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PubMed1995

Quantitative and qualitative genetic variation in two-dimensional DNA gels of human lymphocytoid cell lines.

There is a continuing need for more efficient methods to examine human (and other) populations for altered germinal and somatic cell mutation rates. To this end, we have explored the potential usefulness of two-dimensional (2-D) electrophoresis of human DNA fragments obtained from restriction-enzyme-digested genomic DNA, using samples from father/mother/child trios. On a single 2-D DNA preparation, approximately 2000 DNA fragments varying in size from 1.0 to 5.0 kbp in the first dimension and 0.3 to 2.0 kbp in the second dimension are visualized. To enter into a genetic analysis of quantitative variation, 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 variations that segregated within families according to Mendelian principles. Additionally, of the 2000 spots, 1114 (of which the aforementioned 482 are a subset) were deemed appropriate for the study of qualitative variation. A total of 142 variable spots were identified; the heterozygosity index for these DNA fragments was 4.4%. The genetic nature of the additional variants was again established by their segregation according to Mendelian principles. We have established the feasibility of cloning fragments from such gels and determining their nucleotide sequence. This technology should be highly efficient in monitoring for mutation resulting in loss/gain/rearrangement events in DNA fragments distributed throughout the genome.

Autoradiography↗
PubMed1991

Mutation-selection balance and metabolic control theory.

The evolution of metabolic control is examined with models that unify approaches of classical quantitative genetics and metabolic control theory. The quantitative traits considered are the activities of enzymes embedded within metabolic pathways. In the models, polygenic mutation alters the enzyme activities (Vmax/Km) according to prescribed distributions, and the population evolves following classical haploid viability selection. Stabilizing selection operates on global properties of the metabolic pathway, including either flux or metabolite pool concentration. Analytical results and numerical simulations demonstrate several important properties of these characters, including skewed, non-Gaussian equilibrium distributions, and an expected positive correlation between activities of enzymes flanking a substrate pool undergoing stabilizing selection. The house-of-cards approximation proved to be accurate in predicting the equilibrium distribution of allelic effects for a biologically reasonable segment of the parameter space. Further experimental and theoretical work is needed before a clear assessment can be made whether the observed variance in enzyme activities is explicable by a mutation-selection balance, and this system provides an excellent opportunity for such a test.

Alleles↗
PubMed1989

Rapid enzyme kinetic assays of individual Drosophila and comparisons of field-caught D. melanogaster and D. simulans.

Techniques for performing numerous enzyme kinetic assays with minimum time and effort would be valuable to studies of the evolutionary genetics of metabolic control and the quantitative genetics of determinants of kinetic parameters. Microtiter plate readers have been used for a variety of repetitious analytical techniques, and instruments are available that can take repetitive readings with sufficient speed to perform kinetic assays. The ability of these instruments to assay rapidly the kinetic properties of small samples makes them potentially useful for a number of problems in population genetics. While the ability to handle large numbers of samples is very attractive, the small sample volumes and optical imprecision of microtiter plates result in some sacrifice in accuracy. This paper presents methods for performing kinetic assays on individual field-caught Drosophila, quantifies the precision of these methods, and characterizes differences among Drosophila melanogaster and D. simulans from samples caught in California and Pennsylvania. Comparisons between field-caught and laboratory reared D. melanogaster show that most of the characters are very similar, with the exception of alpha GPDH, which has a threefold higher mean activity among field-caught flies. The phenotypic correlations are presented with a brief discussion of their relevance to assessing the evolution of metabolic control of these enzymes.

Animals↗
PubMed2005

Evolution in heterogeneous environments and the potential of maintenance of genetic variation in traits of adaptive significance.

The maintenance of genetic variation in traits of adaptive significance has been a major dilemma of evolutionary biology. Considering the pattern of increased genetic variation associated with environmental clines and heterogeneous environments, selection in heterogeneous environments has been proposed to facilitate the maintenance of genetic variation. Some models examining whether genetic variation can be maintained, in heterogeneous environments are reviewed. Genetic mechanisms that constrain evolution in quantitative genetic traits indicate that genetic variation can be maintained but when is not clear. Furthermore, no comprehensive models have been developed, likely due to the genetic and environmental complexity of this issue. Therefore, I have suggested two empirical approaches to provide insight for future theoretical and empirical research. Traditional path analysis has been a very powerful approach for understanding phenotypic selection. However, it requires substantial information on the biology of the study system to construct a causal model and alternatives. Exploratory path analysis is a data driven approach that uses the statistical relationships in the data to construct a set of models. For example, it can be used for understanding phenotypic selection in different environments, where there is no prior information to develop path models in the different environments. Data from Brassica rapa grown in different nutrients indicated that selection changed in the different environments. Experimental evolutionary studies will provide direct tests as to when genetic variation is maintained.

