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PubMed2002

Mapping QTLs regulating morpho-physiological traits and yield: case studies, shortcomings and perspectives in drought-stressed maize.

Comparative analysis of a number of studies in drought-stressed maize (Zea mays L.) reporting quantitative trait loci (QTLs) for abscisic acid concentration, root characteristics, other morpho-physiological traits (MPTs) and grain yield (GY) reveals their complex genetic basis and the influence of the genetic background and the environment on QTL effects. Chromosome regions (e.g. near umc11 on chromosome 1 and near csu133 on chromosome 2) with QTLs controlling a number of MPTs and GY across populations and conditions of different water supply have been identified. Examples are presented on the use of QTL information to elucidate the genetic and physiological bases of the association among MPTs and GY. The QTL approach allows us to develop hypotheses accounting for these associations which can be further tested by developing near isogenic lines (NILs) differing for the QTL alleles. NILs also allow for a more accurate assessment of the breeding value of MPTs and, in some cases, may allow for the map-based cloning of the gene(s) underlying the QTL. Although QTL analysis is still time-consuming and resource-demanding, its integration with genomics and post-genomics approaches (e.g. transcriptome, proteome and metabolome analyses) will play an increasingly important role for the identification and validation of candidate genes affecting MPTs and GY.

Abscisic Acid↗
PubMed2004

A comprehensive genetic map of the cattle genome based on 3802 microsatellites.

A microsatellite-based high-density genetic map facilitates for fine mapping of hereditary traits of interest, characterization of meiosis, and providing a foundation for physical map construction. Here, we developed a comprehensive genetic map on the basis of >880,000 genotypes across the USDA MARC cattle reference families with a potential genetic resolution of 0.8 cM at the 95% confidence level ( approximately 800 kb in the bovine genome). We incorporated 2325 microsatellites into the second-generation genetic map by linkage analysis based on sex-averaged two-point LOD scores (>3.0), of which 2293 were fine-mapped by multipoint linkage analysis. The new 3160-cM map comprised of 29 sex-averaged autosomal linkage groups and a sex-specific X-chromosome linkage group includes 3960 markers with 2389 positions, resulting in an average interval size of 1.4 cM. More than half (51%) of the total length of the map is covered with intervals of 2.0 cM or less, and the largest gap is a 10.2-cM interval on the X-linkage group. The new map should accelerate fine mapping and positional cloning of genes for genetic diseases and economically important traits in cattle, as well as related livestock species, such as sheep and goat.

Animals↗
PubMedDate not supplied

The distribution of the effects of genes affecting quantitative traits in livestock.

Meta-analysis of information from quantitative trait loci (QTL) mapping experiments was used to derive distributions of the effects of genes affecting quantitative traits. The two limitations of such information, that QTL effects as reported include experimental error, and that mapping experiments can only detect QTL above a certain size, were accounted for. Data from pig and dairy mapping experiments were used. Gamma distributions of QTL effects were fitted with maximum likelihood. The derived distributions were moderately leptokurtic, consistent with many genes of small effect and few of large effect. Seventeen percent and 35% of the leading QTL explained 90% of the genetic variance for the dairy and pig distributions respectively. The number of segregating genes affecting a quantitative trait in dairy populations was predicted assuming genes affecting a quantitative trait were neutral with respect to fitness. Between 50 and 100 genes were predicted, depending on the effective population size assumed. As data for the analysis included no QTL of small effect, the ability to estimate the number of QTL of small effect must inevitably be weak. It may be that there are more QTL of small effect than predicted by our gamma distributions. Nevertheless, the distributions have important implications for QTL mapping experiments and Marker Assisted Selection (MAS). Powerful mapping experiments, able to detect QTL of 0.1sigma(p), will be required to detect enough QTL to explain 90% the genetic variance for a quantitative trait.

Animals↗
PubMed1996

Quantitative trait loci influencing cholesterol and phospholipid phenotypes map to chromosomes that contain genes regulating blood pressure in the spontaneously hypertensive rat.

