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PubMed1990

Using molecular markers to estimate quantitative trait locus parameters: power and genetic variances for unreplicated and replicated progeny.

Many of the progeny types used to estimate quantitative trait locus (QTL) parameters can be replicated, e.g., recombinant inbred, doubled haploid, and F3 lines. These parameters are estimated using molecular markers or QTL genotypes estimated from molecular markers as independent variables. Experiment designs for replicated progeny are functions of the number of replications per line (r) and the number of replications per QTL genotype (n). The value of n is determined by the size of the progeny population (N), the progeny type, and the number of simultaneously estimated QTL parameters (q - 1). Power for testing hypotheses about means of QTL genotypes is increased by increasing r and n, but the effects of these factors have not been quantified. In this paper, we describe how power is affected by r, n, and other factors. The genetic variance between lines nested in QTL genotypes (sigma 2n:q) is the fraction of the genetic variance between lines (sigma 2n) which is not explained by simultaneously estimated intralocus and interlocus QTL parameters (phi 2Q); thus, sigma 2n:q = sigma 2n - phi 2Q. If sigma 2n:q not equal to 0, then power is not efficiently increased by increasing r and is maximized by maximizing n and using r = 1; however, if sigma 2n:q = 0, then r and n affect power equally and power is efficiently increased by increasing r and is maximized by maximizing N.r. Increasing n efficiently increases power for a wide range of values of sigma 2n:q.sigma 2n:q = 0 when the genetic variance between lines is fully explained by QTL parameters (sigma 2n = phi 2Q).(ABSTRACT TRUNCATED AT 250 WORDS)

Alleles↗
PubMed2002

Application of a mixed inheritance model to the detection of quantitative trait loci in swine.

The primary goal of this study was to investigate statistical properties of a mixed inheritance model for the localization of quantitative trait loci (QTL). This is based on the analysis of phenotypic data for the amount of intramuscular fat (IMF) scored on 305 individuals originating from a cross between Duroc and Norwegian Landrace breeds. Marker genotype information is available for F1 and F2 generations. Statistical procedures compared involve i) the interval mapping, ii) the composite interval mapping, iii) a regression method, and iv) a mixed inheritance model accounting for a random animal additive genetic effect and relationships between individuals. The basic statistical properties of the latter approach are then assessed using Monte Carlo simulations showing slight unconservativeness as compared to chi(2)2df and reasonable power to detect QTL of moderate effects. In the analysis of IMF data, the significant evidence for the existing QTL is detected on chromosome 6. A chromosomal region recommended for a second-step fine mapping analysis is identified between markers SW1823 and S0228, based on three types of confidence intervals derived by using: i) the Jackknife algorithm, ii) the numerical variance approximation, and iii) the LOD score approach. The Jackknife algorithm was additionally used to quantify each family's contribution to the test statistic and to the estimate of QTL position.

Animals↗
PubMed2002

A linkage tournament: affection status, parametric analysis, multivariate traits, and enhancements to variance components and relative pairs.

Linkage tests to localize oligogenes have been extended during the past year. Using simulated data and multiplex selection we find that several tests on affected sib pairs have comparable power and type I error. Three variants of SIBPAL2 are favoured when substantial numbers of normal sibs are included, but performance relative to the BETA benchmark degrades rapidly as normal sibs are depleted by selective sampling or typing. Neglect of this fact may explain recent failure of retrospective collaboration to confirm asthma candidates in the 5q cytokine region that are supported by other studies. A fully quantitative trait favours variance components under complete ascertainment and two options in SIBPAL2 under multiplex selection, with substantial gain in power from covariance analysis if the covariate is independent of the candidate locus. A dichotomy and liability threshold give virtually identical results in the SOLAR variance components program. Comparison with single-marker parametric analysis suggests that extension to multiple markers would be competitive with nonparametric methods in power, and superior in depth of genetic analysis. The simulated examples illustrate common problems encountered with linkage scans for oligogenes. They show that nonparametric methods provide no panacea for analytical problems posed by different phenotypes and methods of ascertainment.

Asthma↗
PubMed2002

On the use of double haploids for detecting QTL in outbred populations.

