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J W Curtsinger

Publications and source records attributed to J W Curtsinger.

At least 19 recordsLinked to original sources
PubMed2005

Analysis of two components of flight using recombinant inbred lines of Drosophila melanogaster.

Complex activities require precise coordination of their components for successful action. The genetic basis underlying coordination of traits may range from relatively static pleiotropic associations to more flexible genetic associations that recombine in phenotypes under continuous selective modification by the environment. Successful flight in insects depends on the precise integration of numerous component physiological processes. Here we examine the genetic basis of two of its components, flight duration and rate. To study flight we created recombinant inbred populations from stocks of this laboratory known for their significantly longer duration flights. A heritable basis for these traits was found and determined to be positively correlated between sexes. Correlations of flight length with rate were negative within sexes, suggesting a trade-off, but were significant in males only. Composite interval mapping using the recombinant inbred (RI2) design was used to locate the QTLs for these traits and test for pleiotropy. Four QTLs affecting duration or wing beat rate were found on chromosomes II and III. Tests for pleiotropy showed some effects on traits of QTLs were common to both sexes while others were sex-specific. No QTL was pleiotropic for both traits, suggesting that correlations between flight duration and rate of wing beat are determined by a combination of linkage and environmental factors.

Animals↗
PubMed2002

Nucleotide variations in the lxd region of Drosophila melanogaster: characterization of a candidate modifier of lifespan.

We have investigated the structure and function of several proteins that might influence adult lifespans in Drosophila melanogaster. The present report focuses on the gene lxd ('low xanthine dehydrogenase'), which lies in a region of chromosome III identified by QTL-mapping as potentially important for lifespan. DNA sequence of a 3780 bp genomic fragment containing the lxd locus reveals differences between long-lived and control inbred lines. In order to determine the importance of nucleotide replacements, the intron/exon boundaries have been determined, based on peptide alignment and conserved amino acids. We identified four exons in the lxd coding region. The deduced amino acid sequence of exon 4 shows 46.5% identity with Escherichia coli MoaC sequences. There are eight nucleotide substitutions in exons differentiating the inbred lines, three in exon 3 and five in exon 4. One of the exon 4 substitutions has resulted in a Thr-Ile replacement at the protein surface, but not entirely solvent exposed. This substitution is potentially a modifier of lifespan via oxygen defense, but since the activities of three molybdoenzymes are unaffected in inbred lines, this possibility seems remote.

Amino Acid Sequence↗
PubMed2001

Locomotor activity as a function of age and life span in Drosophila melanogaster overexpressing hsp70.

Heat shock protein induction might be responsible for the longevity increase conferred by exposure to non-lethal stresses. To test this hypothesis, we studied in transgenic Drosophila melanogaster overexpressing hsp70 and controls, two behavioral variables (spontaneous locomotor activity and climbing activity) to evaluate the rate of aging, and life span. The results showed that in flies kept in groups, life span was decreased in transgenic flies compared to the parental line, but the contrary was observed in individually kept flies. Hsp70 overexpression had no dramatic effect on life span. Furthermore, we did not detect any advantage of Drosophila overexpressing hsp70 on the two measurements of locomotor activity. These results indicate that the rate of aging in transgenic flies is not different than in non-transgenic lines and that they are not more able to cope with the effects of aging on locomotor activity.

Aging↗
PubMed2000

The influence of environmentally induced heterogeneity on age-specific genetic variance for mortality rates.

Using parametric models that describe the increase in mortality rates with age, we demonstrate that environmentally induced heterogeneity among genetically identical individuals is sufficient to generate biased estimates of age-specific genetic variance. Although the magnitude of the bias may change with age, one general trend emerges: the true genetic variance at the oldest ages is likely to be dramatically underestimated. Our results are robust to different manifestations of heterogeneity and suggest that such a bias is a general feature of these models. We note that age-dependent estimates of genetic variance for characters that are correlated with mortality (either genetically or environmentally) can be expected to be similarly affected. The results are independent of sample size and suggest that the bias may be more widespread in the literature than is currently appreciated. Our results are discussed with reference to existing data on mortality variance in Drosophila melanogaster.

Aging↗
PubMed2000

Genetic analysis of extended lifespan in Drosophila melanogaster III. On the relationship between artificially selected and wild stocks.

