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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↗
PubMed2005

A computational method to detect epistatic effects contributing to a quantitative trait.

We develop a new computational method to detect epistatic effects that contribute to a complex quantitative trait. Rather than looking for epistatic effects that show statistical significance when considered in isolation, we search for a close approximation to the quantitative trait by a sum of epistatic effects. Our search algorithm consists of a sequence of random walks around the space of sums of epistatic effects. An important feature of our approach is that there is learning between random walks, i.e. the control mechanism that chooses steps in our random walks adapts to the experiences of earlier random walks. We test the effectiveness of our algorithms by applying them to synthetic datasets where the phenotype is a sum of epistatic effects plus normally distributed noise. Our test statistic is the rate of success that our methods achieve in identifying the underlying epistatic effects. We report on the effectiveness of our methods as we vary parameters that are intrinsic to the computation (length of random walks and degree of learning) as well as parameters that are extrinsic to the computation (number of markers, number of individuals, noise level, architecture of the epistatic effects).

Algorithms↗
PubMed2003

Quantitative structure-activity relationship (QSAR) analysis of aromatic effector specificity in NtrC-like transcriptional activators from aromatic oxidizing bacteria.

A quantitative structure-activity relationship (QSAR) approach was taken to provide mechanistic insights into the interaction between the chemical structure of inducing compounds and the transcriptional activation of aromatic monooxygenase operons among the XylR/DmpR subclass of bacterial NtrC-like transcriptional regulators. Compared to XylR and DmpR, a broader spectrum of effector compounds was observed for the TbuT system from Ralstonia pickettii PKO1. The results of QSAR analysis for TbuT suggested that a steric effect, rather than hydrophobic or electronic effects, may be the predominant factor in determining aromatic effector specificity, and the active site of the regulator may positively interact not only with the methyl moiety but also with the most electron-rich aryl side of an aromatic effector.

Bacterial Proteins↗
PubMed2003

Molecular dissection of a quantitative trait locus: a phenylalanine-to-tyrosine substitution in the transmembrane domain of the bovine growth hormone receptor is associated with a major effect on milk yield and composition.

We herein report on our efforts to improve the mapping resolution of a QTL with major effect on milk yield and composition that was previously mapped to bovine chromosome 20. By using a denser chromosome 20 marker map and by exploiting linkage disequilibrium using two distinct approaches, we provide strong evidence that a chromosome segment including the gene coding for the growth hormone receptor accounts for at least part of the chromosome 20 QTL effect. By sequencing individuals with known QTL genotype, we identify an F to Y substitution in the transmembrane domain of the growth hormone receptor gene that is associated with a strong effect on milk yield and composition in the general population.

Amino Acid Substitution↗
PubMed2006

Vernalization response in perennial ryegrass (Lolium perenne L.) involves orthologues of diploid wheat (Triticum monococcum) VRN1 and rice (Oryza sativa) Hd1.

Flowering time is important when adapting crop plants to different environments. While high feeding quality of forage grasses is facilitated by repression of flowering, flowering should also be inducible to facilitate grass seed production. Consequently, the identification and characterization of the genes controlling flowering time in forage grasses, including perennial ryegrass (Lolium perenne L.), is of great interest. In this study, three candidate genes for vernalization response genes in perennial ryegrass were identified based on DNA sequence homology to TmVRN1 and TmVRN2 of diploid wheat (Triticum monococcum), and Hd1 of rice (Oryza sativa). High sequence similarity between LpVRN1 and TmVRN1, co-localization of LpVRN1 with a major quantitative trait loci (QTL) for vernalization response in perennial ryegrass, synteny between map-positions of LpVRN1 and TmVRN1, mRNA expression analysis of LpVRN1 alleles during vernalization, and the correspondence between LpVRN1 mRNA expression levels and flowering time leads us to conclude that LpVRN1 is orthologous to TmVRN1 and that its function is conserved between diploid wheat and perennial ryegrass. Of the remaining two candidate genes, a putative Hd1 orthologue, LpCO, co-localized with a second QTL for vernlization response. LpCO has recently been shown to be involved in the photoperiodic regulation of flowering time. While epistasis, at the level of LpVRN1 transcription, was observed between the LpVRN1 and LpCO genomic regions, no differential expression of LpCO transcripts was observed during vernalization. While orthologous genes controlling flowering time can thus be identified, future allele sequencing efforts will reveal if causative polymorphisms are conserved across the grasses.

