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PubMed2002

Marker-assisted introgression of favorable alleles at quantitative trait loci between maize elite lines.

This article reports the marker-assisted introgression of favorable alleles at three quantitative trait loci (QTL) for earliness and grain yield among maize elite lines. The QTL were originally detected in 1992 by means of ANOVA in a population of 96 recombinant inbred lines (RILs). Introgression started from a selected RIL, which was crossed three times to one of the original parents and then self-fertilized, leading to BC(3)S(1) progenies. Markers were used to assist both foreground and background selection at each generation. At the end of the program, the effect of introgression was assessed phenotypically in agronomic trials, and QTL detection was performed by composite interval mapping among BC(3)S(1) progenies. The marker-assisted introgression proved successful at the genotypic level, as analyzed by precision graphical genotypes, although no emphasis was put on the reduction of linkage drag around QTL. Also, QTL positions were generally sustained in the introgression background. For earliness, the magnitude and sign of the QTL effects were in good agreement with those expected from initial RIL analyses. Conversely, for yield, important discrepancies were observed in the magnitude and sign of the QTL effects observed after introgression, when compared to those expected from initial RIL analyses. These discrepancies are probably due to important genotype-by-environment interactions.

Alleles↗

PubMed2004

Quantitative trait locus analysis of plasma cholesterol and triglyceride levels in C57BL/6J x RR F2 mice.

A highly significant cholesterol quantitative trait locus (QTL) (Cq6) was identified on chromosome 1 in C57BL/6J x RR F2 mice. The Cq6 was located over the gene for apolipoprotein A-Il (Apoa2), and the RR allele was associated with increased plasma cholesterol. C57BL/6J has Apoa2a alleles and RR has Apoa2b alleles. Three different Apoa2 alleles are known on the basis of amino acid substitutions at four residues. Analysis with partial Apoa2 congenic strains possessing Apoa2a, Apoa2b, and Apoa2C alleles revealed that the Apoa2b allele is unique in the ability to increase cholesterol among the three Apoa2 alleles, and that the Ala-to-Val substitution at residue 61 may be crucial as far as cholesterol metabolism is concerned. We also investigated the question of whether the Apoa1 gene is responsible for the cholesterol QTLs (Cq4 and Cq5) that had been identified previously on chromosome 9 in C57BL/6J x KK-Ay/a F2 and in KK x RR F2, but not in C57BL/6J x RR F2 mice. Similar to Apoa2 alleles, three different Apoal alleles with two successive amino acid substitutions were revealed among the strains. However, we could not correlate Apoal polymorphisms with the occurrence of QTLs in these three sets of F2 mice.

Alleles↗

PubMed2006

Optimizing selection on multiple identified quantitative trait loci in population with overlapping generations.

A method was developed to model and optimize selection on multiple identified quantitative trait loci (QTLs) and polygenic estimated breeding value, in order to maximize a weighted sum of cumulative response to selection over multiple years in a population with overlapping generations. The model allows for a population with multiple sex-age classes, different number of age class between sires and dams, and varied genetic contribution of the age class. The optimization problem was formulated as a multiple-stage optimal control problem and solved by a forward and backward iteration loop. The practical utility of this method was illustrated in an example of pig breeding population with overlapping generations. The selection response of this method was compared with standard QTL selection and conventional best linear unbiased prediction (BLUP) selection. Simulation results show that optimal selection achieved greater selection response than either standard QTL or conventional BLUP selections. The influence of population structure on optimal selection was significant. Optimal QTL selection and standard QTL selection were more favorable in a population with overlapping generations than discrete generations, and obtained more benefits relative to conventional BLUP selection in a population with overlapping generations. Optimal QTL selection relative to conventional BLUP selection is also more favorable following increase of genetic contribution of two-year-old boars and sows in a population with overlapping generations.

Algorithms↗

PubMed2003

A genome-wide search for quantitative trait loci influencing substance dependence vulnerability in adolescence.

