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PubMed1998

Selection with recurrent backcrossing to develop congenic lines for quantitative trait loci analysis.

SEWALL WRIGHT suggested that genes of large effect on a quantitative trait could be isolated by recurrent backcrossing with selection on the trait. Loci [quantitative trait loci (QTL)] at which the recurrent and nonrecurrent lines have genes of different large effect on the trait would remain segregating, while other loci would become fixed for the gene carried by the recurrent parent. If the recurrent line is inbred and the backcrossing and selection is conducted in a series of replicate lines, in each of which only one backcross parent is selected for each generation, the lines will become congenic to the recurrent parent except for the QTL of large effect and closely linked regions of the genome, and these regions can be identified using a dense set of markers that differ between the parental lines. Such lines would be particularly valuable for subsequent fine-scale mapping and gene cloning; but by chance, even QTL of large effect will be lost from some lines. The probability that QTL of specified effect remain segregating is computed as a function of its effect on the trait, the intensity of selection, and the number of generations of backcrossing. Analytical formulas are given for one or two loci, and simulation is used for more. It is shown that the method could have substantial discriminating ability and thus potential practical value.

Chromosome Mapping↗
PubMed2003

Correlation between quantitative traits and correlation between corresponding LOD scores: detection of pleiotropic effects.

BACKGROUND: We address the question of whether statistical correlations among quantitative traits lead to correlation of linkage results of these traits. Five measured quantitative traits (total cholesterol, fasting glucose, HDL cholesterol, blood pressure, and triglycerides), and one derived quantitative trait (total cholesterol divided by the HDL cholesterol) are used for phenotype correlation studies. Four of them are used for linkage analysis. RESULTS: We show that although correlation among phenotypes partially reflects the correlation among linkage analysis results, the LOD-score correlations are on average low. The most significant peaks found by using different traits do not often overlap. CONCLUSION: Studying covariances at specific locations in LOD scores may provide clues for further bivariate linkage analyses.

Adult↗
PubMed1992

Deoxyribonucleic acid fingerprint bands linked to loci coding for quantitative traits in chickens.

Efficacy of DNA fingerprint (DFP) bands in marker-assisted selection programs for quantitative traits in chickens was evaluated. A cross between two populations of White Plymouth Rock chickens that had been selected for 31 generations for high (HW) or low (LW) 8-wk body weight served as the base population for the experiment. Full- and half-sib families were produced over four generations and 400 offspring were measured for body weight at 8 wk (BW8) and shank length at 12 wk of age (SL12). Distributions were constructed for each quantitative trait in offspring of one F1 sire. The DFP produced from mixed blood of the individuals within each tail of the distribution were compared. From a total of 13 DFP bands that were disparate in intensity between the tails, four bands were chosen for analysis. Matings were made between males and females based on the presence or absence of these bands, but were limited to individuals that were within .5 standard deviation of the mean for the distribution of a particular trait. Quantitative traits of the resulting progeny were analyzed to determine whether parental type (presence or absence of the DFP band) influenced expression of the trait in the offspring. One band out of the four tested was associated with SL12, was an effective predictor of phenotype for both SL12 and BW8, and appeared to be inherited in a dominant fashion.

Animal Husbandry↗
PubMed2005

Meat quality traits were unaffected by a quantitative trait locus affecting leg composition traits in Texel sheep.

A QTL affecting leg muscle and fat traits has been identified within the New Zealand Texel population. The QTL maps to a region on OAR 2 with a two-marker haplotype test established at markers BULGE20 and BM81124. These markers encompass the likely position of Growth Differentiation Factor 8 (GDF8). The pleiotropic effects of this QTL on meat quality traits are tested. Objective measures of meat quality including pH, color (L*, a*, and b*), and tenderness (as assessed by Warner-Bratzler shear force measurements) were assessed on longissimus and semi-membranosus muscles of 540 progeny from six Texel sires. Four of these sires were subsequently identified as segregating for leg muscle and fat traits. For these segregating sires, comparison of progeny that had inherited the favorable haplotype from their sire with those that had received the alternate haplotype revealed no significant differences in the meat quality traits assessed. This finding suggests that the muscling QTL does not have pleiotropic effects on meat quality. A general scan for meat quality QTL was carried out using genotype data for eight markers from FCB128 to RM356 flanking 122cM of OAR 2 using Haley-Knott regression. This analysis revealed two QTL for a single sire. A QTL detected in the region of Marker INRA40 for color L* mapped to a site close to the muscling QTL, but there was evidence to suggest it is at a distinct locus. The QTL in the region of Marker RM356 might map distal to Marker RM356, as no peak was observed. This QTL, which seems to affect pH, color a*, color b*, and Warner-Bratzler shear measurements, requires further characterization.

