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PubMed1996

Naturally occurring variation in copia expression is due to both element (cis) and host (trans) regulatory variation.

Significant differences in levels of copia [Drosophila long terminal repeat (LTR) retrotransposon] expression exist among six species representing the Drosophila melanogaster species complex (D. melanogaster, Drosophila mauritiana, Drosophila simulans, Drosophila sechellia, Drosophila yakuba, and Drosophila erecta) and a more distantly related species (Drosophila willistoni). These differences in expression are correlated with major size variation mapping to putative regulatory regions of the copia 5' LTR and adjacent untranslated leader region (ULR). Sequence analysis indicates that these size variants were derived from a series of regional duplication events. The ability of the copia LTR-ULR size variants to drive expression of a bacterial chloramphenicol acetyltransferase reporter gene was tested in each of the seven species. The results indicate that both element-encoded (cis) and host-genome-encoded (trans) genetic differences are responsible for the variability in copia expression within and between Drosophila species. This finding indicates that models purporting to explain the dynamics and distribution of retrotransposons in natural populations must consider the potential impact of both element-encoded and host-genome-encoded regulatory variation to be valid. We propose that interelement selection among retrotransposons may provide a molecular drive mechanism for the evolution of eukaryotic enhancers which can be subsequently distributed throughout the genome by retrotransposition.

Animals↗

PubMed1991

Associations between DNA sequence variation and variation in expression of the Adh gene in natural populations of Drosophila melanogaster.

A large part of the genetic variation in alcohol dehydrogenase (ADH) activity level in natural populations of Drosophila melanogaster is associated with segregation of an amino acid replacement polymorphism at nucleotide 1490, which generates a difference in electrophoretic mobility. Part of the allozymic difference in activity level is due to a catalytic efficiency difference, which is also caused by the amino acid replacement, and part is due to a difference in the concentration of ADH protein. A previous site-directed in vitro mutagenesis experiment clearly demonstrated that the amino acid replacement has no effect on the concentration of ADH protein, nor does a strongly associated silent polymorphism at nucleotide 1443. Here we analyze associations between polymorphisms within the Adh gene and variation in ADH protein level for a number of chromosomes derived from natural populations. A sequence length polymorphism within the first intron of the distal (adult) transcript, 1, is in strong linkage disequilibrium with the amino acid replacement. Among a sample of 46 isochromosomal lines analyzed, all but one of the 14 Fast lines have 1 and all but one of the 32 Slow lines lack 1. The exceptional Fast line has an unusually low level of ADH protein (typical of Slow lines) and the exceptional Slow line has an unusually high level (typical of Fast lines). These results suggest that the 1 polymorphism may be responsible for the average difference in ADH protein between the allozymic classes. A previous experiment localized the effect on ADH protein to a 2.3-kb restriction fragment. DNA sequences of this fragment from several alleles of each allozymic type indicate that no other polymorphisms within this region are as closely associated with the ADH protein level difference as the 1 polymorphism.

Alcohol Dehydrogenase↗

PubMed1996

Association of genetic variation with interindividual variation in ambulatory blood pressure.

OBJECTIVE: To determine whether genetic and non-genetic components of interindividual variation in systolic and diastolic blood pressure are constant throughout the day or are time or activity dependent. METHODS: We obtained 24 h ambulatory blood pressure recordings in 263 members of 68 unrelated nuclear families (i.e. parents and their offspring) representative of the Caucasian population of Rochester, MN, USA. Using the time each patient got into bed as a reference point, we identified 198 records in which this reference point was preceded by eight consecutive active hours (out of bed) and followed by four consecutive inactive hours (in bed) in which four or more blood pressure readings taken each hour were judged to be technically satisfactory. For each hourly mean for systolic and diastolic blood pressure, we estimated total interindividual variance, variance associated with concomitant variables (generation; sex within generation strata; and age, height, weight, body mass index, and abdomen-to-hip ratio within generation and sex strata), and variance associated with additive genetic effects (i.e. the chief cause of resemblance between relatives). To assess trends in each component of interindividual blood pressure variance over the 12 h period, we estimated the slope of the linear regression line fit to the hourly estimates. RESULTS: For systolic blood pressure, total interindividual variance did not change significantly (slope of regression line = -0.23, P = 0.717). In contrast, total interindividual variance for diastolic blood pressure was greater during active hours than inactive hours (slope of regression line = -5.53, P < 0.001). For both systolic and diastolic blood pressure, variance associated with the concomitant variables was greater during active hours than during inactive hours (for systolic blood pressure slope of regression line = -2.98, P = 0.001; for diastolic blood pressure slope of regression line = -6.14, P < 0.001). Likewise, for both systolic and diastolic blood pressure, variance associated with additive genetic effects was also greater during active hours than during inactive hours (for systolic blood pressure slope of regression line = -1.65, P = 0.090; for diastolic blood pressure slope of regression line = -1.47, P = 0.018). CONCLUSIONS: This study demonstrates that components of interindividual variation in blood pressure are not constant, but are time or activity dependent.