Amino Acid Sequence↗
PubMed2000

The relationship between loci for mating system and fitness-related traits in Mimulus (Scrophulariaceae): a test for deleterious pleiotropy of QTLs with large effects.

Loci with large phenotypic effects are generally not thought to be important in the evolution of quantitative traits because of their deleterious pleiotropic effects, yet empirical studies of such pleiotropic effects are lacking. Here I use molecular markers to test the extent of deleterious pleiotropy of quantitative trait loci (QTLs) that have large effects on mating system differences between the wild plants Mimulus guttatus and M. platycalyx (Scrophulariaceae). Six fitness-related traits, namely germination rate (GR), number of nodes (NN), number of flowers (NF), plant height (HT), above-ground biomass (WT), and flowering time (FT) were examined in a growth chamber for a backcross population between M. guttatus and M. platycalyx (with M. platycalyx as recurrent parent). Interval mapping based upon a linkage map consisting of isozyme and random amplified polymorphic DNA (RAPD) markers detected no QTL for fitness-related traits near the mating system QTLs. Single-marker analysis based upon 13 markers flanking the mating system QTLs detected three significant marker-fitness trait associations, and these associations indicate beneficial effects of mating system loci. This suggests that QTLs with large effects on mating system traits do not have significant deleterious pleiotropic effects, and that they could be important factors in adaptive evolution of Mimulus.

Alleles↗
PubMed2007

Detection of quantitative trait loci affecting lameness and leg conformation traits in Danish Holstein cattle.

Lameness is an important factor for culling animals. Strong legs and feet improve herd life of dairy cows. Therefore, many countries include leg and feet conformation traits in their breeding programs, often as early predictors of longevity. However, few countries directly measure lameness related traits to include these in a breeding program. Lameness indices in 3 different lactations and 5 leg conformation traits (rear legs side view, rear legs rear view, hock quality, bone quality, and foot angle) were measured on granddaughters of 19 Danish Holstein grandsires with 33 to 105 sons. A genome scan was performed to detect quantitative trait loci (QTL) based on the 29 autosomes using microsatellite markers. Data were analyzed across and within families for QTL affecting lameness and leg conformation traits. A regression method and a variance component method were used for QTL detection. Two QTL each for lameness in the first [Bos taurus autosome (BTA); BTA5, BTA26] and second (BTA19, BTA22) lactations were detected. For the 5 different leg conformation traits, 7 chromosome-wise significant QTL were detected across families for rear legs side view, 5 for rear legs rear view, 4 for hock quality, 4 for bone quality, and 1 for foot angle. For those chromosomes where a QTL associated with 2 different traits was detected (BTA1, BTA11, BTA15, BTA26, and BTA27), a multitrait-1-QTL model and a multitrait-2-QTL model were performed to characterize these QTL as single QTL with pleiotropic effects or distinct QTL.

Animals↗
PubMed2004

A powerful and robust new linkage statistic for discordant sibling pairs.

Previously, Szatkiewicz and colleagues evaluated the performance of a wide variety of statistics for quantitative-trait-locus linkage, using discordant sibling pairs. They found that the most powerful statistics, in general, were a score statistic and a "composite statistic." However, whereas these two statistics have equal power under ideal conditions, each has limitations that reduce its power in certain circumstances. The score statistic depends on estimates of trait parameters and can lose a lot of power if those estimates are incorrect. The composite statistic is not sensitive to trait-parameter estimates but does depend on arbitrary weights that must be chosen on the basis of the ascertainment scheme. In this report, we elucidate the algebraic relationship between the score and composite statistics and then use that relationship to suggest a new statistic that combines the best properties of both. We call our new statistic the "robust discordant pair" (RDP) statistic. We report simulation studies to show that the RDP statistic does, indeed, have all of the strengths and none of the weaknesses of the score and composite statistics.

Computer Simulation↗
PubMed2002

Investigating the probability of sign inconsistency in the regression coefficients of markers flanking quantitative trait loci.