Adaptation, Biological↗
PubMed1998

Combining data from morphological traits and genetic markers to determine transmission cycles in the tape worm, Echinococcus granulosus.

Species of Echinococcus (Cestoda: Taeniidae) require 2 mammalian hosts to complete their life-cycle; a carnivorous definitive host, and a herbivorous or omnivorous intermediate host. For most species of Echinococcus, the definitive host range is restricted to 1 or a few species, but the intermediate host range is very broad. Programmes to control hydatid disease attempt to break the life-cycle of the parasite and their effectiveness is therefore enhanced by an understanding of local patterns of transmission. Although it is known that the rostellar hooks of protoscoleces may be influenced by the species of intermediate host in which they develop, the application of this knowledge to infer transmission cycles has been limited, because the intermediate host effect has not been isolated from other environmental and genetic components of phenotypic variance. This study presents a method for separating these potentially confounding genetic and environmental effects, by combining quantitative genetic analyses of hook traits with data on population structure from neutral genetic markers. The method was applied to 5 hook traits (hook number, total length of large hooks, blade length of large hooks, total length of small hooks, blade length of small hooks) measured on protoscoleces from 2 intermediate host types (sheep and macropod marsupials) in Australia. Although genetic variance was similar for all traits, they differed markedly in the extent of environmental variance attributed to development in different host types. Total length of small hooks was the trait most affected, with 49-60% of phenotypic variance being explained by environmental differences between intermediate host species. Blade length of small hooks was least affected, with none of the phenotypic variance due to intermediate host origin. These data suggest that hook measurements of adult worms from naturally infected definitive hosts could be used to determine the intermediate host species from which infection was acquired, if the appropriate traits are measured.

Alleles↗
PubMed2004

Dealing with the genotype x environment interaction via a modelling approach: a comparison of QTLs of maize leaf length or width with QTLs of model parameters.

Quantitative genetics of adaptive traits is made difficult by the genotypexenvironment interaction. A classical assumption is that QTLs identified in both stressed and control conditions correspond to constitutive traits whereas those identified only in stressed treatments are stress-specific and correspond to adaptive traits. This hypothesis was tested by comparing, in the same set of experiments, two ways of analysing the genetic variability of the responses of maize leaf growth to water deficit. One QTL detection was based on raw phenotypic traits (length and width of leaf 6) of 100 recombinant inbred lines (RILs) in four experiments with either well-watered or stressing conditions in the field or in the greenhouse. Another detection followed a method proposed recently which consists of analysing intrinsic responses of the same RILs to environmental conditions, determined jointly over several experiments. QTLs of three responses were considered: (i) leaf elongation rate per unit thermal time in the absence of stress, (ii) its response to evaporative demand in well-watered plants, and (iii) its response to soil water status in the absence of evaporative demand. The QTL of leaf length differed between experiments, but colocalized in seven cases out of 13 with QTLs of the intrinsic leaf elongation rate, even in experiments with stressing conditions. No colocalization was found between QTLs of leaf length under water deficit and QTLs of responses to air or soil water status. By contrast, QTLs of leaf width colocalized in all experiments, regardless of environmental conditions. The classical method of identifying the QTL of constitutive versus adaptive traits therefore did not apply to the experiments presented here. It is suggested that identification of the QTL of parameters of response curves provides a promising alternative for dealing with the genetic variability of adaptive traits.

Circadian Rhythm↗
PubMed1997

Commercial approaches to genetic selection for growth and feed conversion in domestic poultry.

Tremendous genetic progress has been observed historically for growth and feed conversion through the efforts of the primary breeding companies. However, significant between-strain variation still exists due to differences in selection emphasis and selection techniques practiced by these organizations. This paper provides an overview of methods currently employed in commercial poultry breeding with reference to factors complicating program design and future challenges facing the industry. Mass selection for body weight has resulted in a significant reduction in the number of days required to grow bird to market weight with indirect improvements in feed conversion. Direct selection for feed conversion is accomplished through part record testing of males that have been preselected for body weight, conformation, and defect traits. Data are commonly subjected to complex statistical analysis both to correct feed conversion for variation in body weight and to improve the accuracy of breeding value estimates. Feed conversion breeding values of male sibs are sometimes used for the selection of female candidates as well. Selection for growth rate and efficiency has resulted in negative complications, such as ascites, reduced reproductive performance, skeletal abnormalities, and increased carcass fatness. Some of these factors may be partially ameliorated through modified selection practices. If not addressed by the breeding industry, the disruption of physiological homeostasis might ultimately represent economic and genetic barriers to further progress in improving growth and efficiency. Modern techniques in molecular genetics, utilized in conjunction with traditional quantitative genetic approaches, will provide additional opportunities to circumvent these physiological complications associated with genetic selection for growth and feed efficiency.