Adolescent↗

PubMed2001

No impact of blood pressure variability on microalbuminuria and left ventricular geometry: analysis of daytime variation, diurnal variation and 'white coat' effect.

OBJECTIVE: To investigate the influence of blood pressure variability on target organ involvement. METHODS: Using a cross-sectional study of a hypertension clinic at a district general hospital, 420 patients with newly diagnosed untreated essential hypertension referred on a consecutive basis from general practice and 146 normal subjects drawn at random from the Danish National Register underwent a variety of measurements which included: echocardiography with determination of left ventricular mass index and relative wall thickness and early morning urine albumin/creatinine ratio. Mean, standard deviation and coefficient of variation of automated clinic values; daytime, night-time and full 24-h period were extracted from 24-h ambulatory blood pressure (ABP) monitoring. 'White coat' effect and dip were calculated. Hypertensives were classified into subjects with high or low variability, into 'white coat' hypertensives or established hypertensives and into dippers or non-dippers. RESULTS: Standard deviation of daytime blood pressure (BP) was positively associated with target organ damage and BP level, which was not the case when variability was expressed as a coefficient of variation. Patients with high variability exhibited no more significant target organ damage than patients with low variability, but patients with established hypertension had significantly more target organ damage than the 'white coat' hypertensives. The 'white coat' effect as such was not associated with increased target organ involvement. Non-dippers had significantly more cardiac target organ damage than dippers, but the difference disappeared after correction for different 24-h BP level. CONCLUSION: BP variability data obtained by non-invasive ABP monitoring does not seem to improve the information inherent in the BP level.

Adult↗

PubMed2006

Variation in the epigenetic silencing of FLC contributes to natural variation in Arabidopsis vernalization response.

Vernalization, the cold-induced acceleration of flowering, involves the epigenetic silencing of the floral repressor gene FLOWERING LOCUS C (FLC). We investigated the molecular basis for variation in vernalization in Arabidopsis natural accessions adapted to different climates. A major variable was the degree to which different periods of cold caused stable FLC silencing. In accessions requiring long vernalization, FLC expression was reactivated following nonsaturating vernalization, but this reactivation was progressively attenuated with increasing cold exposure. This response was correlated with the rate of accumulation of FLC histone H3 Lys 27 trimethylation (H3K27me3). Thus, variation in epigenetic silencing of FLC appears to have contributed to Arabidopsis adaptation.

Alleles↗

PubMed2005

Nucleotide variation at the myrosinase-encoding locus, TGG1, and quantitative myrosinase enzyme activity variation in Arabidopsis thaliana.