The frequent coincidence of hypertension and dyslipidemia suggests that related genetic factors might underlie these common risk factors for cardiovascular disease. To investigate whether quantitative trait loci (QTLs) regulating lipid levels map to chromosomes known to contain genes regulating blood pressure, we used a genome scanning approach to map QTLs influencing cholesterol and phospholipid phenotypes in a large set of recombinant inbred strains and in congenic strains derived from the spontaneously hypertensive rat and normotensive Brown-Norway (BN.Lx) rat fed normal and high cholesterol diets. QTLs regulating lipid phenotypes were mapped by scanning the genome with 534 genetic markers. A significant relationship (P < 0.00006) was found between basal HDL2 cholesterol levels and the D19Mit2 marker on chromosome 19. Analysis of congenic strains of spontaneously hypertensive rat indicated that QTLs regulating postdietary lipid phenotypes exist also on chromosomes 8 and 20. Previous studies in the recombinant inbred and congenic strains have demonstrated the presence of blood pressure regulatory genes in corresponding segments of chromosomes 8, 19, and 20. These findings provide support for the hypothesis that blood pressure and certain lipid subfractions can be modulated by linked genes or perhaps even the same genes.

Animals↗
PubMed2006

Semiparametric variance-component models for linkage and association analyses of censored trait data.

Variance-component (VC) models are widely used for linkage and association mapping of quantitative trait loci in general human pedigrees. Traditional VC methods assume that the trait values within a family follow a multivariate normal distribution and are fully observed. These assumptions are violated if the trait data contain censored observations. When the trait pertains to age at onset of disease, censoring is inevitable because of loss to follow-up and limited study duration. Censoring also arises when the trait assay cannot detect values below (or above) certain thresholds. The latent trait values tend to have a complex distribution. Applying traditional VC methods to censored trait data would inflate type I error and reduce power. We present valid and powerful methods for the linkage and association analyses of censored trait data. Our methods are based on a novel class of semiparametric VC models, which allows an arbitrary distribution for the latent trait values. We construct appropriate likelihood for the observed data, which may contain left or right censored observations. The maximum likelihood estimators are approximately unbiased, normally distributed, and statistically efficient. We develop stable and efficient numerical algorithms to implement the corresponding inference procedures. Extensive simulation studies demonstrate that the proposed methods outperform the existing ones in practical situations. We provide an application to the age at onset of alcohol dependence data from the Collaborative Study on the Genetics of Alcoholism. A computer program is freely available.

Age of Onset↗
PubMed2006

Identifying genes associated with a quantitative trait or quantitative trait locus via selective transcriptional profiling.

Genetical genomics is an approach that blends the mapping of quantitative trait loci (QTL) with microarray analysis. The approach can be used to identify associations between the allelic state of a genomic region and a gene's transcript abundance. However, the large number of microarrays required for adequate power results in high material and labor costs that prevent wide adoption of the genetical genomics strategy outside of some well-funded laboratories. We present a method called selective transcriptional profiling that involves selecting an optimal subset of individuals to microarray from a larger set of individuals for which relatively inexpensive quantitative trait and molecular marker data are available. We show how to use microarray data from the selected individuals, along with the trait and marker data from all individuals, to identify genes whose transcript abundance is associated with a quantitative trait of interest through linkage to a trait QTL or correlation with the trait. Our methods for selection and analysis are derived within a missing data framework.

Alleles↗
PubMed2006

A gene-based high-resolution comparative radiation hybrid map as a framework for genome sequence assembly of a bovine chromosome 6 region associated with QTL for growth, body composition, and milk performance traits.

