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PubMed2004

Quantitative genomics: exploring the genetic architecture of complex trait predisposition.

Most phenotypes with agricultural or biomedical relevance are multifactorial traits controlled by complex contributions of genetics and environment. Genetic predisposition results from combinations of relatively small effects due to variations within a large number of genes, known as QTL. Well over 200 QTL have been reported for growth and body composition traits in the mouse, which likely represent at least 50 to 100 distinct genes. Molecular biology has yielded significant advances in understanding these traits at the metabolic and physiological levels; however, little has been learned regarding the identity and nature of the underlying polygenes. In addition to the significantly poor precision inherent to QTL localization, it is very difficult to differentiate between co-localization and coincidence when comparing QTL with other QTL and with potential candidate genes. The wide gap between our knowledge of physiological mechanisms underlying complex traits and the nature of genetic predisposition significantly impairs discovery of genes underlying QTL. Identification and genetic mapping of key transcriptional, proteomic, metabolomic, and endocrine events will uncover large lists of significant positional candidate genes for growth and body composition. However, integration of experimental approaches to jointly evaluate predisposition and physiology will increase success of QTL identification by merging the power of recombination with functional analysis. Measuring physiologically relevant subphenotypes within a structured QTL mapping population will not only facilitate pathway-specific prioritization among candidate genes, but may also directly identify genes underlying QTL. This would advance our understanding of the genetic architecture of complex traits by testing the central hypothesis that genes controlling predisposition to a quantitative trait are primarily involved in trans-regulation of the primary physiological pathways that regulate the trait.

Animals↗
PubMed2000

High stressful temperature and genetic variation of five quantitative traits in Drosophila melanogaster.

Variation of five quantitative traits (thorax length, wing length, sternopleural bristle number, developmental time and larva-to-adult viability) was studied in Drosophila melanogaster reared at standard (25 degrees C) and high stressful (32 degrees C) temperatures using half-sib analysis. In all traits, both phenotypic and environmental variances increased at 32 degrees C. For genetic variances, only two statistically significant differences between temperature treatments were found: the among-sire variance of viability and the among-dam variance of developmental time were higher under stress. Among-sire genetic variances and evolvabilities were generally higher at 32 degrees C but narrow sense heritabilities were not. The results of the present work considered in the context of other studies in D. melanogaster indicate different patterns of genetic variation between stressful and nonstressful environments for the traits examined. Data on thorax length and viability agree with the hypothesis that genetic variance can be increased under extreme environmental conditions.

Animals↗
PubMed2003

Genetic variability at neutral markers, quantitative trait land trait in a subdivided population under selection.

Genetic variability in a subdivided population under stabilizing and diversifying selection was investigated at three levels: neutral markers, QTL coding for a trait, and the trait itself. A quantitative model with additive effects was used to link genotypes to phenotypes. No physical linkage was introduced. Using an analytical approach, we compared the diversity within deme (H(S)) and the differentiation (F(ST)) at the QTL with the genetic variance within deme (V(W)) and the differentiation (Q(ST)) for the trait. The difference between F(ST) and Q(ST) was shown to depend on the relative amounts of covariance between QTL within and between demes. Simulations were used to study the effect of selection intensity, variance of optima among demes, and migration rate for an allogamous and predominantly selfing species. Contrasting dynamics of the genetic variability at markers, QTL, and trait were observed as a function of the level of gene flow and diversifying selection. The highest discrepancy among the three levels occurred under highly diversifying selection and high gene flow. Furthermore, diversifying selection might cause substantial heterogeneity among QTL, only a few of them showing allelic differentiation, while the others behave as neutral markers.

Computer Simulation↗
PubMed1990

Quantitative estimation of the genetic risk associated with the induction of heritable translocations at low-dose exposure: ethylene oxide as an example.

This paper explores how quantitative risk assessment methods might be extended to analysis of risks to the human germ line. High inhalation exposures to ethylene oxide are reported to cause heritable translocations in male mice with a steep and nonlinear dose-response-curve. We explore quantitative estimation of risk to humans from low exposures based on these animal data, addressing questions of tissue dosimetry for this alkylating agent, expected equivalency of doses across species, germ-cell sensitivity, and extrapolation of dose-response relationship to low exposure levels. Various dose-response models are discussed in terms of their applicability to genetic end points and their ability to reflect the underlying basis of induced heritable translocations.

Administration, Inhalation↗
PubMed2006

Qualitative and quantitative polymerase chain reaction analysis for genetically modified maize MON863.