The Arabidopsis thaliana TGG1 gene encodes thioglucoside glucohydrolase (myrosinase), an enzyme catalysing the hydrolysis of glucosinolate compounds. The enzyme is involved in plant defence against some insect herbivores, and is present in species of the order Capparales (Brassicales). Nucleotide variation was surveyed by sequencing c. 2.4 kb of the TGG1 locus in a sample of 28 worldwide A. thaliana accessions, and one Arabidopsis lyrata ssp. lyrata individual. Myrosinase activity was quantified for 27 of these same A. thaliana accessions, plus five additional others. Overall, estimated nucleotide diversity in A. thaliana was low compared to other published A. thaliana surveys, and the frequency distribution was skewed toward an excess of low-frequency variants. Furthermore, comparison to the outgroup species A. lyrata demonstrated that A. thaliana exhibited an excess of high-frequency derived variants relative to a neutral equilibrium model, suggesting a selective sweep. A. thaliana accessions differed significantly in total myrosinase activity, but analysis of variance detected no statistical evidence for an association between quantitative enzyme activity and alleles at the TGG1 myrosinase-encoding locus. We thus conclude that other, unsurveyed factors primarily affect the observed myrosinase activity levels in this species. The pattern of nucleotide variation was consistent with a model of positive selection but might also be compatible with a completely neutral model that takes into account the metapopulation behaviour of this highly inbreeding species which experienced a relatively recent worldwide expansion.

Arabidopsis↗

PubMed2005

Genetic variation at the human alpha2B-adrenergic receptor locus: role in blood pressure variation and yohimbine response.

Exaggerated response to alpha2-adrenergic receptor (alpha2-AR) blockade by yohimbine in normotensive subjects is an intermediate phenotype that predicts increased risk for development of hypertension. Here, we assessed the 3 alpha2-AR loci (alpha2A, alpha2B, alpha2C) as candidate genes for their influence on baseline and yohimbine-mediated increase in mean arterial pressure. Because initial results with 173 individuals implicated a possible association of yohimbine response with genetic variation at a site in the alpha2B-AR gene, but not at sites in the other 2 alpha2-AR, we sequenced the alpha2B-AR gene (4.4 kb, including 1.2 kb upstream and 1.9 kb distal to the coding sequence) in those subjects and an additional 81 individuals to search for other alpha2B-AR variants. We identified 25 polymorphisms, of which 14 are previously unreported, and 2 major haplotypes that differ by the presence/absence of a 9-bp in-frame deletion that encodes Glu301 to Glu303. Frequency differences in haplotypes were observed between blacks and whites but did not predict response to yohimbine. Genotyping of 2 additional white cohorts, including 1269 individuals with extremes in blood pressure selected from >50,000 subjects, also failed to reveal an association of the 2 major alpha2B-AR haplotypes with differences in blood pressure. Thus, despite considerable polymorphism in alpha2-AR genes, such variation is not a major determinant of variability in yohimbine response and by inference, in susceptibility to essential hypertension.

Adrenergic alpha-Antagonists↗

PubMed2002

Variations in abundance: genome-wide responses to genetic variation and vice versa.

How do naturally occurring polymorphisms in DNA sequence relate to variation in gene expression? Recent work to map genetic sources of expression variation has shown a surprising balance between cis and trans effects. Other work suggests some chromosomal clustering of genes by expression pattern. A synthesis of approaches may provide new insight in to adaptive mechanisms in evolution and the population basis of complex traits.

Animals↗

PubMed1996

Genetic variation of intestinal fatty acid-binding protein associated with variation in body mass in aboriginal Canadians.

We hypothesized that genomic variation affecting the primary amino acid sequence of the intestinal fatty acid-binding protein would be related to variation in body mass index and associated clinical phenotypes in aboriginal Canadians. We studied 507 adult native Canadians from an isolated community in Northern Ontario. We found that the frequency of the T54 variant of the intestinal fatty acid-binding protein gene was 0.14 in this sample. The presence of this variant was associated with significant increases in body mass index, percent body fat, and fasting plasma triglyceride concentration (P = 0.012, 0.019, and 0.012, respectively). However, the variant was not associated with the presence of diabetes mellitus. These findings suggest that the T54 variant of the intestinal fatty acid-binding protein is associated with differences in fat metabolism in this aboriginal population.

Adult↗

PubMed2004

Genetic variation in BEACON influences quantitative variation in metabolic syndrome-related phenotypes.