BACKGROUND: A number of different quantitative trait loci (QTL) for various phenotypic traits, including milk production, functional, and conformation traits in dairy cattle as well as growth and body composition traits in meat cattle, have been mapped consistently in the middle region of bovine chromosome 6 (BTA6). Dense genetic and physical maps and, ultimately, a fully annotated genome sequence as well as their mutual connections are required to efficiently identify genes and gene variants responsible for genetic variation of phenotypic traits. A comprehensive high-resolution gene-rich map linking densely spaced bovine markers and genes to the annotated human genome sequence is required as a framework to facilitate this approach for the region on BTA6 carrying the QTL. RESULTS: Therefore, we constructed a high-resolution radiation hybrid (RH) map for the QTL containing chromosomal region of BTA6. This new RH map with a total of 234 loci including 115 genes and ESTs displays a substantial increase in loci density compared to existing physical BTA6 maps. Screening the available bovine genome sequence resources, a total of 73 loci could be assigned to sequence contigs, which were already identified as specific for BTA6. For 43 loci, corresponding sequence contigs, which were not yet placed on the bovine genome assembly, were identified. In addition, the improved potential of this high-resolution RH map for BTA6 with respect to comparative mapping was demonstrated. Mapping a large number of genes on BTA6 and cross-referencing them with map locations in corresponding syntenic multi-species chromosome segments (human, mouse, rat, dog, chicken) achieved a refined accurate alignment of conserved segments and evolutionary breakpoints across the species included. CONCLUSION: The gene-anchored high-resolution RH map (1 locus/300 kb) for the targeted region of BTA6 presented here will provide a valuable platform to guide high-quality assembling and annotation of the currently existing bovine genome sequence draft to establish the final architecture of BTA6. Hence, a sequence-based map will provide a key resource to facilitate prospective continued efforts for the selection and validation of relevant positional and functional candidates underlying QTL for milk production and growth-related traits mapped on BTA6 and on similar chromosomal regions from evolutionary closely related species like sheep and goat. Furthermore, the high-resolution sequence-referenced BTA6 map will enable precise identification of multi-species conserved chromosome segments and evolutionary breakpoints in mammalian phylogenetic studies.

Animals↗
PubMed2006

Quantitative trait linkage analysis using Gaussian copulas.

Mapping and identifying variants that influence quantitative traits is an important problem for genetic studies. Traditional QTL mapping relies on a variance-components (VC) approach with the key assumption that the trait values in a family follow a multivariate normal distribution. Violation of this assumption can lead to inflated type I error, reduced power, and biased parameter estimates. To accommodate nonnormally distributed data, we developed and implemented a modified VC method, which we call the "copula VC method," that directly models the nonnormal distribution using Gaussian copulas. The copula VC method allows the analysis of continuous, discrete, and censored trait data, and the standard VC method is a special case when the data are distributed as multivariate normal. Through the use of link functions, the copula VC method can easily incorporate covariates. We use computer simulations to show that the proposed method yields unbiased parameter estimates, correct type I error rates, and improved power for testing linkage with a variety of nonnormal traits as compared with the standard VC and the regression-based methods.

Analysis of Variance↗
PubMed2003

Genome association studies of complex diseases by case-control designs.

One way to perform linkage-disequilibrium (LD) mapping of genetic traits is to use single markers. Since dense marker maps-such as single-nucleotide polymorphism and high-resolution microsatellite maps-are available, it is natural and practical to generalize single-marker LD mapping to high-resolution haplotype or multiple-marker LD mapping. This article investigates high-resolution LD-mapping methods, for complex diseases, based on haplotype maps or microsatellite marker maps. The objective is to explore test statistics that combine information from haplotype blocks or multiple markers. Based on two coding methods, genotype coding and haplotype coding, Hotelling's T2 statistics TG and TH are proposed to test the association between a disease locus and two haplotype blocks or two markers. The validity of the two T2 statistics is proved by theoretical calculations. A statistic TC, an extension of the traditional chi2 method of comparing haplotype frequencies, is introduced by simply adding the chi2 test statistics of the two haplotype blocks together. The merit of the three methods is explored by calculation and comparison of power and of type I errors. In the presence of LD between the two blocks, the type I error of TC is higher than that of TH and TG, since TC ignores the correlation between the two blocks. For each of the three statistics, the power of using two haplotype blocks is higher than that of using only one haplotype block. By power comparison, we notice that TC has higher power than that of TH, and TH has higher power than that of TG. In the absence of LD between the two blocks, the power of TC is similar to that of TH and higher than that of TG. Hence, we advocate use of TH in the data analysis. In the presence of LD between the two blocks, TH takes into account the correlation between the two haplotype blocks and has a lower type I error and higher power than TG. Besides, the feasibility of the methods is shown by sample-size calculation.