Estimates of the locations and effects of quantitative trait loci (QTL) can be obtained by regressing phenotype on marker genotype. Under certain basic conditions, the signs of regression coefficients flanking QTL must be the same. There is no guarantee, however, that the signs of the regression coefficient estimates will be the same. We use sign inconsistency to describe the situation in which there is disagreement between the signs of the estimated regression coefficients flanking QTL. The presence of sign inconsistency can undermine the effectiveness of QTL mapping strategies that presume intervals whose markers have regression coefficient estimates of differing sign to be devoid of QTL. This article investigates the likelihood of sign inconsistency under various conditions. We derive an analytic expression for the approximate probability of sign inconsistency in the single-QTL case. We also examine sign inconsistency probabilities when multiple QTL are present through simulation. We have discovered that the probability of sign inconsistency can be unacceptably high, even when the conditions for QTL detection are otherwise quite favorable.

Computer Simulation↗
PubMed2001

A quick method for computing approximate thresholds for quantitative trait loci detection.

This article proposes a quick method for computing approximate threshold levels that control the genome-wise type I error rate of tests for quantitative trait locus (QTL) detection in interval mapping (IM) and composite interval mapping (CIM). The procedure is completely general, allowing any population structure to be handled, e.g., BC(1), advanced backcross, F(2), and advanced intercross lines. Its main advantage is applicability in complex situations where no closed form approximate thresholds are available. Extensive simulations demonstrate that the method works well over a range of situations. Moreover, the method is computationally inexpensive and may thus be used as an alternative to permutation procedures. For given values of the likelihood-ratio (LR)-profile, computations involve just a few seconds on a Pentium PC. Computations are simple to perform, requiring only the values of the LR statistics (or LOD scores) of a QTL scan across the genome as input. For CIM, the window size and the position of cofactors are also needed. For the approximation to work well, it is suggested that scans be performed with a relatively small step size between 1 and 2 cM.

Biometry↗
PubMed2006

Powdery mildew resistance in roses: QTL mapping in different environments using selective genotyping.

Podosphaera pannosa, the causal agent of rose powdery mildew, hampers the production of cut roses throughout the world. A major tool to control this disease is the use of resistant plant material. Single resistance genes, like Rpp1, may be overcome within a few years by high risk pathogens like powdery mildews. Durable resistance could be achieved using quantitative resistances. Here we describe mapping of QTLs for resistance to P. pannosa in six different environments (artificial and natural infections in the greenhouse over 3 years and natural infections in the field over 2 years). AFLPs, RGAs and other marker types were used to construct an integrated linkage map for the diploid population 97/7 containing 233 markers. In a selective genotyping procedure, marker segregation was analysed for 170 of the up to 270 phenotyped individuals. We identified seven linkage groups with an average length of 60 cM, corresponding to seven rose chromosomes in the haploid set. Using an LOD significance threshold of 3.9 we detected a total of 28 QTLs for the nine powdery mildew disease scores under analysis. Using the data from artificial inoculations with powdery mildew race 9, three resistance QTLs explaining about 84% of the variability were mapped. Twelve and 15 QTLs were detected for resistance to naturally occurring infections in the greenhouse and in the field, respectively, over several years.

Ascomycota↗
PubMed2004

Epistasis of quantitative trait loci under different gene action models.

Modeling and detecting nonallelic (epistatic) effects at multiple quantitative trait loci (QTL) often assume that the study population is in zygotic equilibrium (i.e., genotypic frequencies at different loci are products of corresponding single-locus genotypic frequencies). However, zygotic associations can arise from physical linkages between different loci or from many evolutionary and demographic processes even for unlinked loci. We describe a new model that partitions the two-locus genotypic values in a zygotic disequilibrium population into equilibrium and residual portions. The residual portion is of course due to the presence of zygotic associations. The equilibrium portion has eight components including epistatic effects that can be defined under three commonly used equilibrium models, Cockerham's model, F2-metric, and F(infinity)-metric models. We evaluate our model along with these equilibrium models theoretically and empirically. While all the equilibrium models require zygotic equilibrium, Cockerham's model is the most general, allowing for Hardy-Weinberg disequilibrium and arbitrary gene frequencies at individual loci whereas F2-metric and F(infinity)-metric models require gene frequencies of one-half in a Hardy-Weinberg equilibrium population. In an F2 population with two unlinked loci, Cockerham's model is reduced to the F2-metric model and thus both have a desirable property of orthogonality among the genic effects; the genic effects under the F(infinity)-metric model are not orthogonal but they can be easily translated into those under the F2-metric model through a simple relation. Our model is reduced to these equilibrium models in the absence of zygotic associations. The results from our empirical analysis suggest that the residual genetic variance arising from zygotic associations can be substantial and may be an important source of bias in QTL mapping studies.