Animals↗
PubMed2005

Testing marker-based estimates of heritability in the wild.

Marker-based estimates of heritability are an attractive alternative to pedigree-based methods for estimating quantitative genetic parameters in field studies where it is difficult or impossible to determine relationships and pedigrees. Here I test the ability of the marker-based method to estimate heritability of a suite of traits in a wild population of bighorn sheep (Ovis canadensis) using marker data from 32 microsatellite loci. I compared marker-based estimates with estimates obtained using a pedigree and the animal model. Marker-based estimates of heritability were imprecise and downwardly biased. The high degree of uncertainty in marker-based estimates suggests that the method may be sufficient to detect the presence of genetic variance for highly heritable traits, but not sufficiently reliable to estimate genetic parameters.

Alberta↗
PubMed2006

MHC class IIB alleles contribute to both additive and nonadditive genetic effects on survival in Chinook salmon.

The genes of the major histocompatibility complex (MHC) are found in all vertebrates and are an important component of individual fitness through their role in disease and pathogen resistance. These genes are among the most polymorphic in genomes and the mechanism that maintains the diversity has been actively debated with arguments for natural selection centering on either additive or nonadditive genetic effects. Here, we use a quantitative genetics breeding design to examine the genetic effects of MHC class IIB alleles on offspring survivorship in Chinook salmon (Oncorhynchus tshawytscha). We develop a novel genetic algorithm that can be used to assign values to specific alleles or genotypes. We use this genetic algorithm to show simultaneous additive and nonadditive effects of specific MHC class IIB alleles and genotypes on offspring survivorship. The additive effect supports the rare-allele hypothesis as a potential mechanism for maintaining genetic diversity at the MHC. However, contrary to the overdominance hypothesis, the nonadditive effect led to underdominance at one heterozygous genotype, which could instead reduce variability at the MHC. Our algorithm is an advancement over traditional animal models that only partition variance in fitness to additive and nonadditive genetic effects, but do not allocate these effects to specific alleles and genotypes. Additionally, we found evidence of nonrandom segregation during meiosis in females that promotes an MHC allele that is associated with higher survivorship. Such nonrandom segregation could further reduce variability at the MHC and may explain why Chinook salmon has one of the lowest levels of MHC diversity of all vertebrates.

Alleles↗
PubMed2001

HbA(1c) levels are genetically determined even in type 1 diabetes: evidence from healthy and diabetic twins.

HbA(1c), a measure of blood glucose regulation, reflects glucose levels in the preceding months. In diabetes, HbA(1c) levels predict the risk of microvascular complications. The aim of this study was to determine whether genetic factors could influence HbA(1c) levels in normal subjects and type 1 diabetic patients. We performed a classical twin study of HbA(1c) in healthy nondiabetic female twins and 42 monozygotic (MZ) and 47 dizygotic (DZ) pairs. Interclass correlations (r) were higher in MZ (r = 0.77) compared with DZ (r = 0.53) twin pairs, suggesting a substantial genetic effect; this was confirmed by quantitative genetic model fitting. Additive genetic effects (heritability) explained 62% (95% CI 47-75) of population variance in HbA(1c); the remainder was attributable to the influence of unique environment (23% [15-36]) and age (14% [5-28]). Multivariate modeling showed that genetic factors also have a substantial influence on fasting glucose levels (51%). However, HbA(1c) heritability could not be explained by genes in common with fasting glucose. In the patients with type 1 diabetes, HbA(1c) levels were correlated in 33 MZ twins concordant for diabetes (r = 0.68; P < 0.001) but also in 45 MZ twins discordant for the disease (r = 0.52; P < 0.001). These significant correlations for HbA(1c) in both concordant and discordant pairs indicate a diabetes-independent familial effect. Thus, HbA(1c) levels are largely genetically determined and independent of the genes influencing fasting glucose. Even in type 1 diabetes, familial (i.e., diabetes-independent) factors influence protein glycation, implying that familial factors may explain, in part, the risk for microvascular complications, as indicated by high HbA(1c) levels.

Adult↗
PubMed1995

Microevolution and the genetic structure of parasite populations.