Case-Control Studies↗
PubMed2005

Integrative genetic analysis of transcription modules: towards filling the gap between genetic loci and inherited traits.

Genetic loci that regulate inherited traits are routinely identified using quantitative trait locus (QTL) mapping methods. However, the genotype-phenotype associations do not provide information on the gene expression program through which the genetic loci regulate the traits. Transcription modules are 'self-consistent regulatory units' and are closely related to the modular components of gene regulatory network [Ihmels, J., Friedlander, G., Bergmann, S., Sarig, O., Ziv, Y. and Barkai, N. (2002) Revealing modular organization in the yeast transcriptional network. Nat. Genet., 31, 370-377; Segal, E., Shapira, M., Regev, A., Pe'er, D., Botstein, D., Koller, D. and Friedman, N. (2003) Module networks: identifying regulatory modules and their condition-specific regulators from gene expression data. Nat. Genet., 34, 166-176]. We used genome-wide genotype and gene expression data of a genetic reference population that consists of mice of 32 recombinant inbred strains to identify the transcription modules and the genetic loci regulating them. Twenty-nine transcription modules defined by genetic variations were identified. Statistically significant associations between the transcription modules and 18 classical physiological and behavioral traits were found. Genome-wide interval mapping showed that major QTLs regulating the transcription modules are often co-localized with the QTLs regulating the associated classical traits. The association and the possible co-regulation of the classical trait and transcription module indicate that the transcription module may be involved in the gene pathways connecting the QTL and the classical trait. Our results show that a transcription module may associate with multiple seemingly unrelated classical traits and a classical trait may associate with different modules. Literature mining results provided strong independent evidences for the relations among genes of the transcription modules, genes in the regions of the QTLs regulating the transcription modules and the keywords representing the classical traits.

Animals↗
PubMed2002

Genetic dissection of quantitative trait loci specifying sedative/hypnotic sensitivity to ethanol: mapping with interval-specific congenic recombinant lines.

BACKGROUND: Linkage studies alone do not produce sufficient resolution to narrow the location of a quantitative trait locus (QTL) to a small-enough chromosomal region for gene identification. One solution to this problem is to use interval-specific congenic recombinant (ISCR) lines to narrow the chromosomal interval known to contain the QTL. In previous work, we mapped four QTLs for differential ethanol sensitivity in the inbred long-sleep (ILS) and inbred short-sleep (ISS) strains and generated reciprocal congenic strains in which each full QTL interval from ILS was bred onto the ISS background and vice versa. METHODS: ISCR lines were derived by identifying mice carrying recombination events in the congenic interval during backcrossing of the ISS.ILS.Lore congenics to ISS. Recombinant mice were backcrossed to ISS, and progeny carrying the ISCR chromosome were identified and tested to determine whether the ISCR region carried the donor Lore QTL. RESULTS: We developed multiple ISCR lines for each Lore QTL, in which the QTL interval was broken into a number of smaller intervals. For all four QTLs, we reduced the size of the interval, in one case to 3.7 cM. CONCLUSIONS: Use of ISCR lines can narrow each Lore candidate region to a few centimorgans. Such an interval size is conducive to brute-force approaches to identify candidate genes, entailing bioinformatics, gene expression, and DNA sequencing strategies.

Alcohol Drinking↗
PubMed1996

Quantitative trait loci for ethanol sensitivity in the LS x SS recombinant inbred strains: interval mapping.