This study describes results from a genome-wide search for quantitative trait loci (QTL) influencing substance dependence vulnerability in adolescence. We utilized regression-based multipoint (and single-point) QTL mapping procedures designed for selected sibpair samples. Selected sibling pairs included 250 proband-sibling pairs from 192 families. Clinical probands (13-19 years of age) were drawn from consecutive admissions to substance abuse treatment facilities in the Denver metropolitan area; siblings of probands ranged in age from 12 to 25 years. In addition to the selected sample, a community-based sample of 3676 adolescents and young adults were utilized to define a clinically-significant, heritable, age- and sex-normed index of substance dependence vulnerability-a priori and independent of our linkage results. Siblings and their parents were genotyped for 374 STR micro-satellite markers distributed across the 22 autosomes (average inter-marker distance=9.2 cM). Non-parametric single-point linkage results indicated 17 markers on 11 chromosomes with nominally significant tests of linkage; six markers with LOD scores greater than 1.0 and one marker (D3S1614) with a LOD score of 2.2. Multipoint mapping corroborated two locations and provided preliminary evidence for linkage to regions on chromosome 3q24-25 (near markers D3S1279 and D3S1614) and chromosome 9q34 (near markers D9S1826 and D9S1838).

Adolescent↗

PubMed2005

Quantitative trait locus-specific genotype x alcoholism interaction on linkage for evoked electroencephalogram oscillations.

We explored the evidence for a quantitative trait locus (QTL)-specific genotype x alcoholism interaction for an evoked electroencephalogram theta band oscillation (ERP) phenotype on a region of chromosome 7 in participants of the US Collaborative Study on the Genetics of Alcoholism. Among 901 participants with both genotype and phenotype data available, we performed variance component linkage analysis (SOLAR version 2.1.2) in the full sample and stratified by DSM-III-R and Feighner-definite alcoholism categories. The heritability of the ERP phenotype after adjusting for age and sex effects in the combined sample and in the alcoholism classification sub-groups ranged from 40% to 66%. Linkage on chromosome 7 was identified at 158 cM (LOD = 3.8) in the full sample and at 108 in the non-alcoholic subgroup (LOD = 3.1). Further, we detected QTL-specific genotype x alcoholism interaction at these loci. This work demonstrates the importance of considering the complexity of common complex traits in our search for genes that predispose to alcoholism.

Alcoholism↗

PubMed2003

Effects of including a quantitative trait locus in selection under different waiting plans of young bulls.

The advantage of using the genotype of a quantitative trait locus (QTL) in selection schemes of dairy cattle was quantified using stochastic simulation. Three selection plans were studied. In the first plan, young bulls waited for 3 yr until their sisters completed a lactation and then were evaluated and selected based on an animal model. In a second plan, young bulls waited for 5 yr until their daughters completed a lactation. An intermediate 4-yr waiting plan was also studied. Simulation was for 16 yr with overlapping generations. Population and model parameters were proportional to the U.S. Holstein population. The advantage of using a QTL was quantified as the percentage of superiority of QTL-assisted over QTL-free selection using cumulative genetic response. Percentage of superiority was reported for four selection pathways: active sires, young bulls, bull dams, and first lactation cows. A general trend was observed: low superiority in early years of selection that increased to a plateau in later years and then decreased. The superiority of the QTL information was greatest in the 3-yr waiting plan and least in the 4-yr waiting plan. Superiority at plateau for selection pathways ranged from 16 to 26% for the 3-yr waiting plan, from 3 to 12% for the 4-yr waiting plan, and from 5 to 13% for the 5-yr waiting plan. The contribution to selection response attributed to the QTL and the polygenes was quantified. The rate at which the favorable allele approached fixation and the accuracy of predicting breeding values on the percentage of superiority were studied.

Animals↗

PubMed2004

Combining congenic coverage with gene profiling in search of candidates for blood pressure quantitative trait loci in Dahl rats.

Chromosomes (Chr) 10 and 16 of the Dahl salt-sensitive (S) rat harbor quantitative trait loci (QTLs) for blood pressure (BP). To facilitate gene discovery of these QTLs, gene profiling based on microarrays was combined with fine QTL mapping to identify potential candidate genes that are differentially expressed. First, the region harboring the BP QTL on Chr 16 was narrowed by comparative congenic mapping. In this endeavor, a number of new chromosome markers were generated and used to physically define the chromosome interval in question. Second, in an effort to minimize the costs of gene profiling without sacrificing the chance of gene discovery, a combination congenic strain was produced by replacing one segment of Chr 10 along with one segment of Chr 16 of the hypertensive S rat by those of the normotensive Lewis (LEW) rat. Both of these regions are known to contain BP QTLs. Third, kidneys of this combination congenic strain and the S strain were employed for expression profiling studies. Finally, a comparison between the two strains yielded a number of potentially differentially expressed candidates. Six Established Sequence Tags (ESTs)/genes among them were located in Chr 10 regions and 1 was found in a Chr 16 region, and the genetic make-ups of all these regions were shown to be different between S and LEW. However, none of these ESTs/genes identified by gene profiling were located in an interval containing a QTL. Thus, the present study highlights the importance of correlating the results of gene expression profiling with fine congenic mapping.