The power to detect quantitative trait loci (QTL) using the double haploid (DH), full-sib (FS) and hierarchical (HI) designs implemented in outbred fish populations was assessed for interval mapping using deterministic methods. The predictions were tested using simulation. The DH design was most efficient for the range of designs and parameters considered and was most beneficial when the FS design was not very powerful. The difference between the design was largest for a low amount of residual genetic variation. Accounting for an increase of the environmental variance due to the genetic constitution of the double haploid progeny changed the magnitude of the power, but the ranking of the designs remained the same. As large full sib family sizes can be obtained in fish, the practical value of HI designs as a strategy for increasing the power of QTL mapping experiments is limited when compared with the FS design. Overall, the results suggested that the DH design could be a very useful tool for QTL mapping in fish, and of particular importance when the effect of the QTL is low and the residual genetic variation from other chromosomes can be controlled by using multiple markers.

Animals↗
PubMed2000

Linkage disequilibrium analysis of biallelic DNA markers, human quantitative trait loci, and threshold-defined case and control subjects.

Linkage disequilibrium (LD) mapping has been applied to many simple, monogenic, overtly Mendelian human traits, with great success. However, extensions and applications of LD mapping approaches to more complex human quantitative traits have not been straightforward. In this article, we consider the analysis of biallelic DNA marker loci and human quantitative trait loci in settings that involve sampling individuals from opposite ends of the trait distribution. The purpose of this sampling strategy is to enrich samples for individuals likely to possess (and not possess) trait-influencing alleles. Simple statistical models for detecting LD between a trait-influencing allele and neighboring marker alleles are derived that make use of this sampling scheme. The power of the proposed method is investigated analytically for some hypothetical gene-effect scenarios. Our studies indicate that LD mapping of loci influencing human quantitative trait variation should be possible in certain settings. Finally, we consider possible extensions of the proposed methods, as well as areas for further consideration and improvement.

Alleles↗
PubMed2003

Stochastic search variable selection for identifying multiple quantitative trait loci.

In this article, we utilize stochastic search variable selection methodology to develop a Bayesian method for identifying multiple quantitative trait loci (QTL) for complex traits in experimental designs. The proposed procedure entails embedding multiple regression in a hierarchical normal mixture model, where latent indicators for all markers are used to identify the multiple markers. The markers with significant effects can be identified as those with higher posterior probability included in the model. A simple and easy-to-use Gibbs sampler is employed to generate samples from the joint posterior distribution of all unknowns including the latent indicators, genetic effects for all markers, and other model parameters. The proposed method was evaluated using simulated data and illustrated using a real data set. The results demonstrate that the proposed method works well under typical situations of most QTL studies in terms of number of markers and marker density.

Bayes Theorem↗
PubMed2006

Quantitative structure/activity relationship modelling of pharmacokinetic properties using genetic algorithm-combined partial least squares method.

Quantitative structure/activity relationship (QSAR) approaches have widely been applied to gain deeper understandings of the relationships between ADME parameters and molecular structure and properties. QSAR models for predicting ADME properties are required to cover structurally diverse compounds. In the present investigation, we describe application of genetic algorithm-combined partial least squares (GA-PLS) method to QSAR modelling of various ADME properties. By selecting an appropriate set of molecular descriptors automatically by the use of genetic algorithm, many ADME properties could be well-explained by simple molecular descriptors derived from 2-dimensional chemical structure.

Algorithms↗
PubMed2004

Contributions of Portuguese cattle breeds to genetic diversity using marker-estimated kinships.

The quantitative assessment of genetic diversity within and between populations is important for decision-making in genetic conservation plans. In our study, we applied the livestock core set method to define the contribution of 15 cattle breeds, 11 of which are Portuguese indigenous cattle breeds, to genetic diversity. In livestock core set theory genetic diversity is defined as the maximum genetic variance that can be obtained in a random-mating population that is bred from the populations present in that core set. Two methods to estimate marker-estimated kinships to obtain the contributions to the core set were used in this study: the weighted log-linear model (WLM) and the weighted log-linear mixed model (WLMM). The breeds that contributed most to diversity in the core set were Holstein-Friesian followed by the Portuguese Mertolenga and Cachena for both WLM and WLMM methods. The ranking of relative contributions of cattle breeds was maintained when we considered only the Portuguese cattle breeds. Furthermore, we were able to identify the marginal contributions and respective losses of diversity for each of the 11 Portuguese cattle breeds when we considered a subset of populations that are not threatened of being lost (the Safe set composed of the four exotic breeds present in this study). When WLM was used losses in genetic diversity ranged from 2.68 to 0.65% while the loss in founder genome equivalents ranged from 37.37 to 8.43% for Mertolenga and Brava de Lide breeds respectively. When WLMM was used losses in genetic diversity and founder genome equivalents were less extreme than for the WLM method, ranging from 1.27 to 0.69 and 26.8 to 12.99 respectively.

Animals↗
PubMed2001

A quantitative trait locus influencing estrogen levels maps to a region homologous to human chromosome 20.

