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PubMed2005

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

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

Algorithms↗
PubMed2001

Classification methods for confronting heterogeneity.

Recursive partitioning/tree models are discussed as a method of dissecting the complex nature of traits with different causal mechanisms operating in different subsets of the data (e.g., different genes operating in different subsets of families). In addition to the straightforward application of classification and regression trees to define more homogeneous subsets of the data on which to conduct further analysis, developments incorporating linkage analysis into the definition of the regression trees (Shannon et al., 2000) are discussed. The pros and cons of recursive partitioning vs. the related approach of context-dependent analysis (Turner et al., 1999) are also reviewed as two promising analysis strategies that may be useful for genetic dissection of complex traits.

Genetic Diseases, Inborn↗
PubMed2002

QTL analysis of genotype x environment interactions affecting cotton fiber quality.

Cotton is unusual among major crops in that large acreages are grown under both irrigated and rainfed conditions, making genotype x environment interactions of even greater importance than usual in designing crop-improvement strategies. We describe the impact of well-watered versus water-limited growth conditions on the genetic control of fiber quality, a complex suite of traits that collectively determine the utility of cotton. Fiber length, length uniformity, elongation, strength, fineness, and color (yellowness) were influenced by 6, 7, 9, 21, 25 and 11 QTLs (respectively) that could be detected in one or more treatments. The genetic control of cotton fiber quality was markedly affected both by general differences between growing seasons ("years") and by specific differences in water management regimes. Seventeen QTLs were detected only in the water-limited treatment while only two were specific to the well-watered treatment, suggesting that improvement of fiber quality under water stress may be even more complicated than improvement of this already complex trait under well-watered conditions. In crops such as cotton with widespread use of both irrigated and rainfed production systems, the need to manipulate larger numbers of genes to confer adequate quality under both sets of conditions will reduce the expected rate of genetic gain. These difficulties may be partly ameliorated by efficiencies gained through identification and use of diagnostic DNA markers, including those identified herein.

Adaptation, Physiological↗
PubMed2006

Genetic association mapping and genome organization of maize.

Association mapping, a high-resolution method for mapping quantitative trait loci based on linkage disequilibrium, holds great promise for the dissection of complex genetic traits. The recent assembly and characterization of maize association mapping panels, development of improved statistical methods, and successful association of candidate genes have begun to realize the power of candidate-gene association mapping. Although the complexity of the maize genome poses several significant challenges to the application of association mapping, the ongoing genome sequencing project will ultimately allow for a thorough genome-wide examination of nucleotide polymorphism-trait association.

Chromosome Mapping↗
PubMed2004

Genetic variation in carbon isotope discrimination in six European populations of Castanea sativa Mill. originating from contrasting localities.

The objective of this study was to evaluate the variability of physiological performances of Castanea sativa Mill. in relation to drought tolerance, among and within European populations coming from contrasting environmental conditions. Forty-eight open-pollinated families from a stratified sample (temperature/precipitation) of six naturalized populations from Spain, Italy and Greece were grown for one growth period under two temperature regimes (25 and 32 degrees C), in combination with two watering regimes in growth chambers. Complementary to growth traits analysed in a previous study, carbon isotope discrimination (Delta), a complex physiological trait involved in acclimation and adaptive processes, was studied. anova indicated significant Delta variability for C. sativa populations across Europe and, thereby, variation in adaptedness to drought. The European pattern of Delta variability matches the previously reported one for the centre of origin of C. sativa (Ponto-Caucasian region). This suggests that common mechanisms of drought adaptedness, involving both genetic and physiological determinants, give C. sativa the capacity to colonize a wide range of site conditions. The highest Delta values, indicating the lowest water-use efficiency (WUE), were found within each treatment for populations originating from Mediterranean drought-prone sites. These populations also had the highest phenotypic plasticity of Delta. Significant among-family genetic variation in Delta was found. The heritability based on the joint anova was estimated at 0.31 +/- 0.07. The estimates of the coefficients for the additive variance varied in the range 2.6-4.0%, suggesting possibilities for selection on WUE and adaptedness to drought. The genetic correlations between Delta and growth traits were generally strong and negative, especially in the two high temperature treatments.