Animals↗
PubMed2001

Linkage analysis of quantitative traits in randomly ascertained pedigrees: comparison of penetrance-based and variance component analysis.

Penetrance-based linkage analysis and variance component linkage analysis are two methods that are widely used to localize genes influencing quantitative traits. Using computer programs PAP and SOLAR as representative software implementations, we have conducted an empirical comparison of both methods' power to map quantitative trait loci in extended, randomly ascertained pedigrees, using simulated data. Two-point linkage analyses were conducted on several quantitative traits of different genetic and environmental etiology using both programs, and the lod scores were compared. The two methods appear to have similar power when the underlying quantitative trait locus is diallelic, with one or the other method being slightly more powerful depending on the characteristics of the quantitative trait and the quantitative trait locus. In the case of a multiallelic quantitative trait locus, however, the variance component approach has much greater power. These findings suggest that one should give careful thought to the likely allelic architecture of the quantitative trait to be analyzed when choosing between these two analytical approaches. It may be the case in general that linkage methods which explicitly or implicitly rely on the assumption of a diallelic trait locus fare poorly when this assumption is incorrect.

Chromosome Mapping↗
PubMed1997

A two-stage half-sib design for mapping quantitative trait loci in food animals.

Daughter and granddaughter half-sib designs for mapping quantitative trait loci were modified to increase experimental power. This new design includes a two-stage procedure, in contrast to conventional one-step half-sib designs. In stage 1, a few progeny of each sire are genotyped for marker loci. Based on the analyses of stage 1 data, some sires are chosen to continue genotyping more progeny for stage 2. When multiple chromosomes are under investigation, chromosomes and sires for stage 2 are selected based on the analysis of stage 1 data. Sire selection results in increased frequency of heterozygous genotypes of interest in stage 2 if the markers are linked to those genes. Chromosome selection can increase the proportion of chromosomes with segregating quantitative trait loci in stage 2 if not all of the chromosomes evaluated in stage 1 have segregating quantitative trait loci. Numerical results indicated that two-stage half-sib designs are generally more powerful than conventional designs when 1) the noncentrality parameter is moderate or larger, 2) larger quantitative trait loci are mapped using tightly linked markers in larger families, and 3) variation is large in numbers and sizes of segregating quantitative trait loci among the chromosomes evaluated in stage 1.

Animals↗
PubMed2006

Quantitative-trait-locus mapping in the presence of locus heterogeneity.

Locus heterogeneity is a concern for quantitative trait locus mapping where phenotypes are likely to be influenced by more than one gene. We introduce a model which generalizes the locus heterogeneity model of Smith (1961) from dichotomous traits to quantitative traits and consider some test statistics for this model. The type I error rates and the power of these statistics are assessed through simulation studies. These statistics are applied to a linkage study of asthma genes.

Asthma↗
PubMed1998

Quantitative trait loci and metabolic pathways.

The interpretation of quantitative trait locus (QTL) studies is limited by the lack of information on metabolic pathways leading to most economic traits. Inferences about the roles of the underlying genes with a pathway or the nature of their interaction with other loci are generally not possible. An exception is resistance to the corn earworm Helicoverpa zea (Boddie) in maize (Zea mays L.) because of maysin, a C-glycosyl flavone synthesized in silks via a branch of the well characterized flavonoid pathway. Our results using flavone synthesis as a model QTL system indicate: (i) the importance of regulatory loci as QTLs, (ii) the importance of interconnecting biochemical pathways on product levels, (iii) evidence for "channeling" of intermediates, allowing independent synthesis of related compounds, (iv) the utility of QTL analysis in clarifying the role of specific genes in a biochemical pathway, and (v) identification of a previously unknown locus on chromosome 9S affecting flavone level. A greater understanding of the genetic basis of maysin synthesis and associated corn earworm resistance should lead to improved breeding strategies. More broadly, the insights gained in relating a defined genetic and biochemical pathway affecting a quantitative trait should enhance interpretation of the biological basis of variation for other quantitative traits.