Estrogen, a steroid hormone, regulates reproduction and has been implicated in several diseases. We performed a genome-wide scan using multipoint linkage analysis implemented in a general pedigree-based variance component approach to identify genes with measurable effects on variation in estrogen levels in baboons. A microsatellite polymorphism, D20S171, located on human chromosome 20q13.11, showed strong evidence of linkage with a LOD score of 3.06 (P = 0.00009). This region contains several potential candidate genes including melanocortin 3 receptor (MC3R), cytochrome P-450 subfamily XXIV (CYP24), and breast carcinoma amplified sequence (BCAS1). This is the first evidence of a quantitative trait locus with a significant effect on estrogen.

Aging↗
PubMed2004

Genetic analysis of blood pressure in C3H/HeJ and SWR/J mice.

Hypertension is a complex phenotype induced by multiple environmental and genetic factors. Quantitative trait locus (QTL) analysis is a powerful method for identifying genomic regions underlying complex diseases. We conducted a QTL analysis of blood pressure in mice using 217 F(2) progeny (males and females) from a cross between the normotensive C3H/HeJ and hypertensive SWR/J inbred strains. Our analysis identified significant QTL controlling blood pressure on chromosome 1 [Chr 1; Bpq8; peak 78 cM; 95% confidence interval 64-106 cM; logarithm of the odds ratio (LOD) 3.5; peak marker D1Mit105] and on Chr 16 (Bpq9; peak 56 cM; 95% confidence interval 46-58 cM; LOD 3.6; peak marker D16Mit158). Bpq8 was previously identified in a cross between C57BL/6J and A/J mice, and we narrowed this QTL from 42 to 18 cM (95% confidence interval 68-86 cM) by combining the data from these crosses. By examining Bpq8 for regions where ancestral alleles were conserved among the high allele strains (C57BL/6J, SWR/J) and different from the low allele strains (A/J, C3H/HeJ), we identified a 2.3-cM region where the high allele strains shared a common haplotype. Bpq8 is concordant with known QTL in both rat and human, suggesting that the causal gene underlying Bpq8 may be conserved as a disease gene in human hypertension.

Animals↗
PubMed2003

Dopa decarboxylase (Ddc) affects variation in Drosophila longevity.

Mutational analyses in model organisms have shown that genes affecting metabolism and stress resistance regulate life span, but the genes responsible for variation in longevity in natural populations are largely unidentified. Previously, we mapped quantitative trait loci (QTLs) affecting variation in longevity between two Drosophila melanogaster strains. Here, we show that the longevity QTL in the 36E;38B cytogenetic interval on chromosome 2 contains multiple closely linked QTLs, including the Dopa decarboxylase (Ddc) locus. Complementation tests to mutations show that Ddc is a positional candidate gene for life span in these strains. Linkage disequilibrium (LD) mapping in a sample of 173 alleles from a single population shows that three common molecular polymorphisms in Ddc account for 15.5% of the genetic contribution to variance in life span from chromosome 2. The polymorphisms are in strong LD, and the effects of the haplotypes on longevity suggest that the polymorphisms are maintained by balancing selection. DDC catalyzes the final step in the synthesis of the neurotransmitters, dopamine and serotonin. Thus, these data implicate variation in the synthesis of bioamines as a factor contributing to natural variation in individual life span.

Animals↗
PubMed2006

On locating multiple interacting quantitative trait loci in intercross designs.

A modified version (mBIC) of the Bayesian Information Criterion (BIC) has been previously proposed for backcross designs to locate multiple interacting quantitative trait loci. In this article, we extend the method to intercross designs. We also propose two modifications of the mBIC. First we investigate a two-stage procedure in the spirit of empirical Bayes methods involving an adaptive (i.e., data-based) choice of the penalty. The purpose of the second modification is to increase the power of detecting epistasis effects at loci where main effects have already been detected. We investigate the proposed methods by computer simulations under a wide range of realistic genetic models, with nonequidistant marker spacings and missing data. In the case of large intermarker distances we use imputations according to Haley and Knott regression to reduce the distance between searched positions to not more than 10 cM. Haley and Knott regression is also used to handle missing data. The simulation study as well as real data analyses demonstrates good properties of the proposed method of QTL detection.

Algorithms↗
PubMed2003

Identification of quantitative trait loci for yield and yield components in an advanced backcross population derived from the Oryza sativa variety IR64 and the wild relative O. rufipogon.

