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PubMed2006

Genome-wide scan reveals that genetic variation for transcriptional plasticity in yeast is biased towards multi-copy and dispensable genes.

One of the most important aspects of the evolution of development and physiology is the interplay between gene expression and the environment, by which traits become altered in response to environmental triggers. This feature is known as phenotypic plasticity. When different genotypes show different levels of plasticity for a trait, then they show genotype-by-environment interaction, or GEI. It is now clear that gene expression plays an important role in organismic-level phenotypic plasticity, but we know very little about whether gene expression itself is subject to genetic variation for phenotypic plasticity (GEI). Given that gene regulation is likely to have evolved to respond to environmental changes, it is of central importance to understand how environmental and genetic variation interact to produce variation in gene expression. Here we investigate genetic variation for phenotypic plasticity in the yeast transcriptome for the whole genome. Six strains of Saccharomyces cerevisiae were grown in four different environments representing a continuum of rich and poor natural conditions. Using DNA-microarray data and an ANOVA analysis with a stringent criterion of significance, we found significant genetic variation for transcriptional plasticity (GEI) among strains for approximately 5% of the genes in the genome. There are about twice as many genes that show genetic variation for phenotypic plasticity as show genetic variation in transcription level independent of the environment. We also found that genes with genetic variation for plasticity were less likely to be essential and were significantly biased towards genes that have paralogs.

Adaptation, Physiological↗

PubMed2005

Reduction of observer variation using matched CT-PET for lung cancer delineation: a three-dimensional analysis.

PURPOSE: Target delineation using only CT information introduces large geometric uncertainties in radiotherapy for lung cancer. Therefore, a reduction of the delineation variability is needed. The impact of including a matched CT scan with 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) and adaptation of the delineation protocol and software on target delineation in lung cancer was evaluated in an extensive multi-institutional setting and compared with the delineations using CT only. METHODS AND MATERIALS: The study was separated into two phases. For the first phase, 11 radiation oncologists (observers) delineated the gross tumor volume (GTV), including the pathologic lymph nodes of 22 lung cancer patients (Stages I-IIIB) on CT only. For the second phase (1 year later), the same radiation oncologists delineated the GTV of the same 22 patients on a matched CT-FDG-PET scan using an adapted delineation protocol and software (according to the results of the first phase). All delineated volumes were analyzed in detail. The observer variation was computed in three dimensions by measuring the distance between the median GTV surface and each individual GTV. The variation in distance of all radiation oncologists was expressed as a standard deviation. The observer variation was evaluated for anatomic regions (lung, mediastinum, chest wall, atelectasis, and lymph nodes) and interpretation regions (agreement and disagreement; i.e., >80% vs. <80% of the radiation oncologists delineated the same structure, respectively). All radiation oncologist-computer interactions were recorded and analyzed with a tool called "Big Brother." RESULTS: The overall three-dimensional observer variation was reduced from 1.0 cm (SD) for the first phase (CT only) to 0.4 cm (SD) for the second phase (matched CT-FDG-PET). The largest reduction in the observer variation was seen in the atelectasis region (SD 1.9 cm reduced to 0.5 cm). The mean ratio between the common and encompassing volume was 0.17 and 0.29 for the first and second phases, respectively. For the first phase, the common volume was 0 in 4 patients (i.e., no common point for all GTVs). In the second phase, the common volume was always >0. For all anatomic regions, the interpretation differences among the radiation oncologists were reduced. The amount of disagreement was 45% and 18% for the first and second phase, respectively. Furthermore, the mean delineation time (12 vs. 16 min, p<0.001) and mean number of corrections (25 vs. 39, p<0.001) were reduced in the second phase compared with the first phase. CONCLUSION: For high-precision radiotherapy, the delineation of lung target volumes using only CT introduces too great a variability among radiation oncologists. Implementing matched CT-FDG-PET and adapted delineation protocol and software reduced observer variation in lung cancer delineation significantly with respect to CT only. However, the remaining observer variation was still large compared with other geometric uncertainties (setup variation and organ motion).

Aged↗

PubMed2005

Comparative losses of quantitative and molecular genetic variation in finite populations of Drosophila melanogaster.