Journal Article↗
PubMed2004

Mapping quantitative trait loci affecting dairy conformation to chromosome 27 in two Holstein grandsire families.

Preliminary marker association results for quantitative trait loci affecting conformation traits using the granddaughter design and 8 large US Holstein grandsire families revealed strong associations in two families between the predicted transmitting abilities for dairy conformation and marker genotypes on bovine chromosome 27. Those results were based on single marker-trait associations in a genome-scan to identify broad chromosomal regions potentially containing genes affecting traits of interest. Results presented here describe continued study of quantitative trait loci on chromosome 27 for eventual incorporation into a marker-assisted selection program. Tests of marker associations for family 8 (91 sons) indicated an association with a microsatellite marker located near the telomere of chromosome 27. Interval analysis performed using additional marker genotypes generated for family 8 yielded further evidence for a quantitative trait locus in this region. No evidence was found for associations with milk production traits in this family in this region. An association was also detected in family 2 (240 sons) with a microsatellite marker located approximately 21 cM from the centromere of chromosome 27. Interval analysis performed for family 2 yielded evidence for a quantitative trait locus for dairy conformation near BMS689 with evidence of associations with fat percentage in the same region. Identification of quantitative trait loci affecting dairy conformation and fat components supports results reported by other groups, providing additional evidence that genes affecting fat metabolism are located on bovine chromosome 27.

Animals↗
PubMed2005

Mapping quantitative trait loci using linkage disequilibrium: marker- versus trait-based methods.

Two approaches for mapping quantitative trait loci (QTL) using linkage disequilibrium at the population level were investigated. In the trait-based (TB) approach, the frequencies of marker alleles (or genotypes) are compared in individuals selected from the two tails of the trait distribution. The TB approach uses phenotypic information only in the selection step. In the marker-based (MB) approach, the quantitative trait values for the marker genotypes in the selected individuals are compared. The MB approach uses both the difference in marker allele (or genotype) frequencies and the phenotypic values of each marker genotype in the selected samples. We quantify the power of each approach and show that the power of the MB approach is greater than or equal to that of the TB approach. The advantage of the former is expected to increase with increasing number of traits phenotyped. Our accurate predictions obviate the need for elaborate simulation studies.

Humans↗
PubMed2006

Genetic association tests based on ranks (GATOR) for quantitative traits with and without censoring.

Linkage disequilibrium mapping of quantitative traits is a powerful method for dissecting the genetic etiology of complex phenotypes. Quantitative traits, however, often exhibit characteristics that make their use problematic. For example, the distribution of the trait may be censored, highly skewed, or contaminated with outlying values. We propose here a rank-based framework for deriving tests of gene and trait association that explicitly take censoring into account and are insensitive to skewness and outlying values. Standard methods for mapping quantitative traits do not take these characteristics into account, which leads to the discarding of valuable information or their improper application. We show how this framework can be applied in nuclear families and discuss its implementation in general pedigrees. The power and efficacy of the approach is illustrated through a series of simulation experiments in which the approach is compared to existing methods.

Age of Onset↗
PubMed1991

Use of recombinant inbred strains to identify quantitative trait loci in psychopharmacology.

Unlike simple Mendelian characteristics, individual differences in complex quantitative phenotypes studied in psychopharmacology are generally distributed continuously and are likely to be influenced by many genes. Recombinant inbred (RI) strains are valuable not only for their traditional use of detecting major gene segregation and linkage but also for identifying associations between quantitative traits and quantitative trait loci (QTL) that account for relatively small amounts of variation in phenotypes as well as loci that account for greater amounts of variation. When applied to published data on genetic markers and on amphetamine, alcohol, and morphine responses in BXD RI strains (RI strains developed from the cross between C57BL/6J and DBA/2J progenitor inbred strains), the RI QTL approach identified several significant associations beyond known major gene effects. Together, significant associations explain more than half of the genetic variance for these measures. The RI QTL approach is especially valuable for investigating the QTL underpinnings of genetic correlations among measures. It is recommended that psychopharmacogenetic research focus on the BXD RI strains. The cumulative and integrative nature of such a program of research is the major benefit of the RI QTL association approach for molecular genetic analysis of psychopharmacological processes, their physiological infrastructure, and their interface with other behavioral and biological systems.