Animals↗

PubMed2002

Linkage analysis of quantitative trait loci in multiple line crosses.

Simple line crosses, for example, backcross and F2, are commonly used in mapping quantitative trait loci (QTL). However, these simple crosses are rarely used alone in commercial plant breeding; rather, crosses involving multiple inbred lines or several simple crosses but connected by shared inbred lines may be common in plant breeding. Mapping QTL using crosses of multiple lines is more relevant to plant breeding. Unfortunately, current statistical methods and computer programs of QTL mapping are all designed for simple line crosses or multiple line crosses but under a regular mating system. It is not straightforward to extend the existing methods to handle multiple line crosses under irregular and complicated mating designs. The major hurdle comes from irregular inbreeding, multiple generations, and multiple alleles. In this study, we develop a Bayesian method implemented via the Markov chain Monte Carlo (MCMC) algorithm for mapping QTL using complicated multiple line crosses. With the MCMC algorithm, we are able to draw a complete path of the gene flow from founder alleles to their descendents via a recursive process. This has greatly simplified the problem caused by irregular mating and inbreeding in the mapping population. Adopting the reversible jump MCMC algorithm, we are able to simultaneously search for multiple QTL along the genome. We can even infer the posterior distribution of the number of QTL, one of the most important parameters in QTL study. Application of the new MCMC based QTL mapping procedure is demonstrated using two different mating designs. Design I involves two inbred lines and their derived F1, F2, and BC populations. Design II is a half-diallel cross involving three inbred lines. The two designs appear different, but can be handled with the same robust computer program.

Algorithms↗

PubMed2006

Haplotype variation in structure and expression of a gene cluster associated with a quantitative trait locus for improved yield in rice.

By constructing nearly isogenic lines (NILs) that differ only at a single quantitative trait locus (QTL), we fine-mapped the yield-improving QTL qGY2-1 to a 102.9-kb region on rice chromosome 2. Comparison analysis of the genomic sequences in the mapped QTL region between the donor (Dongxiang wild rice, Oryza rufipogon Griff.) and recurrent (Guichao2, Oryza sativa ssp. indica) parents used for the development of NILs identified the haplotypes of a leucine-rich repeat receptor kinase gene cluster, which showed extensive allelic variation. The sequences between genes in the cluster had a very high rate of divergence. More importantly, the genes themselves also differed between two haplotypes: Only 92% identity was observed for one allele, and another allele was found to have completely lost its allelic counterpart in Guichao2. The other six shared genes all showed >98% identity, and four of these exhibited obvious regulatory variation. The same haplotype segments also differed in length (43.9-kb in Guichao2 vs. 52.6-kb in Dongxiang wild rice). Such extensive sequence variation was also observed between orthologous regions of indica (cv. 93-11) and japonica (cv. Nipponbare) subspecies of Oryza sativa. Different rates of sequence divergence within the cluster have resulted in haplotype variability in 13 rice accessions. We also detected allelic expression variation in this gene cluster, in which some genes gave unequal expression of alleles in hybrids. These allelic variations in structure and expression suggest that the leucine-rich repeat receptor kinase gene cluster identified in our study should be a particularly good candidate for the source of the yield QTL.

Alleles↗

PubMed2003

Detection of different quantitative trait loci for antibody responses to keyhole lympet hemocyanin and Mycobacterium butyricum in two unrelated populations of laying hens.