We are mapping the genes (quantitative trait loci or QTLs) that are responsible for individual differences in ethanol sensitivity, measured as the duration of loss of righting, reflex (LORR) and blood ethanol concentrations upon recovery of the righting reflex (BEC). The Long-Sleep (LS) and Short-Sleep (SS) selected lines of mice manifest an 18-fold difference in LORR and serve as a rodent model for ethanol sensitivity. The LS x SS recombinant inbred (RI) series, developed from LS and SS lines, are an important resource for QTL mapping of ethanol-related responses. The current report summarizes the initial QTL analysis of LORR and BEC in the LS x SS strains and compares the results of correlational analysis with an interval-mapping approach. The data provide strong evidence for QTLs that influence ethanol sensitivity on mouse chromosomes 1 and 2 and possible QTLs on chromosomes 1, 3, 4, 5, 6, 7, 12, 13, 16, and 18. These results are compared to those from an F2 cross which confirms QTLs on chromosomes 1, 2, 4, and 18.

Alcohol Drinking↗
PubMed2002

Use of randomization testing to detect multiple epistatic QTLs.

Here, we describe a randomization testing strategy for mapping interacting quantitative trait loci (QTLs). In a forward selection strategy, non-interacting QTLs and simultaneously mapped interacting QTL pairs are added to a total genetic model. Simultaneous mapping of epistatic QTLs increases the power of the mapping strategy by allowing detection of interacting QTL pairs where none of the QTL can be detected by their marginal additive and dominance effects. Randomization testing is used to derive empirical significance thresholds for every model selection step in the procedure. A simulation study was used to evaluate the statistical properties of the proposed randomization tests and for which types of epistasis simultaneous mapping of epistatic QTLs adds power. Least squares regression was used for QTL parameter estimation but any other QTL mapping method can be used. A genetic algorithm was used to search for interacting QTL pairs, which makes the proposed strategy feasible for single processor computers. We believe that this method will facilitate the evaluation of the importance at epistatic interaction among QTLs controlling multifactorial traits and disorders.

Algorithms↗
PubMed2003

Fine linkage mapping enables dissection of closely linked quantitative trait loci for seed dormancy and heading in rice.

Two quantitative trait loci (QTLs) for seed dormancy (tentatively designated Sdr1) and heading date ( Hd8) have been mapped to approximately the same region on chromosome 3 by interval mapping of backcross inbred lines derived from crosses between the rice cultivars Nipponbare (japonica) and Kasalath (indica). To clarify whether Sdr1 and Hd8 could be dissected genetically, we carried out fine-scale mapping with an advanced backcross progeny. We selected a BC(4)F(1) plant, in which a small chromosomal region including Sdr1 and Hd8, on the short arm of chromosome 3, remained heterozygous, whereas all the other chromosomal regions were homozygous for Nipponbare. Days-to-heading and seed germination rate in the BC(4)F(2) plants showed continuous variation. Ten BC(4)F(2) plants with recombination in the vicinity of Sdr1 and Hd8 were selected on the basis of the genotypes of the restriction fragment length polymorphism (RFLP) markers flanking both QTLs. Genotypes of those plants for Sdr1 and Hd8 were determined by advanced progeny testing of BC(4)F(4) families. Sdr1 was mapped between the RFLP markers R10942 and C2045, and co-segregated with C1488. Hd8 was also mapped between C12534S and R10942. Six recombination events were detected between Sdr1 and Hd8. These results clearly demonstrate that Sdr1 and Hd8 were tightly linked. Nearly isogenic lines for Sdr1 and Hd8 were selected by marker-assisted selection.

Chromosome Mapping↗
PubMed2003

[Mapping of QTLs controlling chlorophyll content in rice].