Quantitative genetic variation, the main determinant of the ability to evolve, is expected to be lost in small populations, but there are limited data on the effect, and controversy as to whether it is similar to that for near neutral molecular variation. Genetic variation for abdominal and sternopleural bristle numbers and allozyme heterozygosity were estimated in 23 populations of Drosophila melanogaster maintained at effective population sizes of 25, 50, 100, 250 or 500 for 50 generations, as well as in 19 highly inbred populations and the wild outbred base population. Highly significant negative regressions of proportion of initial genetic variation retained on inbreeding due to finite population size were observed for both quantitative characters (b = -0.67 +/- 0.14 and -0.58 +/- 0.11) and allozyme heterozygosity (b = -0.79 +/- 0.10), and the regression coefficients did not differ significantly. Thus, quantitative genetic variation is being lost at a similar rate to molecular genetic variation. However, genetic variation for all traits was lost at rates significantly slower than predicted by neutral theory, most likely due to associative overdominance. Positive, but relatively low correlations were found among the different measures of genetic variation, but their low magnitudes were attributed to large sampling errors, rather than differences in the underlying processes of loss.

Animals↗

PubMed2002

Structure of variation in enzyme activity in natural Drosophila melanogaster populations.

Enzyme activity variation was assessed in several isofemale lines originating from two Hungarian Drosophila melanogaster populations. Samples from each population were taken from from two villages; 8-9 isofemale lines were established from each village. The activities of ADH, alphaGPDH, IDH and 6PGDH were determined in the adults (in the F1 generation) and in the larvae (in the F3 generation) as well. Enzyme activities were measured on starch gel after electrophoresis. The activity of the enzyme was detected in a single individual and it was also possible to determine its genotype. The results showed that most of the variation occurred within sites for all four enzymes. This within site variation was more or less equally partitioned into within and between isofemale line (family) components. A smaller portion of variation was attributable to the differences between the populations. Nevertheless, adult alphaGPDH, and larval IDH and 6PGDH activities exhibited significant differences between the two populations. Variation in larval activities of all enzymes was higher than that of the adults, but 6PGDH had considerably higher variation in the adults. The greater variation in larval activities probably reflected the greater environmental variation in the microhabitat of the larvae compared to that of the adults. Larval activities of the investigated enzymes showed much stronger correlation than adult activities. The correlation pattern in the adults differed greatly between the two populations.

Animals↗

PubMed1990

Molecular and phenotypic variation in the achaete-scute region of Drosophila melanogaster.

Variation in quantitative characters underlies much adaptive evolution and provides the basis for selective improvement of domestic species, yet the genetic nature of quantitative variation is poorly understood. Many loci affecting quantitative traits have been identified by the segregation of mutant alleles with major qualitative effects. These alleles may represent an extreme of a continuum of allelic effects, and most quantitative variation could result from the segregation of alleles with subtle effects at loci identified by alleles with major effects. The achaete-scute complex in Drosophila melanogaster plays a central part in bristle development and has been characterized at the molecular level. The hypothesis that naturally occurring quantitative variation in bristle number could be associated with wild-type alleles of achaete-scute was tested by correlating phenotypic variation in bristle number with molecular variation in restriction maps in this region among chromosomes extracted from natural populations. DNA insertion variation in the achaete-scute region was found to be strongly associated with variation in bristle number.

Alleles↗

PubMed2004

Natural variation in cardiac metabolism and gene expression in Fundulus heteroclitus.

Individual variation in gene expression is important for evolutionary adaptation and susceptibility to diseases and pathologies. In this study, we address the functional importance of this variation by comparing cardiac metabolism to patterns of mRNA expression using microarrays. There is extensive variation in both cardiac metabolism and the expression of metabolic genes among individuals of the teleost fish Fundulus heteroclitus from natural outbred populations raised in a common environment: metabolism differed among individuals by a factor of more than 2, and expression levels of 94% of genes were significantly different (P < 0.01) between individuals in a population. This unexpectedly high variation in metabolic gene expression explains much of the variation in metabolism, suggesting that it is biologically relevant. The patterns of gene expression that are most important in explaining cardiac metabolism differ between groups of individuals. Apparently, the variation in metabolism seems to be related to different patterns of gene expression in the different groups of individuals. The magnitude of differences in gene expression in these groups is not important; large changes in expression have no greater predictive value than small changes. These data suggest that variation in physiological performance is related to the subtle variation in gene expression and that this relationship differs among individuals.