Qualitative and quantitative analytical methods were developed for the new event of genetically modified (GM) maize, MON863. One specific primer pair was designed for the qualitative polymerase chain reaction (PCR) method. The specificity and sensitivity of the designed primers were confirmed. PCR was performed on genomic DNAs extracted from MON863, other GM events, and cereal crops. Single PCR product was obtained from MON863 by the designed primer pair. Eight test samples including GM maize MON863 were prepared at 0.01 approximately 10% levels and analyzed by PCR. Limit of detection of the method was 0.01% for GM maize MON863. On the other hand, another specific primer pair and probe were also designed for quantitative method using a real-time polymerase chain reaction. As a reference molecule, a plasmid was constructed from a taxon-specific DNA sequence for maize, a universal sequence for a cauliflower mosaic virus (CaMV) 35S promoter used in most genetically modified organisms, and a construct-specific DNA sequence for the MON863 event. Six test samples of 0.1, 0.5, 1.0, 3.0, 5.0 and 10.0% of GM maize MON863 were quantitated for the validation of this method. At the 3.0% level, the bias (mean vs true value) for MON863 was 3.0%, and its relative standard deviation was 5.5%. Limit of quantitation of the method was 0.5%. These results show that the developed PCR methods can be used to qualitatively and quantitatively detect GM maize MON863.

DNA Primers↗
PubMed1992

Quantitative evidence that the genetic basis of human mortality operates at the translation level: a preliminary assessment.

The dying off of human population cohorts due to different age related diseases rigorously follows stochastically derived rules. The existence of such rules suggests a common, fundamental mechanism for human mortality. We show here, by a simple quantitative analysis, that the progressive loss with age of genetic triplet code information (anticodons) in body cells, as described by the statistics of extremes in order theory, serves as such a mechanism.

Adult↗
PubMed1995

Genetic epidemiologic analysis of quantitative phenotypes using Gibbs sampling.

We analyzed two quantitative traits (Q1 and Q2) provided in the 'Common Disease' data set with the aim of detecting both genetic and environmental determinants. We used linear regression for screening measured variables, maximum likelihood segregation and linkage analyses for detecting and localizing unmeasured genes, and Gibbs sampling for joint segregation and linkage analyses with estimation of gene-environment interaction and polygenic effects. For both Q1 and Q2, we successfully detected the unmeasured codominant major gene (MG) that was tightly linked to candidate gene C2. We also detected all of the measured variables used in generating Q1 (age, Q3, candidate gene C5) and Q2 (EF). Although our final models differed slightly from the true data generation models, our multifaceted analytic approach was successful in characterizing the determinants of Q1 and Q2.

Alleles↗
PubMed1987

Genetic architecture and adaptation: quantitative analysis of sheep and refuse tip populations of the Australian sheep blowfly, Lucilia cuprina.

Phenotypic differentiation between geographic areas and between sheep and adjacent refuse tip populations was assessed by quantitative analysis of population samples of L. cuprina from New South Wales (Lismore) and Victoria (Mansfield). In addition the genetic structure of populations has been defined and compared by biometrical analysis techniques. For all morphological and fitness characters examined significant phenotypic differentiation was observed both between geographic localities and between sheep and non-sheep populations of each locality. Diallel analysis of the populations revealed architectural differences between sheep and non-sheep populations for both fecundity and egg hatchability. Sheep populations only, regardless of locality, displayed dominant gene effects on these fitness traits. The results suggest that refuse tip populations may be other than transients and that the differentiation may reflect differing patterns of adaptation and history of selection of the populations. The relevance of such differentiation to the successful establishment of a chemical and/or autocidal control zone is considered.

Adaptation, Physiological↗
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↗
PubMed2006

Quantitative trait loci define genes and pathways underlying genetic variation in longevity.

Quantitative trait locus (QTL) mapping provides a means to discover and roughly position regions of the genome that harbor genes responsible for natural variation in a complex trait. QTL mapping has been utilized extensively in the pursuit of genes contributing to longevity, chiefly in two animal models, the nematode Caenorhabditis elegans and the dipteran insect Drosophila melanogaster. Research on both species has demonstrated that a relatively small set of loci accounts for most of their genetic variance in lifespan. QTL mapping complements the discovery of longevity genes by mutagenesis screens, because the two procedures are predicted to unveil overlapping but distinct types of genes. We argue that information gained from animal models, even invertebrates, can greatly facilitate the process of gene identification and testing of homologous genes in humans.

Aging↗
PubMed2003

Quantitative risk factors as indices of alcoholism susceptibility.