The development of polymerase chain reaction-based methods for assessing the genotypes of small individual organisms will promote groundbreaking investigations of the genetic architecture of parasite populations. Both quantitative genetic models and general knowledge of parasite natural history are useful for making general predictions about the distribution of genetic variation over geographic space. However, designing experimental studies to assess relationships between specific life history variables and patterns of genetic structure in natural populations will be challenging. Traditional biochemical-genetic methods have already been used to study a limited number of parasite populations, and inferred patterns of genetic structure are distinctly different between certain species. Some of these differences in genetic architecture may be explained by parasite or host factors that either promote or retard the dissemination of life cycle stages over geographic space. Many additional empirical studies are needed to characterize basic features of parasite populations, including the spatial distribution and group size of random mating populations and levels of gene flow among parasite subpopulations.

Animals↗
PubMed1996

Do animal models have a place in the genetic analysis of quantitative human behavioural traits?

It seems that the genetic basis of common psychiatric diseases such as schizophrenia and manic-depressive psychosis is amenable to the genetic mapping strategies that have been successful in other complex disorders such as diabetes. The next challenge is the genetic dissection of quantitative behavioural traits such as mood, personality and intelligence. Quantitative traits pose new problems for gene cloning experiments. We argue that one way forward is by using animal models. One of the features of quantitative traits is that the DNA sequence variants which are responsible for them are unlikely to be immediately recognizable. In contrast to many qualitative traits where a discrete phenotypic difference is often the consequence of an inactivating mutation, the allelic variation responsible for quantitative traits probably has a more subtle basis. This distinction means that strategies to clone the genetic basis of quantitative behavioural traits will have to rely on functional assays of alleles thought to be important in determining the phenotype. We suggest that an efficient strategy for detecting sequences that give rise to quantitative behavioural traits can be devised in the mouse. The importance and utility of the mouse for quantitative trait analysis make it worthwhile to investigate mouse models of human behaviour; these advantages outweigh the difficulties that arise in attempts to validate the animal models. As an example we review the evidence that validates rodent emotionality as an animal model for susceptibility to human anxiety. We show that there is good evidence that rodent emotionality is a central nervous system state with a genetic basis, and that there are neuropharmacological and neuroanatomical parallels with human anxiety. Furthermore, our own work has shown that the genetic basis of the trait is relatively simple, and that the task of characterizing it at a molecular level is feasible. We expect that future experiments will show us how genetic variation gives rise to quantitative behavioural traits.

Animals↗
PubMed1984

Easy calculations of lod scores and genetic risks on small computers.

A computer program that calculates lod scores and genetic risks for a wide variety of both qualitative and quantitative genetic traits is discussed. An illustration is given of the joint use of a genetic marker, affection status, and quantitative information in counseling situations regarding Duchenne muscular dystrophy.

Computers↗
PubMed2005

On the theoretical and empirical framework for studying genetic interactions within and among species.

We present a quantitative genetic (QG) interpretation of the Bateson-Dobzhansky-Muller (BDM) genetic model of speciation in order to unify the theoretical framework for understanding how the genetic differentiation of populations is associated with the process of speciation. Specifically, we compare the QG theory of joint scaling with the Turelli-Orr mathematical formulation of the BDM model. By formally linking the two models, we show that a wealth of empirical methods from QG can be brought to bear on the study of the genetic architecture of hybrid phenotypes to better understand the connections, if any, between microevolution within populations and macroevolution in the origin of species. By integrating the two theories, we make additional novel predictions that enrich the opportunities for empirically testing speciation genetic theory or facets of it, such as Haldane's rule. We show that the connection between the two theories is simple and straightforward for autosomal genes but not for sex-linked genes. Differences between the two approaches highlight key conceptual issues concerning the relevance of epistasis to evolution within and among lineages and to differences in the process of speciation in hermaphrodites and in organisms with separate sexes.

Animals↗
PubMed2002

Temporal variation in divergent selection on spine number in threespine stickleback.