Adaptation, Physiological↗
PubMed1987

Plant genetic resources: prediction by isozyme markers and ecology.

Linkage or association of genetic markers to quantitative traits of agronomic importance can substantially simplify the genetic analysis of complex quantitative traits. Enzyme marker genes are ideal candidates for quantitative genetic analysis. We have recently applied this powerful methodology to the analysis of genetic resources of wild cereals in Israel, primarily wild emmer wheat, Triticum dicoccoides, and wild barley, Hordeum spontaneum, the progenitors of cultivated wheats and barley, respectively. We have found that allelic isozyme markers and ecological factors provide an important predictive method for identifying elite genotypes characterized by single or multiple disease resistances, high protein content, and a variety of quantitative traits of agronomic importance including germination, earliness, biomass, and yield variables. Our predictive methodology could be improved by additional crossing tests in an attempt to verify the results derived from the correlation analysis and thus establish the linkage relationships between the marker gene and the quantitative trait under discussion. This methodology, if further developed by additional isozyme and DNA markers, verified by crossing tests and gene mapping, could substantially contribute to the sampling and utilization of the genetic resources of wild gene pools for crop improvement.

Agriculture↗
PubMed1993

Use of the regressive models in linkage analysis of quantitative traits.

Use of the regressive models to account for residual familial correlations in linkage analysis of complex quantitative traits can increase the power to detect linkage. This is especially observed when the effect of the gene to be mapped is small or when the residual correlations are substantial.

Chromosome Mapping↗
PubMed2006

Admixture in European Populus hybrid zones makes feasible the mapping of loci that contribute to reproductive isolation and trait differences.

The use of admixed human populations to scan the genome for chromosomal segments affecting complex phenotypic traits has proved a powerful analytical tool. However, its potential in other organisms has not yet been evaluated. Here, we use DNA microsatellites to assess the feasibility of this approach in hybrid zones between two members of the 'model tree' genus Populus: Populus alba (white poplar) and Populus tremula (European aspen). We analyzed samples of both species and a Central European hybrid zone (N=544 chromosomes) for a genome-wide set of 19 polymorphic DNA microsatellites. Our results indicate that allele frequency differentials between the two species are substantial (mean delta=0.619+/-0.067). Background linkage disequilibrium (LD) in samples of the parental gene pools is moderate and should respond to sampling schemes that minimize drift and account for rare alleles. LD in hybrids decays with increasing number of backcross generations as expected from theory and approaches background levels of the parental gene pools in advanced generation backcrosses. Introgression from P. tremula into P. alba varies strongly across marker loci. For several markers, alleles from P. tremula are slightly over-represented relative to neutral expectations, whereas a single locus exhibits evidence of selection against P. tremula genotypes. We interpret our results in terms of the potential for admixture mapping in these two ecologically divergent Populus species, and we validate a modified approach of studying genotypic clines in 'mosaic' hybrid zones.

Alleles↗
PubMed2025

Scalable screening of ternary-code DNA methylation dynamics associated with human traits.

Epigenome-wide association studies (EWASs) are transforming our understanding of the interplay between epigenetics and complex human traits. We introduce the methylation screening array (MSA) to enable scalable and quantitative screening of trait-associated DNA cytosine modifications in large human populations. The MSA integrates EWASs and cell-type-linked methylation signatures, covering diverse traits and diseases. Using the MSA to profile the ternary-code DNA methylations-dissecting 5-methylcytosine (5mC), 5-hydroxymethylcytosine (5hmC), and unmodified cytosine-revealed a previously unappreciated role of 5hmC in mediating human trait associations and epigenetic clocks. We demonstrated that 5hmCs complement 5mCs in defining epigenetic cell identities. In-depth analyses highlighted the cell-type context of EWAS and genome-wide association study (GWAS) hits. Targeting aging, we uncovered shared and tissue-specific 5hmC aging dynamics and tissue-specific rates of mitotic hyper- and hypomethylation. These findings chart a landscape of the complex interplay of the two forms of cytosine modifications in diverse human tissues and their roles in health and disease.

