only partly true that the genomes of inbred strains exist as a patchwork of segments of sequence identity and difference. We show that the definition of haplotype blocks is not robust and that methods for QTL mapping may fail if they assume a simple block-like structure.

Alleles↗
PubMedDate not supplied

The complex genetic architecture of Drosophila life span.

Continuous phenotypic variation in life span results from segregating genetic variation at multiple loci, the environmental sensitivity of expression of these loci, and the history of environmental variation experienced by the organism throughout its life. We have mapped quantitative trait loci (QTL) that produce variation in the life span of mated Drosophila melanogaster using a panel of recombinant inbred lines (RIL) that were backcrossed to the parental strains from which they were derived. Five QTL were identified that influence mated life span, three were male-specific, one was female-specific, and one affected life span in both sexes. The additive allelic effects and dominance of QTL were highly sex-specific. One pair of QTL also exhibited significant epistatic effects on life span. We summarize all of the QTL mapping data for Drosophila life span, and outline future prospects for disentangling the genetic and environmental influences on this trait.

Animals↗
PubMed1999

Quantitative trait loci affecting survival and fertility-related traits in Caenorhabditis elegans show genotype-environment interactions, pleiotropy and epistasis.

We have identified, using composite interval mapping, quantitative trait loci (QTL) affecting a variety of life history traits (LHTs) in the nematode Caenorhabditis elegans. Using recombinant inbred strains assayed on the surface of agar plates, we found QTL for survival, early fertility, age of onset of sexual maturity, and population growth rate. There was no overall correlation between survival on solid media and previous measures of survival in liquid media. Of the four survival QTL found in these two environments, two have genotype-environment interactions (GEIs). Epistatic interactions between markers were detected for four traits. A multiple regression approach was used to determine which single markers and epistatic interactions best explained the phenotypic variance for each trait. The amount of phenotypic variance accounted for by genetic effects ranged from 13% (for internal hatching) to 46% (for population growth). Epistatic effects accounted for 9-11% of the phenotypic variance for three traits. Two regions containing QTL that affected more than one fertility-related trait were found. This study serves as an example of the power of QTL mapping for dissecting the genetic architecture of a suite of LHTs and indicates the potential importance of environment and GEIs in the evolution of this architecture.

Animals↗