The BEACON gene (also known as UBL5) was identified as differentially expressed between lean and obese Psammomys obesus, a polygenic animal model of obesity, type 2 diabetes, and dyslipidemia. The human homologue of BEACON is located on chromosome 19p, a region likely to contain genes affecting metabolic syndrome-related quantitative traits as established by linkage studies. To assess whether the human BEACON gene may be involved in influencing these traits, we exhaustively analyzed the complete gene for genetic variation in 40 unrelated individuals and identified four variants (three novel). The two more common variants were tested for association with a number of quantitative metabolic syndrome-related traits in two large cohorts of unrelated individuals. Significant associations were found between these variants and fat mass (P = 0.026), percentage of fat (P = 0.001), and waist-to-hip ratio (P = 0.031). The same variants were also associated with total cholesterol (P = 0.024), LDL cholesterol (P = 0.019), triglycerides (P = 0.006), and postglucose load insulin levels (P = 0.018). Multivariate analysis of these correlated phenotypes also yielded a highly significant association (P = 0.0004), suggesting that BEACON may influence phenotypic variation in metabolic syndrome-related traits.

Adult↗

PubMed2003

Genetic parameters for within-litter variation in piglet birth weight and change in within-litter variation during suckling.

The objective of this study was to ascertain whether maternal additive genetic variance exists for within-litter variation in birth weight and for change in within-litter variation in piglet weight during suckling. A further objective was to estimate maternal genetic correlations of these two traits with mortality, birth weight, growth, and number of piglets born alive. Data were obtained from Lövsta research station, Swedish University of Agricultural Sciences, and included 22,521 piglets born in 2,003 litters by 1,074 Swedish Yorkshire sows. No cross fostering was used in the herd. The following seven traits were analysed in a multivariate animal (sow) model: number of piglets born alive, within-litter SD in birth weight, within-litter SD in piglet weight at 3 wk of age, mean weight at birth, mean weight at 3 wk of age, proportion of stillborn piglets, and proportion of dead piglets during suckling. Maternal genetic variance for the change in within-litter SD in piglet weight during suckling was assessed from the estimated additive genetic covariance components by conditioning on within-litter SD in birth weight. Similarly, mean growth of piglets during suckling was assessed from the additive genetic covariance components by conditioning on mean weight at birth. The heritability for within-litter SD in birth weight was 0.08 and 0.06 for within-litter SD in piglet weight at 3 wk. The genetic correlation between these two traits was 0.71. Little maternal genetic variance was found for the change in within-litter SD in piglet weight during suckling, and opportunity for genetic improvement of this trait by selective breeding seems limited. The genetic correlation of within-litter SD in birth weight with proportion of dead piglets during suckling was 0.25 and of within-litter SD in birth weight with mean growth of piglets was -0.31. The maternal genetic variance and heritability found for within-litter SD in birth weight indicates that genetic improvement of this trait by selective breeding is possible. In addition, selection for sows' capacity to give birth to homogeneous litters may be advantageous for piglet survival, piglet growth, and litter homogeneity at weaning.

Animals↗

PubMed1980

Relationship of strain variation and feed restriction to variation in blood pressure and response to heat stress.

The response to controlled heat stress and its relationship to blood pressure of chickens differing in body weight and subjected to feed restriction were studied. The genetic variation in body weight associated with strain differences was not related to variation in blood pressure. Blood pressure of the large weight strain was significant reduced when body weight was reduced by restriction of feed consumption, while a similar body weight reduction in a slower growing strain did not result in a decreased blood pressure. The resistance to heat stress of the strains selected for growth was significantly less than that of a slow growing randombred control strain. Restriction of feed consumption of the growth selected strains so that body weights were drastically reduced resulted in a significantly increase in resistance to heat stress.

Animals↗

PubMed1996

[Visual evaluation of liver function with 99mTc-GSA scintigraphy: interobserver variation and intraobserver variation].