Mapping of QTLs controlling chrolophyll content was conducted with the method of multiple-trait composite interval mapping, based on a recombinant inbred (RI) population consisting of 131 lines (F10) derived from a cross between two indica rice varieties, Acc8558 and H359, and on a corresponding genetic map comprising 147 RFLP and 78 AFLP markers. Six QTLs for contents of chlorophyll a and chlorophyll b were detected, respectively. Among them, five QTLs were the same between the two characters. These QTLs were mainly distributed on chromosomes 1 and 4, indicating that the two chromosomes were more important for chlorophyll content. qChlA1c and qChlB1b (these two QTLs were mapped at the same location) showed relatively large effects at all the four observation times and showed the largest effects at the sword leaf period. Another two QTLs (qChlA4a/qChlB4a and qChlA4b/qChlB4b) exhibited significant effects only at the second observation time, suggesting that they might act only at specific developmental stages.

Chlorophyll↗
PubMed2005

SNP detection and genetic mapping of porcine genes encoding enzymes in hepatic metabolic pathways and evaluation of linkage with carcass traits.

We have previously identified and mapped porcine expressed sequence tags (ESTs) derived from genes that are preferentially expressed in liver. The aim of the present study was to identify single nucleotide polymorphisms (SNPs) in porcine genes encoding enzymes in hepatic metabolic pathways and use the SNPs for mapping. Furthermore, these genes, which are involved in utilization and partitioning of nutrients, were examined for their effects on carcass and meat quality traits by linkage analyses. In total, 100 ESTs were screened for SNPs by single strand conformation polymorphism analyses across a diverse panel of animals with a 36% success rate. Twelve of 36 polymorphic loci segregated in a three-generation Duroc x Berlin Miniature Pig (F2) resource population, the DUMI resource population, and were genetically mapped. Interval mapping of the corresponding chromosomes was performed to verify mapping of the genes within quantitative trait loci (QTL) regions detected in this resource population. QTL with genome-wide significance were detected in the vicinity of GNMT, ESTL147 and HGD. These loci therefore are positional candidate genes.

Animals↗
PubMed2006

[Molecular mapping of the gene(s) controlling petal-loss trait in Brassica napus].

An F2 population derived from a cross between apetalous line' APT02 'and normal petalled cultivar 'ZS NO.4' was used for molecular marker searching and chromosomal mapping of the gene(s) controlling petal-loss trait in Brassica napus. Twenty pairs of AFLP primers and 170 pairs of SRAP primers were selected and screened from two parents. In further selection through bulked segregant analysis (BSA) approach, one SRAP marker e8m3_4 (600 bp) and one AFLP marker E3247_15 (150 bp) were obtained and found to be linked to the gene(s) controlling petal-loss trait, with the genetic distance of 5 cM and 13.5 cM. A linkage map in Brassica napus was constructed. It consisted of 213 AFLP56 SSR loci and a morphology marker throughout 17 main linkage groups, two triplet and four linkage pairs. Total length of the map covered 2,487.1 cM, and average interval between markers was 10.09 cM. By genetic mapping, the gene(s) controlling petal-loss trait (WHB)was mapped in LG4.

Amplified Fragment Length Polymorphism Analysis↗
PubMed2001

Human brain mapping in dystonia reveals both endophenotypic traits and adaptive reorganization.

Dystonia has a wide clinical spectrum from early-onset generalized to late-onset sporadic, task-specific forms. The genetic origin of the former has been clearly established. A critical role of repetitive skilled motor tasks has been put forward for the latter, while underlying vulnerability traits are still being searched for. Using magnetoencephalography, we looked for structural abnormalities reflecting a preexisting dysfunction. We studied finger representations of both hands in the primary sensory cortex, as compared in 23 patients with unilateral task-specific dystonia and 20 control subjects. A dramatic disorganization of the nondystonic hand representation was found in all patients, and its amount paralleled the severity of the dystonic limb motor impairment. Abnormalities were also observed in the cortex coding the dystonic limb representation, but they were important only in the most severely affected patients. The abnormal cortical finger representations from the nondystonic limb appear to be endophenotypic traits of dystonia. That finger representations from the dystonic limb were almost normal for the less severely affected patients may be due to intrinsic beneficial remapping in reaction against the primary disorder.

Adaptation, Physiological↗