Humans↗
PubMed1983

The lidgap defect in mice: update and hypotheses.

The open eye defect in the mouse can result from the action of mutant genes or of teratogens. Among the genetic forms, the lidgap series poses a particular challenge. The lidgap defect appears to be a complex genetic trait and may serve as a model for the genetic analysis of other genetically complex morphological defects in mammals. Extensive breeding data, together with data on the response of the trait to in utero treatment with cortisone, have been analyzed. The results lead us to propose a model involving a single major locus with a series of alleles of graded strength, hypomorphs. The ranking is lg greater than lgstn = lgSt greater than lgM1. The lg/lg genotype alone can be sufficient to produce the lidgap trait, but the "weaker" alleles require a second or even third locus acting in the same pathway. In addition, there is evidence that a recessive suppressor locus is present in the system. These hypotheses are testable and some experiments to develop them further are discussed.

Alleles↗
PubMed2003

X-linked and lineage-dependent inheritance of coping responses to stress.

Coping-or how one routinely deals with stress-is a complex behavioral trait with bearing on chronic disease and susceptibility to psychiatric disorders. This complexity is a result of not only underlying multigenic factors, but also important non-genetic ones. The defensive burying (DB) test, although originally developed as a test of anxiety, can accurately measure differences in coping strategies by assaying an animal's behavioral response to an immediate threat with ethological validity. Using offspring derived from reciprocal crosses of two inbred rat strains differing in DB behaviors, we provide convergent phenotypic and genotypic evidence that coping styles are inherited in an X-linked fashion. We find that first-generation (F(1)) males, but not females, show maternally derived coping styles, and second-generation (F(2)) females, but not males, show significant differences in coping styles when separated by grandmaternal lineage. By using a linear modeling approach to account for covariate effects (sex and lineage) in QTL analysis, we map three quantitative trait loci (QTL) on the X Chromosome (Chr) ( Coping-1, Approach-1, and Approach-2) associated with coping behaviors in the DB paradigm. Distinct loci were associated with different aspects of coping, and their effects were modulated by both the sex and lineage of the animals, demonstrating the power of the general linear modeling approach and the important interplay of allelic and non-allelic factors in the inheritance of coping behaviors.

Adaptation, Psychological↗
PubMed1997

Integrated methods to solve the biological basis of common diseases.

Biological variations influence population variations of many common traits. Identification of the biological basis of many common diseases has been particularly difficult, but new reagents and analytical tools will greatly facilitate this process. The goal of this review is to discuss how to identify the biological basis of common traits by using mouse models. No single method will work for all traits. Understanding complex problems will require broadly based holistic approaches that use a wide array of tools and resources. A multiplicity of developed methods together provide the tools needed to identify the biological basis of any common trait. These tools, whole-genome linkage maps, maps of expressed genes, and statistical methods, deal with the complexities of multiple loci or correlated traits. This review provides some criteria for making choices about the likely productive approaches at each stage in the process of finding genes that influence common traits.

Animals↗
PubMed2005

A comparison of recovered bipolar patients, healthy relatives of bipolar probands, and normal controls using the short TEMPS-A.