Animals↗

PubMed2002

Patterned variation in murine MHC promoters.

To compare variation in regulatory and coding DNA, promoter sequences have been obtained from wild-derived mice and laboratory rats. The sequences are from the proximal promoter of the H2Aa, H2Ab, H2Eb, and H2K genes of 24 wild-derived inbred strains and a sample of the corresponding exon 2 sequences and of the RT1.Ba gene of six strains of laboratory rat. They reveal a high level of variation in the mouse MHC class II promoters (H2A and H2E), a low level in MHC class I (H2K), and none in the rat. The variation is pronounced in and around the cAMP response element, a major binding site for modulating promoter activity in response to external stimulation. This finding, together with the different levels of variation in MHC classes I and II, is suggestive of natural selection. However, selection operating via the MHC coding sequences must also contribute, as indicated by the minimal variation in both the MHC class II promoter and coding sequences of the rat. Furthermore CIITA (trans-activator of class II) of the mouse has been reported to have minimal variation in its promoter and none in its coding sequence. Taken together these data suggest that the regulatory and coding sequences undergo coselection. Each of the mouse class II promoters has a pattern of variation that appears to be basically dimorphic, with further variation added by recombination/mutation. The dimorphic allelic lineages are in marginally detectable linkage disequilibrium with the exon 2 sequences, particularly in H2Aa, thus lending further support to the coevolution hypothesis.

Amino Acid Sequence↗

PubMed1976

Darwin's finches: population variation and natural selection.

Van Valen's model, which relates morphological variation to ecological variation in an adaptive scheme, was investigated with individually marked and measured Darwin's finches on two adjacent Galápagos islands, Santa Cruz and Daphne Major. Results show that environmental heterogeneity is correlated with large continuous, morphological variation: variation in bill dimensions of Geospiza fortis is greater on Santa Cruz than on Daphne, as is environmental heterogeneity. Within populations of this species, different phenotypes distribute themselves in different habitat patches, select foods of different sizes and hardness, and exploit them with efficiencies that are phenotype- (bill size) dependent. These data constitute indirect evidence that natural selection has a controlling influence over the level of phenotypic variation exhibited by a population. Further evidence is that phenotypes did not survive equally well during the study period; on Daphne island G. fortis was apparently subjected to directional selection on bill tip length and G. scandens to normalizing selection on body weight and bill depth. Other factors which may have contributed to the establishment of a difference in variation between Santa Cruz and Daphne populations are the founder effect, genetic drift, and assortative mating. Annual climatic unpredictability is considered a source of environmental heterogeneity which, through its effect upon food supply, favors large morphological variation. It is predicted that species of large individual size are more influenced by this than are small species, and consequently exhibit greater size-corrected variation. The prediction is tested with data from six Geospiza species, and found to be correct.

Adaptation, Biological↗

PubMed1982

Genetic variation in natural populations: problem of electrophoretically cryptic alleles.

Electrophoretic studies have shown that the average frequency of heterozygous loci per individual is about 12% in Drosophila and other invertebrates and about 6% in vertebrates. It is estimated that only about two-thirds of all amino acid substitutions change net electric charge; hence, a large fraction of all genetic variation may be undetected by electrophoresis. Peptide mapping of 11 independent alleles coding for alcohol dehydrogenase in Drosophila melanogaster has uncovered one cryptic variant; thus, the frequency of electrophoretically cryptic variation is apparently low, about 9% in this sample. Nevertheless, with a simple model it is shown that this degree of cryptic variation, if it is typical of other loci, would substantially change our current estimates of genetic variation: the average heterozygosity would increase from about 12% to about 25% for invertebrates and from about 6% to 21% for vertebrates. A variety of techniques--including sequential electrophoresis and heat or urea denaturation--have been used by various investigators to detect electrophoretically cryptic variation. These techniques appear to be less effective than peptide mapping for detecting cryptic variation, but, like peptide mapping, they suggest that standard electrophoresis may detect most of the protein variation present in natural populations. The charge-state model of protein variation proposes that the "alleles" detected by electrophoresis are extremely diverse classes consisting of many electrophoretically cryptic alleles. The alcohol dehydrogenase peptide-mapping results are inconsistent with the charge-state model.