We introduced a new imaging grade to evaluate liver function with 99mTc-GSA and studied its diagnostic value using interobserver variation and intraobserver variation. One hundred four patients with liver disease were injected 185 MBq/3 mg of 99mTc-GSA. Anterior images of cardiac blood-pool and liver at 5 min after injection were divided into four grades on the basis of following four categories. Faint cardiac blood-pool image, without clear demonstration of its peripheral boundary was classed in grade I; weaker cardiac blood-pool than liver was grade II; almost same appearance of blood-pool with liver was grade III and stronger blood-pool than liver was grade IV. Three radiologists reviewed the images independently. They followed the same process three months after initial evaluation. kappa-Test was employed to evaluate the goodness of agreement. Three pairs in the first reading showed excellent interobserver agreement (0.88, mean kappa-value) and another three pairs in the first and second reading also showed excellent intraobserver agreement (0.87, mean kappa-value). Quantitative indices obtained from time-activity curves for blood-pool and liver showed significant differences across four groups. Plasma retention rate of indocyanine green also showed significant difference between grade II and grade III. Imaging grade possesses high intra- and interobserver agreement and provides a good discrimination for liver function.

Adolescent↗

PubMed2002

Genetic variation and population differentiation of Michelia formosana (Magnoliaceae) based on cpDNA variation and RAPD fingerprints: relevance to post-Pleistocene recolonization.

We used sequence variation of the atpB- rbcL intergenic spacer of cpDNA and nested clade analysis to assess the phylogeographic pattern of Michelia formosana, a species restricted to Taiwan and the Ryukyus. In total, 31 haplotypes were identified and clustered into four major chlorotypes. Genetic composition of nearly all populations was heterogeneous and paraphyletic phylogenetically. Although the apportionment of cpDNA variation hardly revealed a geographic pattern due to the coancestry of dominant sequences, some chlorotypes were restrictedly distributed. According to the patterns of clade dispersion and displacement, a reconstructed minimum spanning network revealed that historical events of past fragmentation and range expansion, associated with glaciation, may have shaped the phylogeographic patterns of M. formosana. Four possible refugia were identified: the Iriomote and Ishigaki Islands (the southern Ryukyus), Wulai (northern Taiwan), and Nanjen (southern Taiwan), on the basis of the interior positions of their haplotypes in the network and the high level of nucleotide diversity. Given insufficient time for coalescence at the cpDNA locus since the late Pleistocene recolonization, lineage sorting led to low levels of genetic differentiation among populations. In contrast, hierarchical examination of the random amplified polymorphic DNA (RAPD) data scored from six populations across three geographical regions, using an analysis of molecular variance (AMOVA), indicated high genetic differentiation both among populations (Phi(ST) = 0.471) and among regions (Phi(CT) = 0.368). An unweighted pair group method with arithmetic mean (UPGMA) tree of the RAPD fingerprints revealed that populations of two offshore islands of eastern Taiwan ( M. formosana var. kotoensis) were clustered with geographically remote populations of the Ryukyus instead of those in southern Taiwan, suggesting some historical division due to geographic barriers of the central mountain range. In contrast to the paraphyly of the nearly neutral cpDNA alleles, differentiated RAPDs may have experienced diversifying selection.

Journal Article↗

PubMed1985

Diurnal variation of methotrexate transport and accumulation in hepatocytes--a consequence of variations in cellular glutathione.

Diurnal variation of the methotrexate (MTX) initial influx and net uptake in isolated rat liver cells was studied in dependence on diurnal variation of cellular glutathione. It was found that the most significant differences concerning the MTX initial transport and accumulation were observed between hepatocytes prepared at 1200 hr when cellular glutathione reached its maximum, and those isolated at 0000 hr when liver glutathione had its minimal concentration. The initial influx of MTX was the biggest in cells isolated at 0000 hr and the smallest in cells prepared at 1200 hr. The Km values in cells with low cellular glutathione (at 1800 and 0000 hr) were about three times smaller than in cells with high glutathione (at 0700 and at 1200 hr), whereas the Vmax value remained unchanged. Titration of external membrane SH groups by [203Hg]p-CMBS revealed a much larger amount of free SH groups on cells having low glutathione level than on those with high glutathione. Despite big initial influx of MTX found in cells with low cellular glutathione, net accumulation of MTX was significantly smaller in these cells as compared with hepatocytes having high glutathione level. In conclusion, the present studies confirmed a statement of the preceding paper on the important role of cellular glutathione played in methotrexate transport and accumulation in rat liver cells.