Animals↗
PubMed2005

A method for identifying genes related to a quantitative trait, incorporating multiple siblings and missing parents.

When studying either qualitative or quantitative traits, tests of association in the presence of linkage are necessary for fine-mapping. In a previous report, we suggested a polytomous logistic approach to testing linkage and association between a di-allelic marker and a quantitative trait locus, using genotyped triads, consisting of an individual whose quantitative trait has been measured and his or her two parents. Here we extend that approach to incorporate marker information from entire nuclear families. By computing a weighted score function instead of a maximum likelihood test, we allow for both an unspecified correlation structure between siblings and "informative" family size. Both this approach and our original approach allow for population admixture by conditioning on parental genotypes. The proposed method allows for missing parental genotype data through a multiple imputation procedure. We use simulations based on a population with admixture to compare our method to a popular non-parametric family-based association test (FBAT), testing the null of no association in the presence of linkage.

Alleles↗
PubMed2006

The genetic basis of floral traits associated with mating system evolution in Leptosiphon (Polemoniaceae): an analysis of quantitative trait loci.

Mapping of quantitative trait loci (QTL) was used to investigate the genetic architecture of divergence in floral characters associated with the mating system, an important adaptive trait in angiosperms. Two species of Leptosiphon (Polemoniaceae), one strongly self-fertilizing (L. bicolor) and the other partially outcrossing (L. jepsonii), were crossed to produce F2 and both backcross progenies. For each crossing population, a linkage map was created using amplified fragment length polymorphism markers, and QTL were identified for several dimensions of floral size. For each of the five traits examined, three to seven QTL were detected, with independent datasets yielding congruent results in some but not all cases. The phenotypic effect of individual QTL was generally moderate. We estimated that many of the QTL were additive or showed dominance toward L. bicolor, whereas comparison of mean trait values for parental and cross progenies showed apparent overall dominance of L. jepsonii traits. Colocalization of QTL for different dimensions of floral size was consistent with high phenotypic correlations between floral traits. Substantial segregation distortion was observed in marker loci, the majority favoring alleles from the large-flowered parent. A low frequency of male sterility in the F2 population is consistent with the Dobzhansky-Muller model for the evolution of reproductive isolation.

Biological Evolution↗
PubMed2004

On the integration of alcohol-related quantitative trait loci and gene expression analyses.

BACKGROUND: Quantitative trait loci (QTLs) have been detected for a wide variety of ethanol-related phenotypes, including acute and chronic ethanol withdrawal, acute locomotor activation, and ethanol preference. This study was undertaken to determine whether the process of moving from QTL to quantitative trait gene (QTG) could be accelerated by the integration of functional genomics (gene expression) into the analysis strategy. METHODS: Six ethanol-related QTLs, all detected in C57BL/6J and DBA/2J intercrosses were entered into the analysis. Each of the QTLs had been confirmed in independent genetic models at least once; the cumulative probabilities for QTL existence ranged from 10 to 10. Brain gene expression data for the C57BL/6 and DBA/2 strains (n = 6 per strain) and an F2 intercross sample (n = 56) derived from these strains were obtained by using the Affymetrix U74Av2 and 430A arrays; additional data with the U74Av2 array were available for the extended amygdala, dorsomedial striatum, and hippocampus. Low-level analysis was performed by using multiple methods to determine the likelihood that a transcript was truly differentially expressed. For the 430A array data, the F2 sample was used to determine which of the differentially expressed transcripts within the QTL intervals were cis-regulated and, thus, strong candidates for QTGs. RESULTS: Within the 6 QTL intervals, 39 transcripts (430A array) were identified as being highly likely to be differentially expressed between the C57BL/6 and DBA/2 strains at a false discovery rate of 0.01 or better. Twenty-eight of these transcripts showed significant (logarithm of odds > or =3.6) to highly significant (logarithm of odds >7) cis-regulation. The process correctly detected Mpdz (chromosome 4) as a candidate QTG for acute withdrawal. CONCLUSIONS: Although improvements are needed in the expression databases, the integration of QTL and gene expression analyses seems to have potential as a high-throughput strategy for moving from QTL to QTG.