Alleles↗

PubMed2003

Biological variation of soluble CD163.

A soluble plasma form of CD163 (sCD163) was recently identified. The protein has anti-inflammatory effects in vitro and is elevated in patients with myelo-monocytic leukaemia and infection. For rational use and evaluation of this potential new quantity it is important to have knowledge of its biological variability and to use a methodology that has a sufficiently analytical quality. The day-to-day and diurnal biological variabilities of sCD163 were studied in 12 healthy people using a sandwich ELISA. The within-run-, between run- and total analytical coefficients of variation were estimated to 3.6%, 4.8% and 6.0%, respectively. The day-to-day within-subject biological variation was estimated to 9.0%, and the between-subject biological variation to 35.9%. A diurnal variation in sCD163 concentrations with 14% lower values in the night (supine position) was observed. The ratio between total analytical variation and within-subject biological variation was 0.67. The index of individuality, calculated as the ratio between within-subject biological variation and between-subject biological variation, was low and similar to complement factors and immunoglobulins. A low index of individuality is important in a monitoring situation where small changes from the set point of the individual can be detected in serial measurements. For this purpose, the critical difference for a series of results in the same patient (significant at p < 0.05) was calculated to 30% for samples taken on different days and measured in separate runs.

Aged↗

PubMed2003

Gene expression variation in the adult human retina.

Despite evidence that differences in gene expression levels contribute significantly to phenotypic variation across individuals, there has been only limited effort to study gene expression variation in human tissue. To characterize expression variation in the normal human retina, we utilized a custom retinal microarray to analyze 33 normal retinas from 19 donors, aged 29-90 years. Statistical models were designed to separate and quantify biological and technical sources of variation, including age, gender, eye laterality, gene function and age-by-gender interaction. Although the majority of the 9406 genes analyzed showed relatively stable expression levels across different donors (for an average gene the expression level value of 95 out of a 100 individuals fell within a 1.23-fold range), 2.6% of genes showed significant donor-to-donor variation, with a false discovery rate of 10%. The mean expression ratio standard deviation was 0.15+/-0.8, log2, with a range of 0.09-0.99. Genes selectively expressed in photoreceptors showed higher expression variation than other gene classes. Gender, age and other donor-specific factors contributed significantly to the expression variation of multiple genes, and groups of genes with an age- and gender-associated expression pattern were identified. Our findings show that a significant fraction of gene expression variation in the normal human retina is attributable to identifiable biological factors. The greater expression variability of many genes central to retinal function (including photoreceptor-specific genes) may be partially explained by the dynamics of the vision process, and raises the possibility that photoreceptor gene expression levels may contribute to phenotypic diversity across normal adult retinas. In addition, as such diversity may result in different levels of disease susceptibility, exploring its sources may provide insights into the pathogenesis of retinal disease.

Adult↗

PubMed1995

Variation in tolerance to Bacillus thuringiensis among and within populations of the spruce budworm (Lepidoptera: Tortricidae) in Ontario.

Variation in tolerance to Bacillus thuringiensis Berliner subsp. kurstaki (strain HD-1-S-1980) among and within populations of the spruce budworm, Choristoneura fumiferana (Clemens), was assessed in the laboratory. Force-feeding assays using offspring of females collected as pupae from nine locations throughout Ontario and from a laboratory colony (DCF) demonstrated limited variation in tolerance among populations. Variation among populations was comparable with the variation observed among repeated assays with different batches of larvae from the DCF colony. Population LC50s were not significantly associated with age of the outbreak, host-plant species, incidence of the microsporidian Nosema fumiferanae (Thomson), or size of the female parent. Upper limits for genetic variation in tolerance were estimated by examining variation among full-sibling families within same populations. Mortality of individual families ranged from 6.5 to 70.9% within five field populations and from 2.7 to 93.3% within two laboratory colonies in response to a dose that caused a mean mortality of 40%. Familial factors accounted for 32.8% of the phenotypic variation in response across field populations, as compared with 3% for population factors. These data suggest that the phenotypic variation in tolerance to B. thuringiensis has a substantial genetic component and may provide a basis for evolution of resistance given sufficient selection pressure.

Animals↗

PubMed1996

Regional variations of ultrasonic integrated backscatter in normal and myopathic left ventricles. A new multi-view approach.