Crosses, Genetic↗
PubMed1977

Genetic selection of mice for quantitative responsiveness of lymphocytes to phytohemagglutinin.

A two-way selection was performed in mice according to the quantitative in vitro response of lymph node lymphocytes to the mitogenic activity of phytohemagglutinin (PHA). The foundation population was composed of outbred mice produced by reciprocal mating of equal numbers of mice from four different colonies. The selective breeding was carried out by mating of mice at each generation giving the best or the lowest response, respectively. The progressive interline separation produced by 6 generations of selective breeding demonstrates that responsiveness to PHA is submitted to polygenic regulation. The heritability of the character investigated is 0.28 +/- 0.08. The interline separation is also found with another T mitogen, concanavalin A (Con A). In spleen cells PHA and Con A produce a similar interline difference. In contrast, the purified protein derivative of tuberculin (PPD) stimulated both lines equally, and E. coli lipopolysaccharide gave only a slightly higher response in high line. This finding implies that our selection based upon response to PHA did not influence B cell function.

Animals↗
PubMed1998

Bayesian mapping of multiple quantitative trait loci from incomplete inbred line cross data.

A novel fine structure mapping method for quantitative traits is presented. It is based on Bayesian modeling and inference, treating the number of quantitative trait loci (QTLs) as an unobserved random variable and using ideas similar to composite interval mapping to account for the effects of QTLs in other chromosomes. The method is introduced for inbred lines and it can be applied also in situations involving frequent missing genotypes. We propose that two new probabilistic measures be used to summarize the results from the statistical analysis: (1) the (posterior) QTL intensity, for estimating the number of QTLs in a chromosome and for localizing them into some particular chromosomal regions, and (2) the locationwise (posterior) distributions of the phenotypic effects of the QTLs. Both these measures will be viewed as functions of the putative QTL locus, over the marker range in the linkage group. The method is tested and compared with standard interval and composite interval mapping techniques by using simulated backcross progeny data. It is implemented as a software package. Its initial version is freely available for research purposes under the name Multimapper at URL http://www.rni.helsinki.fi/mjs.

Bayes Theorem↗
PubMed2005

Genotyping single nucleotide polymorphisms by MALDI mass spectrometry in clinical applications.

Matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry has become one of the most powerful and widely applied technologies for SNP scoring and determination of allele frequencies in the post-genome sequencing era. Although different strategies for allele discrimination combined with MALDI were devised, in practice only primer extension methods are nowadays routinely used. This combination enables the rapid, quantitative, and direct detection of several genetic markers simultaneously in a broad variety of biological samples. In the field of molecular diagnostics, MALDI has been applied to the discovery of genetic markers, that are associated with a phenotype like a disease susceptibility or drug response, as well as an alternative means for diagnostic testing of a range of diseases for which the responsible mutations are already known. It is one of the first techniques with which whole genome scans based on single nucleotide polymorphisms were carried out. It is equally well suited for pathogen identification and the detection of emerging mutant strains as well as for the characterization of the genetic identity and quantitative trait loci mapping in farm animals. MALDI can also be used as a detection platform for a range of novel applications that are more demanding than standard SNP genotyping such as mutation/polymorphism discovery, molecular haplotyping, analysis of DNA methylation, and expression profiling. This review gives an introduction to the application of mass spectrometry for DNA analysis, and provides an overview of most studies using SNPs as genetic markers and MALDI mass spectrometric detection that are related to clinical applications and molecular diagnostics. Further, it aims to show specialized applications that might lead to diagnostic applications in the future. It does not speculate on whether this methodology will ever reach the diagnostic market.