Short-term temporal cycles in ecological pressures, such as shifts in predation regime, are widespread in nature yet estimates of temporal variation in the direction and intensity of natural selection are few. Previous work on threespine stickleback (Gasterosteus aculeatus) has revealed that dorsal and pelvic spines are a defense against gape-limited predators but may be detrimental against grappling insect predators. In this study, we examined a 15-year database from an endemic population of threespine stickleback to look for evidence of temporal shifts in exposure to these divergent predation regimes and correlated shifts in selection on spine number. For juveniles, we detected selection for increased spine number during winter when gape-limited avian piscivores were most common but selection for decreased spine number during summer when odonate predation was more common. For subadults and adults, which are taken primarily by avian piscivores, we predicted selection should generally be for increased spine number in all seasons. Among 59 comparisons, four selection differentials were significant (Bonferroni corrected) and in the predicted direction. However, there was also substantial variability in remaining differentials, including two examples with strong selection for spine reduction. These reversals were associated with increased tendency of the fish to shift to a benthic niche, as determined from examination of stomach contents. These dietary data suggest that increased encounter rates with odonate predation select for spine reduction. Strong selection on spine number was followed by changes in mean spine number during subsequent years and a standard quantitative genetic formula revealed that spine number has a heritable component. Our results provide evidence of rapid morphological responses to selection from predators and suggest that temporal variation in selection may help maintain variation within populations. Furthermore, our findings indicate that variable selection can be predicted if the agents of selection are known.

Animals↗
PubMed2001

Population mixing and the adaptive divergence of quantitative traits in discrete populations: a theoretical framework for empirical tests.

Empirical tests for the importance of population mixing in constraining adaptive divergence have not been well grounded in theory for quantitative traits in spatially discrete populations. We develop quantitative-genetic models to examine the equilibrium difference between two populations that are experiencing different selective regimes and exchanging individuals. These models demonstrate that adaptive divergence is negatively correlated with the rate of population mixing (m, most strongly so when m is low), positively correlated with the difference in phenotypic optima between populations, and positively correlated with the amount of additive genetic variance (G, most strongly so when G is low). The approach to equilibrium is quite rapid (fewer than 50 generations for two populations to evolve 90% of the distance to equilibrium) when either heritability or mixing are not too low (h2 > 0.2 or m > 0.05). The theory can be used to aid empirical tests that: (1) compare observed divergence to that predicted using estimates of population mixing, additive genetic variance/covariance, and selection; (2) test for a negative correlation between population mixing and adaptive divergence across multiple independent population pairs; and (3) experimentally manipulate the rate of mixing. Application of the first two of these approaches to data from two well-studied natural systems suggests that population mixing has constrained adaptive divergence for color patterns in Lake Erie water snakes (Nerodia sipedon), but not for trophic traits in sympatric pairs of benthic and limnetic stickleback (Gasterosteus aculeatus). The theoretical framework we outline should provide an improved basis for future empirical tests of the role of population mixing in adaptive divergence.

Adaptation, Physiological↗
PubMed1999

Estimating linkage disequilibrium between a polymorphic marker locus and a trait locus in natural populations.

Positional cloning of gene(s) underlying a complex trait requires a high-resolution linkage map between the trait locus and genetic marker loci. Recent research has shown that this may be achieved through appropriately modeling and screening linkage disequilibrium between the candidate marker locus and the major trait locus. A quantitative genetics model was developed in the present study to estimate the coefficient of linkage disequilibrium between a polymorphic genetic marker locus and a locus underlying a quantitative trait as well as the relevant genetic parameters using the sample from randomly mating populations. Asymptotic covariances of the maximum-likelihood estimates of the parameters were formulated. Convergence of the EM-based statistical algorithm for calculating the maximum-likelihood estimates was confirmed and its utility to analyze practical data was exploited by use of extensive Monte-Carlo simulations. Appropriateness of calculating the asymptotic covariance matrix in the present model was investigated for three different approaches. Numerical analyses based on simulation data indicated that accurate estimation of the genetic parameters may be achieved if a sample size of 500 is used and if segregation at the trait locus explains not less than a quarter of phenotypic variation of the trait, but the study reveals difficulties in predicting the asymptotic variances of these maximum-likelihood estimates. A comparison was made between the statistical powers of the maximum-likelihood analysis and the previously proposed regression analysis for detecting the disequilibrium.

Genetic Markers↗
PubMed1977

Genetic studies in outpatients: plasma cholesterol in family and twin studies.

Quantitative genetic studies have much potential in partitioning the causes of variation of quantitative traits such as risk factors for atherosclerosis. Only if specific causes of variation are identified can specific therapy be developed to modify risks. There have been extensive family studies of plasma cholesterol which reveal that the level of plasma cholesterol is correlated in family members. However, except for the relatively rare familial hypercholesterolemia the evidence is not convincing that correlations of relatives are due to genetic rather than environmental factors. Early twin studies were interpreted as supporting the hypothesis that levels of plasma cholesterol were strongly influenced by genetic factors. However a recent large study of twins cast doubt upon this hypothesis by finding no significant genetic variance of plasma cholesterol after correcting for differences in total variance of monozygotic and dizygotic twins.

Arteriosclerosis↗