Animals↗

PubMed1977

Daily variations of various parameters of serotonin metabolism in the rat brain. II. Circadian variations in serum and cerebral tryptophan levels: lack of correlation with 5-HT turnover.

Rats submitted to regular 12 h cycles of light and darkness for three weeks were sacrificed at various times of the day. 5-HT, 5-HIAA and tryptophan levels were estimated in the fronto-parietal cerebral cortex. Tyrosine and free and total tryptophan levels in serum were estimated in parallel. Significant circadian variations in 5-HT and 5-HIAA levels were found in cerebral tissues. The peaks of 5-HIAA levels were dectected during the lignt and dark periods respectively, the maximal fluctuations being seen between 17.00 h and 21.00 h, two times separating the light off. Important significant circadian variations in free and total serum tryptophan levels were also observed. In both cases, the maximal levels were found during the middle of the dark phase after the peak of 5-HIAA levels. The circadian rhythm of tyrosine levels in serum was in opposite phase with that of tryptophan (free or total). The diurnal changes in tryptophan content in cerebral tissues seemed thus related to those found in serum. Taking in consideration results obtained in previous studies 16,17 carried out in similar experimental conditions, it was concluded that the parallel increase in serum free tryptophan and in tissues 5-HIAA levels seen during the night were not related to a stimulation of 5-HT turnover. Indeed 5-HT synthesis is minimal at this time16.

Amino Acids↗

PubMed1995

Variation in GABA mini amplitude is the consequence of variation in transmitter concentration.

Miniature postsynaptic currents (minis) in cultured retinal amacrine cells, as in other central neurons, show large variations in amplitude. To understand the origin of this variability, we have exploited a novel form of synapse in which pre- and postsynaptic receptors sample the same quantum of transmitter. At these synapses, mini amplitudes measured simultaneously in the 2 cells show a strong correlation, accounting for, on average, more than half of the variance in amplitude. Two pieces of evidence support the conclusion that variations in the amount of transmitter in different quanta underlie this correlation. First, diazepam, which enhances GABA binding, increases mini amplitude, implying therefore that transmitter concentration is not saturating. Second, we show that amplitude distributions from all cells, even those with a small number of release sites, have the same shape, implying that most or all variance is intrinsic to each release site.

Animals↗

PubMed2003

Life span variations in 128 successive generations of D. melanogaster. I. Evidence that the phenomenon exists and analysis of the variations mode.

Survival of Drosophila melanogaster was estimated in 128 successive generations for 5 years. The resultant 116 samples (58 for females and 58 for males) containing series of individual values of life span (LS; 50-90 values in each series) were analyzed. Each of 58 pairs of samples belonged to a definite generation in a continuous succession where every next generation was an offspring of the preceding one. In total, 10180 Drosophila flies (5100 females and 5080 males) were studied. The mean life span (MLS) was found to be considerably heterogeneous in the series of generations: in many pairs of consecutive generations, MLSs significantly differed within two errors of the mean (P<0.05), and the minimum and maximum MLSs in the series differed from each other almost twofold. The use of the nonparametric Kruskal-Wallis test made it possible to conclusively demonstrate highly significant (P<0.001) differences between LS distributions and their medians in the series of successive generations of D. melanogaster. Highly significant (P<0.0001) positive correlations (from 0.61 to 0.91) between the parameters characterizing the minimum (t(10)), mean, and maximum (t(90)) LSs were found. This indicates considerable consistency of the LS variations in successive generations of the same population, with the proportions of individuals with low and high LSs remaining about the same irrespective of the MLS. It was demonstrated with the use of mathematical simulation that the MLS changes in successive generations may be regarded as an oscillatory process and described as a sum of several (three to five) harmonic components. The calculated determination coefficients were high (93.51 and 88.93% for females and males, respectively). This indicates that the mathematical model used for simulation adequately described the observed variations in MLS. The results are discussed in terms of population gerontology and the problem of geroprotector effectiveness.

Aging↗