Animals↗
PubMed2002

Genes affecting aging: mapping quantitative trait loci in Drosophila melanogaster using amplified fragment length polymorphisms (AFLPs).

This study examines the use of AFLPs (amplified fragment length polymorphisms) for locating QTL for longevity. Inbred long and short-lived lines from selected stocks of D. melanogaster were backcrossed and measurements of life span compiled into a distribution. AFLP markers assorting with long life were screened from the extremes of that distribution. To test their association with further recombination, a second F1 was backcrossed for three generations and measured. Sires and progeny were genotyped for the markers initially screened. Three AFLP primer pairs identified markers assorting with long life in six of 48 sires. An a posteriori test showed that families of sires with putative markers lived significantly longer on average. A second test showed that within families, progeny with markers lived significantly longer than sibs without them. Marker positions were mapped by hybridization to a P1 genomic miniblot. AFLP markers were cloned, sequenced and matched to known genomic sequences in a BLAST search. Positions were compared to QTL known from other studies. The BLAST search indicated hybridization at multiply dispersed sites throughout the genome. Marker positions also corresponded to many from independent QTL maps. These results indicate that some QTL consist of dispersed duplications that contribute independently to longevity.

Aging↗
PubMed2006

DGAT1 and ABCG2 polymorphism in Indian cattle (Bos indicus) and buffalo (Bubalus bubalis) breeds.

BACKGROUND: Indian cattle (Bos indicus) and riverine buffalo (Bubalus bubalis) give a poor yield of milk but it has a high fat and protein percentage compared to taurine cattle. The identification of QTLs (Quantitative Trait Loci) on BTA14 and BTA6 and its subsequent fine mapping has led to identification of two non conservative mutations affecting milk production and composition. Our objective was to estimate the frequency of K232A (DGAT1--diacylglycerol-acyltransferase 1) and Y581S (ABCG2--ATP binding cassette sub family G member 2) polymorphisms in diverse cattle and buffalo breeds of India having large variation in terms of milk production. RESULTS: We screened the reported missense mutations in six cattle and five buffalo breeds. The DGAT1K and ABCG2Y alleles were found to be fixed in Indian cattle and buffalo breeds studied. CONCLUSION: This study provides an indirect evidence that all the Indian cattle and buffalo breeds have fixed alleles with respect to DGAT1 and ABCG2 genes reported to be responsible for higher milk fat yield, higher fat and protein percent.

ATP-Binding Cassette Transporters↗
PubMed2003

Combined segregation and linkage analysis of fibrinogen variability in Israeli families: evidence for two quantitative-trait loci, one of which is linked to a functional variant (-58G > A) in the promoter of the alpha-fibrinogen gene.

The association of alpha- and beta-fibrinogen polymorphisms with plasma fibrinogen levels was examined in a sample of 452 family members from 80 Israeli kindreds. The measured genotype analysis indicated that the beta-fibrinogen -455G > A polymorphism was not associated with fibrinogen levels, while the alpha-fibrinogen -58G > A locus showed a significant association with fibrinogen levels (chi2= 17.7; df = 3; p < 0.001), with the -58A allele being associated with higher levels. Segregation analysis in this sample suggested a recessive quantitative-trait locus (QTL) with a major effect that controlled the sex- and age-adjusted fibrinogen levels. Results from a combined segregation/linkage analysis indicated that a single QTL influencing plasma fibrinogen is in gametic equilibrium with the beta-fibrinogen -455G > A and alpha-fibrinogen -58G > A polymorphisms. An extended analysis with a two-QTL model significantly improved the fit of the model (p < or = 0.001), and gave support for linkage between the fibrinogen QTL and the alpha-fibrinogen polymorphism. In vitro analysis with a DNA fragment containing this variant, linked to a reporter gene, showed 2-fold higher expression of the A allele compared to the G allele in the liver cell line HepG2, both under basal conditions and after stimulation with interleukin 6. These results demonstrate that two QTLs are jointly involved in determining plasma fibrinogen levels in this sample of families, one of which is located close to a functional variant in the alpha-fibrinogen locus.

Cell Line↗