OBJECTIVE: To investigate the presence of temperament dysregulation in healthy relatives of bipolar probands (RBP), a population at high risk for developing mood disorders, by comparing them with clinically recovered bipolar patients (BP) and normal controls (NC). METHOD: 52 RBP and 23 BP were originally recruited for a multicenter genetic study in bipolar disorders. NC (n=102) were also recruited by newspaper advertisement, radio and television announcements, flyers, newsletters, or word of mouth. All volunteers were asked to complete the TEMPS-A Scale, a self-report questionnaire designed to measure temperamental variations in psychiatric patients and healthy volunteers. In scoring temperaments, we relied upon the short validated version of the TEMPS-A [J. Affect. Disord. (2004)], from which traits with loadings <0.035 had been deleted. RESULTS: To examine differences in temperament dimensions among the three groups, a MANCOVA model was constructed using diagnostic group as the fixed factor (BP vs. RBP vs. NC); effects of age and gender were adjusted as covariates. MANCOVA showed overall group effect on the dependent variables (Hotelling's F5,175=6.64, p<0.001). Four dependent variables (dysthymic, cyclothymic, irritable, and anxious temperaments) showed significant between-group differences. RBP showed lower cyclothymic temperament scores than BP, but higher scores than NC. BP and RBP showed higher anxious temperament scores than NC. Hyperthymic scores were significantly highest in the NC. LIMITATION: In view of the small cell sizes, bipolar I vs. bipolar II subanalyses could not be conducted. CONCLUSIONS: Methodologic strengths of the present analyses is that the BP group had clinically recovered, and we used the validated short version of the TEMPS-A for the present analyses. Our findings suggest that some clinically healthy relatives of bipolar probands exhibit a subclinical cyclothymic instability in mood, interest, self-confidence, sleep, and/or energy as well as anxiety proneness that is not observed among normal controls. These traits may represent vulnerability markers and could presumably be used to identify individuals at high risk for developing bipolar spectrum disorders, or specific clinical subtypes (e.g., bipolar I, bipolar II) within this spectrum. This is a conceptual perspective with many unanswered questions. Resolution of these questions will require innovative definitions of phenotypes to be included in the analyses of the temperament subscales in different populations. The temperament subscales themselves need to be calibrated properly, to find out which traits or specific combinations of trains are most promising. More extensive and complex quantitative trait analyses of these temperaments in a much expanded sample are reported elsewhere in this issue [J. Affect. Disord. (2004)].

Adaptation, Psychological↗
PubMed2002

Genetic manipulation and quantitative-trait loci mapping for nitrogen recycling in rice.

Immunocytological studies in this laboratory have suggested that NADH-dependent glutamate synthase (NADH-GOGAT; EC 1.4.1.14) in developing organs of rice (Oryza sativa L. cv. Sasanishiki) is involved in the utilization of glutamine remobilized from senescing organs through the phloem. Because most of the indica cultivars contained less NADH-GOGAT in their sink organs than japonica cultivars, over-expression of NADH-GOGAT gene from japonica rice was investigated using Kasalath, an indica cultivar. Several T0 transgenic Kasalath lines over-producing NADH-GOGAT under the control of a NADH-GOGAT promoter of Sasanishiki, a japonica rice, showed an increase in grain weight (80% as a maximum), indicating that NADH-GOGAT is indeed a key step for nitrogen utilization and grain filling in rice. A genetic approach using 98 backcross-inbred lines (BC(1)F(6)) developed between Nipponbare (a japonica rice) and Kasalath were employed to detect putative quantitative trait loci (QTLs) associated with the contents of cytosolic glutamine synthetase (GS1; EC 6.3.1.2), which is probably involved in the export of nitrogen from senescing organs and those of NADH-GOGAT. Immunoblotting analyses showed transgressive segregations toward lower or greater contents of these enzyme proteins in these BC(1)F(6). Seven chromosomal QTL regions were detected for GS1 protein content and six for NADH-GOGAT. Some of these QTLs were located in QTL regions for various biochemical and agronomic traits affected by nitrogen recycling. The relationships between the genetic variability of complex agronomic traits and traits for these two enzymes are discussed.

Amino Acid Oxidoreductases↗
PubMed2005

Mapping quantitative trait loci in multiple populations of Arabidopsis thaliana identifies natural allelic variation for trichome density.

The majority of biological traits are genetically complex. Mapping the quantitative trait loci (QTL) that determine these phenotypes is a powerful means for estimating many parameters of the genetic architecture for a trait and potentially identifying the genes responsible for natural variation. Typically, such experiments are conducted in a single mapping population and, therefore, have only the potential to reveal genomic regions that are polymorphic between the progenitors of the population. What remains unclear is how well the QTL identified in any one mapping experiment characterize the genetics that underlie natural variation in traits. Here we provide QTL mapping data for trichome density from four recombinant inbred mapping populations of Arabidopsis thaliana. By aligning the linkage maps for these four populations onto a common physical map, the results from each experiment were directly compared. Seven of the nine QTL identified are population specific while two were mapped in all four populations. Our results show that many lineage-specific alleles that either increase or decrease trichome density persist in natural populations and that most of this genetic variation is additive. More generally, these findings suggest that the use of multiple populations holds great promise for better understanding the genetic architecture of natural variation.