The purpose of the present study was to determine whether the cyclic variation of integrated backscatter is measurable and quantifiable in all left ventricular walls and whether the information obtained using both parasternal and apical transducer positions can be used to identify changes in myocardial structure and contractility. The cyclic variation of integrated backscatter was measured from the parasternal long-axis, apical four-chamber and two-chamber views in 26 patients with idiopathic dilated cardiomyopathy (mean age 58 +/- 9 years; ejection fraction 29 +/- 10%) and compared with information obtained from 30 aged-matched healthy volunteers. For each subject, the cyclic variation of integrated backscatter was calculated from 16 predetermined regions-of-interest located within the myocardium of the basal and mid-segments of the left ventricle imaged from the long-axis view and also the basal mid and apical left ventricular segments imaged from the two apical views. The cyclic variation of integrated backscatter was found to be present in 100% of the analysed regions-of-interest in healthy volunteers and in 87.5% of the analysed regions-of-interest in patients with idiopathic dilated cardiomyopathy. The mean value of cyclic variation of integrated backscatter, averaged from all regions-of-interest in the idiopathic dilated cardiomyopathy group, was significantly reduced compared to that in the healthy volunteers group (3.2 +/- 2.5 dB [mean +/- SD] vs 4.8 +/- 2.9 dB, P < 0.0001). Additionally, the healthy volunteers group demonstrated marked regional variability in the magnitude of cyclic variation of integrated backscatter which closely followed the regional changes in the contractile function of the normal heart. These regional differences in the magnitude of the cyclic variation of integrated backscatter were only partially retained in the idiopathic dilated cardiomyopathy group, and suggest that a multi-view approach of the recording of cyclic variation of integrated backscatter can be of value to differentiate normal from myopathic myocardium and to quantify regional differences in myocardial contractile performance throughout the left ventricular walls.

Adult↗

PubMed1991

Ribosomal DNA variation within and between species of rodents, with emphasis on the genus Onychomys.

Patterns of restriction-endonuclease site and length variation at the nuclear rDNA locus (18S + 28S rRNA gene complex) were examined in rodents. Of the 164 restriction sites mapped for seven species, 22 were conserved (mapping to the 18S, 28S, and 5.8S genes and ITS1) in all three Onychomys species as well as in Mus musculus and in three closely related peromyscine rodents, Peromyscus boylii, P. eremicus, and Reithrodontomys megalotis. The nontranscribed spacer (NTS) region revealed most of the variation among these taxa, with the patterns of variation grouping into the following categories, (1) intraindividual variation revealing as many as four site-specific repeat types within an individual, (2) intraspecific and interspecific site variation confined to the NTS, and (3) length variation in both the transcribed and NTS regions. Length variation in the 28S rRNA gene was also examined in 17 additional rodent species, and most size differences mapped to the divergent domain, D8, found in sequence comparisons between Mus and Rattus. The systematic implications of rDNA variation are discussed using the perspective gained from these rodent comparisons.

Animals↗

PubMed1997

Variability of the refractive state: meridional profiles and uniform variation.

Variation of the refractive state as measured with autorefraction is the result of many factors which need to be considered if optometry is to develop a more complete understanding of the behavior of the visual process. Various methods can be applied to develop such an understanding including scatter plots, meridional profiles of variance-covariance, and graphs of uniform variation. These methods are used, in this paper, to investigate some results for autorefraction from a sample of 106 university students studying optometry. Some of the eyes in the sample display variation, some or all of whose characteristics are the same in all meridians of the eye. Such eyes are said to exhibit refractive variation that is partially or completely uniform across the meridians of the eye. Most eyes, however, show variation which appears to depart from uniformity. The typical eye in the sample appears to exhibit variation that is mainly spherical in character and of a small magnitude in keeping with the view that the accommodative system mostly is responsible for this variation. Nevertheless, there is an astigmatic component to the variation. The mean variance-covariance matrices for the right and left eyes are presented.

Accommodation, Ocular↗

PubMed2002

Evolution in the real world: stochastic variation and the determinants of fitness in Carlina vulgaris.