Quantitative trait loci involved in the primary antibody response to keyhole lympet hemocyanin (KLH) and Mycobacterium butyricum were detected in two independent populations of laying hens. The first population was an F2 cross (H/L) of lines divergently selected for either high or low primary antibody responses to SRBC, and the second population was an F2 cross between 2 commercial layer lines displaying differences in feather pecking behavior (FP). Both populations were typed with microsatellite markers widely distributed over the genome with similar intervals between markers. Titers of antibodies binding KLH and M. butyricum were measured for all individuals by ELISA. Two genetic models were applied to detect QTL involved in the humoral immune response: a half-sib model and a line-cross model, both using the regression interval method. In the half-sib analysis, 2 QTL (on GGA14 and GGA27) were detected for the antibody response to KLH for the H/L population, and 2 QTL (on GGA14 and GGA18) were detected for the FP population. Only 1 QTL was detected for M. butyricum on GGA14 in the FP population using the half-sib analysis model. Two QTL were detected for the FP population on GGA2 and GGA3 using the line-cross analysis model. A QTL for the primary antibody response to KLH detected on GGA14 was validated in both populations under the half-sib analysis model. The present data suggest differences in the genetic regulation of antibody responses to two different T-cell dependent antigens.

Aggression↗

PubMed2001

Optimal sibship selection for genotyping in quantitative trait locus linkage analysis.

In this paper we present a novel method for selecting optimally informative sibships of any size for quantitative trait locus (QTL) linkage analysis. The method allocates a quantitative index of potential informativeness to each sibship on the basis of observed trait scores and an assumed true QTL model. Any sample of phenotypically screened sibships can therefore be easily rank-ordered for selective genotyping. The quantitative index is the sibship's expected contribution to the non-centrality parameter. This expectation represents the weighted sum of chi(2) test statistics that would be obtained given the observed trait values over all possible sibship genotypic configurations; each configuration is weighted by the likelihood of it occurring given the assumed true genetic model. The properties of this procedure are explored in relation to the accuracy of the assumed true genetic model and sibship size. In comparison to previous methods of selecting phenotypically extreme sibships for genotyping, the proposed method is considerably more efficient and is robust with regard to the specification of the genetic model.

Chromosome Mapping↗

PubMed2005

Quantitative trait loci and interaction effects responsible for variation in female postmating mortality in Drosophila simulans and D. sechellia introgression lines.

Mating appears to inflict a cost to Drosophila females, resulting in a reduction of their lifespan shortly after mating. Males from different chromosome extracted lines differ significantly in their detrimental effects on postmating female survival, and seminal fluid proteins produced in the male accessory glands are at least partially responsible for the effect. This suggests that there is a genetic basis underlying the male inflicted effect on female's postmating mortality. However, the genes responsible for this effect remain elusive. Using males from introgression lines between D. simulans and D. sechellia genomes and a quantitative trait locus (QTL) mapping approach, we identified chromosomal regions that affect postmating mortality of females. We found a second chromosome QTL with an effect on average female lifespan after mating and a third chromosome QTL with an effect on postmating female mortality rate. Under the general observation of a faster divergence of sex-related genes among closely related species, it is predicted that genes for reproductive traits other than hybrid sterility will show evidence of epistatic effects when brought into a heterospecific background. We detected a significant epistatic genetic effect on postmating female mortality rate that supports this prediction.

Animals↗

PubMed2001

Gibbs sampling-based segregation analysis of asthma-associated quantitative traits in a population-based sample of nuclear families.

Asthma is a common, complex human disease. Elevated serum immunoglobulin E (IgE) levels, elevated blood eosinophil counts, and increased airway responsiveness are physiological traits that are characteristic of asthma. Few studies have investigated major gene effects for these traits in a population-based sample. Further, it is not known if any putative major genes may be common to two or more of these traits. We investigated the existence and nature of major genes modulating asthma-associated quantitative traits in an Australian population-based sample of 210 Caucasian nuclear families. The sharing of these major genes was also investigated. Segregation analysis was based upon a Markov Chain Monte Carlo (Gibbs sampling) approach as implemented in the program BUGS v0.6. All models included adjustment for age, height, tobacco smoke exposure, and gender. The segregation of total IgE levels, blood eosinophil counts, and dose-response slope (DRS) of methacholine challenge were all consistent with major loci at which a recessive allele acted to increase or decrease the phenotype. The respective estimated frequencies of the recessive alleles were 68% (total IgE), 10% (blood eosinophil count), and 27% (DRS). Extensive modelling suggested that the major loci controlling total serum IgE levels, blood eosinophil counts, and airway responsiveness represent different genes. These data provide evidence, for the first time, of the existence of at least 3 distinct genetic pathways involving major gene effects on physiological traits closely associated with asthma. These results have implications for gene discovery programs.