A BC(2)F(2) population developed from an interspecific cross between Oryza sativa (cv IR64) and O. rufipogon (IRGC 105491) was used in an advanced backcross QTL analysis to identify and introduce agronomically useful genes from this wild relative into the cultivated gene pool. The objectives of this study were: (1) to identify putative yield and yield component QTLs that can be useful to improve the elite cultivar IR64; (2) to compare the QTLs within this study with previously reported QTLs in rice as the basis for identifying QTLs that are stable across different environments and genetic backgrounds; and (3) to compare the identified QTLs with previously reported QTLs from maize to examine the degree of QTL conservation across the grass family. Two hundred eighty-five families were evaluated in two field environments in Indonesia, with two replications each, for 12 agronomic traits. A total of 165 markers consisting of 131 SSRs and 34 RFLPs were used to construct the genetic linkage map. By employing interval mapping and composite interval mapping, 42 QTLs were identified. Despite its inferior performance, 33% of the QTL alleles originating from O. rufipogon had a beneficial effect for yield and yield components in the IR64 background. Twenty-two QTLs (53.4%) were located in similar regions as previously reported rice QTLs, suggesting the existence of stable QTLs across genetic backgrounds and environments. Twenty QTLs (47.6%) were exclusively detected in this study, uncovering potentially novel alleles from the wild, some of which might improve the performance of the tropical indica variety IR64. Additionally, several QTLs for plant height, grain weight, and flowering time detected in this study corresponded to homeologous regions in maize containing previously detected maize QTLs for these traits.

Base Sequence↗
PubMed2000

New insights into the metabolic consequences of large-scale mtDNA deletions: a quantitative analysis of biochemical, morphological, and genetic findings in human skeletal muscle.

In order to study putative genotype phenotype correlations in mitochondrial disorders due to large-scale mtDNA deletions we performed a quantitative analysis of biochemical, morphological, and genetic findings in 20 patients. The size of the mtDNA deletions varied from 2 to 7.5 kb with a degree of heteroplasmy ranging from 16% to 78%. Applying improved methods for measuring respiratory chain enzyme activities, we found highly significant inverse correlations between the percentage of cytochrome c oxidase (COX)- negative fibers and citrate synthase (CS) normalized COX ratios. Significant correlations were also established between CS normalized complex I and complex IV ratios as well as between the degree of heteroplasmy of mtDNA deletions and the percentage of ragged red fibers, COX-negative fibers, and CS normalized complex I and complex IV ratios. Our results indicate that the degree of heteroplasmy of mtDNA deletions is mirrored on the histological as well as the biochemical level. Furthermore, our findings suggest that single large-scale deletions equally influence the activities of all mitochondrially encoded respiratory chain enzymes. Even low degrees of heteroplasmy of mtDNA deletions were found to result in biochemical abnormalities indicating the absence of any well-defined mtDNA deletion threshold in skeletal muscle.

Adolescent↗
PubMed2000

[Disorders of endothelium-dependent vascular reactions and of the arginase and NO-synthase pathways of L-arginine metabolism in arterial hypertension].

In normotensive rats (NTR) and spontaneously hypertensive rats (SHR) with high (subgroup 1) and low (subgroup 2) level of the systemic arterial pressure (SAP) we studied an activity of arginase and nitric oxide synthase (NOS) in different tissues, and the content of their metabolites: urea and nitrit anion (NO2-). In isolated preparations of a thoracic aorta we recorded endothelium-dependent (ED) dilator reactions on acetylcholine (Ach). It has been found that in heart, aorta, plasma and erythrocytes of rats (subgroup 2) both the activity of arginase and content of urea increase remarkably. In heart, the activity of arginase reaches 27.96 +/- 5.92 nmol.min-1.mg-1 of protein, in aorta 4.74 +/- 0.99 nmol.min-1.mg-1 of protein (as compared with NTR 1.32 +/- 0.12 nmol.min-1.mg-1 of protein and 1.12 +/- 0.07 nmol.min-1.mg-1 of protein, accordingly). Content of urea in heart reaches 679.5 +/- 121.19 nmol.mg-1 of protein, in aorta 350.6 +/- 63.6 nmol.mg-1 of protein (in NTR it was 36.8 +/- 5.3 nmol.mg-1 of protein and 43.02 +/- +/- 9.55 nmol.min-1.mg-1 of protein, accordingly). It was followed with a decrease in the NOS activity and heterogeneous changes in NO2- content in the tissues under exploration. For example, the activity of NOS in heart and aorta decreased to 0.018 +/- 0.005 nmol.min-1.mg-1 of protein, in aorta 0.183 +/- 0.037 nmol.min-1.mg-1 of protein, accordingly, as compared to 0.093 +/- 0.014 nmol.min-1.mg-1 of protein and 0.41 +/- 0.07 nmol.min-1.mg-1 of protein in NTR. Content of NO2- in aorta decreased by 0.79 +/- 0.06 nmol.mg-1 of protein, but in heart it increased to 0.63 +/- +/- 0.13 nmol.mg-1 of protein, (in NTR it was 2.15 +/- 0.18 nmol.mg-1 of protein and 0264 +/- 0.04 nmol.min-1.mg-1 of protein, accordingly). In rats, subgroup 2, ED dilator responses of the smooth muscle (SM) of the thoracic aorta were inhibited by Ach (10(-6) mol). Their amplitude reduced by almost twice, and a latency for their response became 4 times as much. All the changes in the biochemical parametres in heart, aorta, plasma and erythrocytes, and changes in contractile activity of vascular SM proved to be also characteristic for rats in subgroup 1, but they were less expressed quantitatively. Thus, for the first time we have studied an activity of two alternative pathways for the metabolism of L-arginine on the model of arterial hypertension. The data obtained evidence that at hypertension non-oxidative (arginase) pathway of L-arginine metabolism is activated, while the oxidative pathway (NOS) is inhibited. Changes in the balance between them are followed with an essential inhibition of ED vasodilator responses. All this give us the prove to think of the origin for the arterial pressure increase to be both genetically and quantitatively determined damages in the biochemical homeostasis and dependent on it endothelial regulation of vascular tone.