Alcohol Drinking↗
PubMed2004

Method for using complete and incomplete trios to identify genes related to a quantitative trait.

A number of tests for linkage and association with qualitative traits have been developed, with the most well-known being the transmission/disequilibrium test (TDT). For quantitative traits, varying extensions of the TDT have been suggested. The quantitative trait approach we propose is based on extending the log-linear model for case-parent trio data (Weinberg et al. [1998] Am. J. Hum. Genet. 62:969-978). Like the log-linear approach for qualitative traits, our proposed polytomous logistic approach for quantitative traits allows for population admixture by conditioning on parental genotypes. Compared to other methods, simulations demonstrate good power and robustness of the proposed test under various scenarios of the genotype effect, distribution of the quantitative trait, and population stratification. In addition, missing parental genotype data can be accommodated through an expectation-maximization (EM) algorithm approach. The EM approach allows recovery of most of the lost power due to incomplete trios.

Computer Simulation↗
PubMed2007

Dissecting the heterogeneity of rheumatoid arthritis through linkage analysis of quantitative traits.

OBJECTIVE: To dissect the heterogeneity of rheumatoid arthritis (RA) through linkage analysis of quantitative traits, specifically, IgM rheumatoid factor (IgM-RF) and anti-cyclic citrullinated peptide (anti-CCP) autoantibody titers. METHODS: Subjects, 1,002 RA patients from 491 multiplex families recruited by the North American RA Consortium, were typed for 379 microsatellite markers. Anti-CCP titers were determined based on a second-generation enzyme-linked immunosorbent assay, and IgM-RF levels were quantified by immunonephelometry. We used the Merlin statistical package to perform nonparametric quantitative trait linkage analysis. RESULTS: For each of the quantitative traits, evidence of linkage, with logarithm of odds (LOD) scores of >1.0, was found in 9 regions. For both traits, the strongest evidence of linkage was for marker D6S1629 on chromosome 6p (LOD 14.02 for anti-CCP and LOD 12.09 for RF). Six other regions with LOD scores of >1.0 overlapped between the 2 traits, on chromosomes 1p21.1, 5q15, 8p23.1, 16p12.1, 16q23.1, and 18q21.31. Evidence of linkage to anti-CCP titer but not to RF titer was found in 2 regions (chromosomes 9p21.3 and 10q21.1), and evidence of linkage to RF titer but not to anti-CCP titer was found in 2 regions (chromosomes 5p15.2 and 1q42.3). Several covariates were significantly associated with 1 or both traits, and linkage analysis exploring the covariate effects revealed striking effects of sex in modulating linkage signals for several chromosomal regions. For example, sex had a striking impact on the linkage results for both quantitative traits on chromosome 6p (P = 0.0007 for anti-CCP titer and P = 0.0012 for RF titer), suggesting a sex-HLA region interaction. CONCLUSION: Analysis of quantitative components of RA is a promising approach for dissecting the genetic heterogeneity of this complex disorder. These results highlight the potential importance of sex or other covariates that may modulate some of the genetic effects that influence the risk of specific disease manifestations.

Adult↗
PubMed2003

Quantitative trait locus analysis as a gene discovery tool.

Quantitative trait locus analysis has been a mainstay approach for obtaining a genetic description of complex agronomic traits for plants. What is sometimes overlooked is the role quantitative trait locus (QTL) analysis can play in identifying genes that underlay complex traits. In this chapter, I will describe the basic steps required to conduct QTL analysis in crop plants. This process involves choices by the investigator on type of population to be studied, molecular marker system to be used to genotype the population, and methods for QTL analysis. Examples of cloned genes, first identified as QTL, are also given to persuade the reader of the power of QTL analysis to discover genes controlling traits and phenotypes.

Chromosome Mapping↗