Adolescent↗

PubMed1996

A general Monte Carlo method for mapping multiple quantitative trait loci.

In this paper we address the mapping of multiple quantitative trait loci (QTLs) in line crosses for which the genetic data are highly incomplete. Such complicated situations occur, for instance, when dominant markers are used or when unequally informative markers are used in experiments with outbred populations. We describe a general and flexible Monte Carlo expectation-maximization (Monte Carlo EM) algorithm for fitting multiple-QTL models to such data. Implementation of this algorithm is straightforward in standard statistical software, but computation may take much time. The method may be generalized to cope with more complex models for animal and human pedigrees. A practical example is presented, where a three-QTL model is adopted in an outbreeding situation with dominant markers. The example is concerned with the linkage between randomly amplified polymorphic DNA (RAPD) markers and QTLs for partial resistance to Fusarium oxysporum in lily.

Algorithms↗

PubMed1993

DNA fingerprint bands applied to linkage analysis with quantitative trait loci in chickens.

An efficient approach to detect association between quantitative traits and bands of DNA fingerprint patterns uses intra-family tail analysis, which compares fingerprints of DNA mixes from individuals at the two tails of a phenotypic distribution. In analysis of 67 paternal half-sibs of a meat-type chicken family, of 57 sire bands generated by two probes, one sire-specific band (S6.6) was associated with abdominal fat deposition. The band effect was estimated by a linear model analysis to be 0.88 standard deviations, or about 30% of the family mean. The association between band S6.6 and abdominal fat was further examined by testing progeny of paternal half-sibs of the chickens which were used in the tail analysis, establishing genetic linkage between the DNA marker and a genetic locus affecting abdominal fat deposition.

Adipose Tissue↗

PubMedDate not supplied

The relative efficiency and power of small-pedigree studies of the heritability of a quantitative trait.

Methods to determine the proportion of variability manifested by a quantitative trait that is attributable to additive genetic effects are important tools for human population and statistical geneticists. Though traditional methods based on parent-offspring and sib-pair correlations have been well researched, they are being steadily supplanted or complemented by more powerful pedigree-based variance-component techniques. In this paper, a theoretical investigation of the relative efficiency and power of small (i.e., < 10 members) variance-component pedigree designs for heritability estimation is undertaken. The information gain in adding sibs and generations to pedigrees is discussed. Sample size guidelines based on theoretical power functions are offered, as are directions for future research.

Genetics, Medical↗

PubMed1997

Quick method for confirmation of quantitative trait loci.

Numerous algorithms for the identification and genetic mapping of quantitative trait loci (QTL) have been developed. Methods for confirming QTL maps involve either examination of independent segregating populations or the construction of congenic lines differing only in the QTL of interest. Because these projects require a minimum of several years or thousands of marker assessments in laboratory mice, an alternative, faster congenic method has been proposed. In a preliminary study, we tested this method for confirming QTLs identified in crosses between the ILS and ISS selected lines of mice for differential sensitivity to the hypnotic effects of ethanol. Herein, we report the construction of "segregating congenic" strains in which each QTL is made homozygous in a single generation, whereas the remainder of the genetic background is allowed to segregate. Sensitivity to ethanol among the progeny of such mice is consistent with predictions. Phenotypic variation is high, as expected, due to the background segregation, and statistical significance was attained in only 2 of 7 comparisons. Such segregating congenic populations may be a valuable research tool for confirming QTL map positions and for subsequent assessment of individual pathways and mechanisms of action of individual QTLs.

Alcoholism↗

PubMed2001

A score-statistic approach for the mapping of quantitative-trait loci with sibships of arbitrary size.

The Haseman-Elston method is widely used for the mapping of quantitative-trait loci. However, this method does not use all the information in the data, because it only considers the sib-pair trait-value difference. In addition, the Haseman-Elston method was developed for independent sib pairs; its generalization to nonindependent sib pairs is not straightforward. Here we introduce a score test statistic derived from a normal likelihood based on multiplex sibship data, conditional on identical-by-descent sharing statuses. This score test is asymptotically equivalent to the corresponding likelihood-ratio test, but it is much easier to implement. Because the proposed test uses all of the trait values, it makes more efficient use of the data than does the Haseman-Elston method. The proposed test is naturally applicable to sibships of arbitrary size. The finite-sample properties of the proposed score statistic are evaluated via simulations.

Chromosome Mapping↗