Acetylcholine↗
PubMed2002

Association of cytokine single nucleotide polymorphisms with B7 costimulatory molecules in kidney allograft recipients.

African-American race is associated with an increased risk of allograft loss, suggesting that African-American patients may form an immunologically higher risk group. Previously, we demonstrated that immune cell costimulatory molecule expression is significantly higher in African-Americans than in Caucasians. Polymorphic variations in the genes for cytokines have been associated with a number of immunological conditions, and with transplant rejection. This study was performed to determine the distribution, in African-American and Caucasian renal transplant recipients, of single nucleotide polymorphisms (SNPs) in the following cytokine genes: tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), interleukin (IL)-6, IL-10, and transforming growth factor-beta (TGF-beta). Cytokine production from blood cells was determined, and cell-surface B7 (CD80, CD86) expression was measured. There was a significant link between IL-10 genotype and acute rejection episodes, but only in African-American patients (p < 0.01). Also, African-American patients had a significantly higher probability of having the IL-6 G-allele (p < 0.0001), which is associated with a high production of IL-6 protein. Incubation of blood cells with IL-6 resulted in increased expression of surface CD80 and CD86, while IL-10 decreased CD80 expression. This study demonstrated a clear correlation of the IL-6 G-allele with increased cellular CD80 expression and the IL-10 G-allele with decreased CD80 expression. These data raise the possibility that specific genotypes are associated with local cytokine regulation of cell-surface costimulatory molecule expression. African-American patients may have a genetically determined, quantitatively different immune response than Caucasian patients, contributing to adverse transplant outcomes.

Adult↗
PubMed2006

A note on QTL detecting for censored traits.

Most existing statistical methods for mapping quantitative trait loci (QTL) assume that the phenotype follows a normal distribution and that it is fully observed. However, some phenotypes have skewed distributions and may be censored. This note proposes a simple and efficient approach to QTL detecting for censored traits with the Cox PH model without estimating the baseline hazard function which is "nuisance".

Chromosome Mapping↗
PubMed2000

Ascertainment issues in variance components models.

One of the main concerns in the family studies of complex diseases is the effect that ascertainment and correction for it may have on test procedures and estimators. Elston and Sobel [1979] and Hopper and Mathews [1982] proposed two ways to correct for ascertainment in the study of quantitative trait data. For single ascertainment, using a variance components approach, we present results of simulation studies comparing estimates from these two methods for different selection criteria. We also show results from simulations when ascertained families are analyzed either at random or by correcting for ascertainment. For discordant sibpairs, we compare a variance components model that incorporates ascertainment correction with the extreme discordant sib pairs (EDSP) design proposed by Risch and Zhang [1995]. Our results show that there is minimal difference between the two methods of ascertainment correction. In the presence of effects from a large genetic background and the segregation of a rare gene, both ascertainment affected the polygenic and environmental components of variance but had rather little impact on the estimate of the linked major gene component of variance. The results also show the EDSP is slightly more powerful the variance components procedures for common alleles, and the variance components procedure is much more powerful than using EDSP when there is a rare allele segregating in the population.

Family Health↗