Empirical studies of life histories often ignore stochastic variation, despite theoretical demonstrations of its potential impact on life-history evolution. Here we use a novel approach to explore the effects of stochastic variation on life-history evolution and estimate the selection pressures operating on the monocarpic perennial Carlina vulgaris, in which flowering may be delayed by up to eight years. The approach is novel in that we use modern theoretical techniques to estimate selection pressures and the fitness landscape from a fully parameterised individual-based model. These approaches take into account temporal variation in demographic rates and density dependence. Analysis of 16 years' data revealed significant temporal variation in growth, mortality, and recruitment in our study population. Flowering was strongly size dependent and, unusually for such a species, also age dependent. Individual-based models of the flowering strategy, parameterized using field data, consistently underestimated the size at flowering, when temporal variation in demographic rates was ignored. In contrast, models that incorporated temporal variation in growth, mortality, and recruitment predicted sizes at flowering not significantly different from those observed in the field. Temporal variation in mortality, which had the largest effect on the flowering strategy, selected for increased size at flowering. An analytical approximation is presented to explain this result, extending the "1-year look-ahead criterion" presented in Rees et al. (2000). A fitness landscape generated by following the fate of rare mutant invaders with a broad range of alternative flowering strategies demonstrated that the observed parameters were adaptive. However, the fitness landscape reveals that approximately equal fitness is achieved by a broad range of strategies, providing a mechanism for the maintenance of genetic variation. To understand how the different parameters that defined our models determine the fitness of rare mutants, we numerically estimated the elasticities and sensitivities of mutant fitness. This demonstrated strong selection on a number of the parameters. Elasticities and sensitivities estimated in constant and random environments were significantly positively correlated, and both were negatively related to the standard error of the parameter. This last result is surprising and, we argue, reflects the genetic and phenotypic responses to selection.

Adaptation, Physiological↗

PubMed1995

Variation in dentists' clinical decisions.

OBJECTIVES: The first comprehensive review of the recent literature regarding variation in dentists' clinical treatment decisions is presented. METHODS: Variation among dentists in the clinical decisions they make as well as the methods used for assessing this variation are examined at three levels of aggregation of clinical decisions: the dental practice (or dentist), the patient, and the individual tooth. RESULTS: The extent to which differences in dentists' clinical decisions have been examined is limited. Studies are particularly sparse at the level of the dental practice, where the aggregate of dentists' treatment decisions is reflected. Further, the methods and measures used to assess variation tend to be different across studies, making quantification of variation difficult. Nevertheless, the available information reflects substantial variation in measures such as rates of provision of specific procedures; cost and numbers of procedures recommended for specific patients; and diagnoses, intervention decisions, and treatment selections for individual teeth. CONCLUSIONS: Even when differences in patients are controlled, variation in dentists' clinical decisions is ubiquitous. While its consequences remain undetermined, the variation in basic clinical decisions such as caries diagnosis signals the need to consider the extent to which the appropriateness of care is affected.

Decision Making↗

PubMed2004

Phase and antigenic variation in bacteria.

Phase and antigenic variation result in a heterogenic phenotype of a clonal bacterial population, in which individual cells either express the phase-variable protein(s) or not, or express one of multiple antigenic forms of the protein, respectively. This form of regulation has been identified mainly, but by no means exclusively, for a wide variety of surface structures in animal pathogens and is implicated as a virulence strategy. This review provides an overview of the many bacterial proteins and structures that are under the control of phase or antigenic variation. The context is mainly within the role of the proteins and variation for pathogenesis, which reflects the main body of literature. The occurrence of phase variation in expression of genes not readily recognizable as virulence factors is highlighted as well, to illustrate that our current knowledge is incomplete. From recent genome sequence analysis, it has become clear that phase variation may be more widespread than is currently recognized, and a brief discussion is included to show how genome sequence analysis can provide novel information, as well as its limitations. The current state of knowledge of the molecular mechanisms leading to phase variation and antigenic variation are reviewed, and the way in which these mechanisms form part of the general regulatory network of the cell is addressed. Arguments both for and against a role of phase and antigenic variation in immune evasion are presented and put into new perspective by distinguishing between a role in bacterial persistence in a host and a role in facilitating evasion of cross-immunity. Finally, examples are presented to illustrate that phase-variable gene expression should be taken into account in the development of diagnostic assays and in the interpretation of experimental results and epidemiological studies.

Amino Acid Sequence↗