Alcoholism is a complex disorder involving both genetic and environmental factors and interactions between them. Localizing and characterizing the genetic influences on susceptibility to alcohol dependence may provide new insights into pathology and new avenues for treatment and prevention. However, because of the complex nature of the disorder, the binary categorization of individuals as affected or unaffected may be a poor indicator of their underlying genetic susceptibility. Quantitative risk factors, or endophenotypes, that differentiate levels of severity among affected individuals and levels of susceptibility among unaffected individuals, provide one solution to this problem. Genetic studies of such quantitative risk factors in families of probands with alcohol dependence may help to disentangle the complex genetic architecture of this disorder.

Alcoholism↗
PubMed2001

Patterns of genetic architecture for life-history traits and molecular markers in a subdivided species.

Understanding the utility and limitations of molecular markers for predicting the evolutionary potential of natural populations is important for both evolutionary and conservation genetics. To address this issue, the distribution of genetic variation for quantitative traits and molecular markers is estimated within and among 14 permanent lake populations of Daphnia pulicaria representing two regional groups from Oregon. Estimates of population subdivision for molecular and quantitative traits are concordant, with QST generally exceeding GST. There is no evidence that microsatellites loci are less informative about subdivision for quantitative traits than are allozyme loci. Character-specific comparison of QST and GST support divergent selection pressures among populations for the majority of life-history traits in both coast and mountain regions. The level of within-population variation for molecular markers is uninformative as to the genetic variation maintained for quantitative traits. In D. pulicaria, regional differences in the frequency of sex may contribute to variation in the maintenance of expressed within-population quantitative-genetic variation without substantially impacting diversity at the genic level. These data are compared to an identical dataset for 17 populations of the temporary-pond species, D. pulex.

Animals↗
PubMed1994

Genetic variation detected by quantitative analysis of end-labeled genomic DNA fragments.

The continuing efforts to evaluate specific human populations for altered germinal mutation rates would profit from more efficient and more specific approaches than those of the past. To this end, we have explored the potential usefulness of two-dimensional electrophoresis of DNA fragments obtained from restriction-enzyme-digested genomic DNA. This permits the analysis, on a single preparation, of approximately 2000 DNA fragments varying in size from 1.0 to 5.0 kb in the first dimension and from 0.3 to 2.0 kb in the second dimension. To enter into a genetic analysis, these fragments must exhibit positional and quantitative stability. With respect to the latter, if spots that are the product of two homologous DNA fragments are to be distinguished with the requisite accuracy from spots that are the product of only one fragment, the coefficient of variation of spot intensity should be approximately < or = 0.12. At present, 482 of the spots in our preparations meet these standards. In an examination of preparations based on three Japanese mother/father/child trios, 43 of these 482 spots were found to exhibit variation that segregated within families according to Mendelian principles. We have established the feasibility of cloning a variant fragment from such gels and establishing its nucleotide sequence. This technology should be highly efficient in monitoring for mutations resulting in loss/gain/rearrangement events in DNA fragments distributed throughout the genome.

Base Sequence↗
PubMed2003

LOD score exclusion analyses for candidate QTLs using random population samples.

While extensive analyses have been conducted to test for, no formal analyses have been conducted to test against, the importance of candidate genes as putative QTLs using random population samples. Previously, we developed an LOD score exclusion mapping approach for candidate genes for complex diseases. Here, we extend this LOD score approach for exclusion analyses of candidate genes for quantitative traits. Under this approach, specific genetic effects (as reflected by heritability) and inheritance models at candidate QTLs can be analyzed and if an LOD score is < or = -2.0, the locus can be excluded from having a heritability larger than that specified. Simulations show that this approach has high power to exclude a candidate gene from having moderate genetic effects if it is not a QTL and is robust to population admixture. Our exclusion analysis complements association analysis for candidate genes as putative QTLs in random population samples. The approach is applied to test the importance of Vitamin D receptor (VDR) gene as a potential QTL underlying the variation of bone mass, an important determinant of osteoporosis.

Bone Density↗
PubMed2004

Genetic predisposition to cancer - insights from population genetics.

Individuals differ in their inherited tendency to develop cancer. Major single-gene defects that cause early cancer onset have been known for many years from their inheritance patterns, and inherited defects that have weaker effects on predisposition were also suspected to exist. Recent progress in cancer genetics has identified specific loci that are involved in cancer progression, many of which have key roles in DNA repair, cell-cycle control and cell-death pathways. Those loci, which are often mutated somatically during cancer progression, sometimes also contain inherited mutations. Recent genetic studies and quantitative population-genetic analyses provide a framework for understanding the frequency of inherited mutations and the consequences of these mutations for increased predisposition to cancer.

Age Factors↗