Arabidopsis↗
PubMed1999

Maximum-Likelihood-Binomial method for genetic model-free linkage analysis of quantitative traits in sibships.

Sib-pair linkage studies are widely used to investigate the genetic factors implicated in complex quantitative traits. To analyze these data, we propose a Maximum-Likelihood-Binomial (MLB) approach, which considers the sibship as a whole and relies on the idea of binomial distributions of parental alleles among offsprings. The method is based on the introduction of a latent binary variable capturing the linkage information between the observed quantitative trait and the marker, and the final likelihood can be expressed assuming a parametric distribution for the studied trait but also without any assumption on this distribution. The test for linkage is a simple likelihood ratio test involving a single parameter. The performances of the MLB method are assessed by a simulation study in different kinds of family samples. In the case of families with various sibship sizes, both MLB approaches (assuming or not a parametric distribution for the quantitative trait) provide very consistent results in terms of type I errors and yield power levels generally higher than those of the classical Haseman-Elston method. In the case of extremely discordant sib pairs, we analytically show that, for a common asymptotic type I error, the distribution-free MLB statistic is expected to be more powerful than the test proposed by Risch and Zhang [(1995) Science 268:1584-1589]. In samples including both extremely concordant and discordant sib-pairs, simulation studies show that the MLB approach is at least as powerful as the EDAC method [Gu et al. (1996) Genet Epidemiol 13:513-533]. This MLB method, which can be easily extended to perform multipoint analysis and to account for genetic heterogeneity, appears to be quite an interesting alternative for mapping quantitative trait loci in humans.

Alleles↗
PubMed2004

Estimation of genetic and environmental factors for binary traits using family data.

While the family-based analysis of genetic and environmental contributions to continuous or Gaussian traits is now straightforward using the linear mixed models approach, the corresponding analysis of complex binary traits is still rather limited. In the latter we usually rely on twin studies or pairs of relatives, but these studies often have limited sample size or have difficulties in dealing with the dependence between the pairs. Direct analysis of extended family data can potentially overcome these limitations. In this paper, we will describe various genetic models that can be analysed using an extended family structure. We use the generalized linear mixed model to deal with the family structure and likelihood-based methodology for parameter inference. The method is completely general, accommodating arbitrary family structures and incomplete data. We illustrate the methodology in great detail using the Swedish birth registry data on pre-eclampsia, a hypertensive condition induced by pregnancy. The statistical challenges include the specification of sensible models that contain a relatively large number of variance components compared to standard mixed models. In our illustration the models will account for maternal or foetal genetic effects, environmental effects, or a combination of these and we show how these effects can be readily estimated using family data.

Cluster Analysis↗
PubMed1987

Genetic variance estimates and familial resemblance for body size traits.

To study genetic contribution to complex body size traits, the intrafamilial correlation and regression analyses along with twin study method have been used. The data are based on a sample of 45 MZ and 101 DZ twin pairs, their 125 singleton siblings, 104 fathers and 103 mothers in 146 Punjabi families living in Chandigarh, India. Twin study gives no evidence of inequality of means and variances between zygosities. Within-pair genetic variance ratios, correlations, regressions of offspring on midparent and single parent are all significant at 0.1%, thus indicating strong genetic component. Heritability estimates are higher for longitudinal body traits than the breadth dimensions. The resemblance of the children with the parents of either sex is not equal. Higher maternal influence is indicated for a number of body traits. The results on familial correlations do not support the hypothesis of sex-linked inheritance for any of the traits considered in this investigation. These results have been compared with those from other such studies.

Adult↗