Adult lifespans, age-specific survival, age-specific mortality, survival times on paraquat, and survival times on DDT were assayed in seven lines of Drosophila melanogaster, including two genetically heterogeneous wild lines recently collected from nature, and three inbred and recombinant inbred lines derived from an artificial selection experiment for increased lifespan. Survival on paraquat is positively correlated with adult lifespan. DDT resistance is uncorrelated with either paraquat resistance or lifespan. The wild lines are unexceptional with respect to average lifespan, paraquat resistance, age-specific survivorship, and leveling off of mortality rates at advanced ages, but have high levels of DDT resistance. Cluster analysis groups the wild lines with three unselected laboratory stocks in one cluster, while two long-lived elite recombinant inbred lines form a second cluster. Long-lived laboratory-adapted lines are quantitatively differentiated from the wild stocks, both with respect to average adult lifespans and resistance to an oxidizing agent. We reject the 'recovery' hypothesis, which proposes that Drosophila artificially selected for long life have phenotypes that merely recover the wild state.

Animals↗
PubMed2000

Why do life spans differ? Partitioning mean longevity differences in terms of age-specific mortality parameters.

Populations typically differ in mean life spans because of genetic, environmental, or experimental factors. In this paper methods are presented that clarify the relationship between differences in the longevity of two populations and differences in their underlying age-specific patterns of mortality. Data are examined from rodent and fruit fly (Drosophila melanogaster) experiments that investigated the longevity effects of a variety of environmental and genetic manipulations, including temperature, dietary restriction, laboratory selection for increased longevity, and severe inbreeding. Analyses suggest that longevity differences mediated by temperature and dietary restriction result predominantly from differences in the rate of increase in mortality with age. Increases in longevity through laboratory selection result primarily from a reduction in baseline mortality and not a slowing of the rate of aging. Although the methods are applied primarily in the context of simple mathematical models of mortality (e.g., the Gompertz model), they are quite general and can be applied to mortality models of arbitrary complexity. Mathematica protocols ("notebooks") and computer software have been developed to perform all the analyses discussed and are available from the first author.

Age Factors↗
PubMed1999

The evolution of age-specific mortality rates in Drosophila melanogaster: genetic divergence among unselected lines.

Age-specific effects of spontaneous mutations on mortality rates in Drosophila are inferred from three large demographic experiments. Data were collected from inbred lines that were allowed to accumulate spontaneous mutations for 10, 19, and 47 generations. Estimates of age-specific mutational variance for mortality were based on data from all three experiments, totalling approximately 225,000 flies, using a model developed for genetic analysis of age-dependent traits (the character process model). Both within- and among-generation analyses suggest that the input of genetic variance is greater for early life mortality rates than for mortality at older ages. In females, age-specific mutational variances ranged over an order of magnitude from 5.96 x 10(-3) at 2 wk posteclosion to 0.02 x 10(-3) at 7 wk. The male data show a similar pattern. Age-specific genetic variances were substantially less at generation 47 than at generation 19-an unexplained observation that is likely due to block effects. Mutational correlations among mortality rates at different ages tend to increase with the accumulation of new mutations. Comparison of the mutation-accumulation lines at generations 19 and 47 with their respective control lines suggests little age-specific mutational bias.

Animals↗
PubMed1998

The fractionation experiment: reducing heterogeneity to investigate age-specific mortality in Drosophila.

Age-specific mortality rates decelerate at older ages in both genetically homogenous and heterogeneous populations of Drosophila. One explanation proposed for deceleration is population heterogeneity. This hypothesis suggests that a population consists of sub-populations that differ in mortality characteristics and that the deceleration is the result of selective survival of stronger individuals. Here we describe an experiment that fractionates populations into several sub-populations without changing the physiological characteristics of the post-fractionated populations. Through a careful process of selection of Drosophila eggs, larvae, pupae and adults, we attempt to reduce as much as possible the degree of pre-adult, environmentally induced heterogeneity among individuals of a genetically identical cohort. We then ask whether such cohorts, when compared to non-fractionated populations, exhibit a lesser degree of mortality deceleration at advanced ages. From a total of 106 fractionated and control populations, consisting of 51331 individuals, 101 populations (93% of the fractionated populations and 100% of the control populations) exhibit a significant amount of mortality deceleration late in life. These observations suggest that environmental heterogeneity accrued during larval development is not a major factor contributing to mortality deceleration at older ages.

Aging↗
PubMed1998

Biodemographic trajectories of longevity.

Old-age survival has increased substantially since 1950. Death rates decelerate with age for insects, worms, and yeast, as well as humans. This evidence of extended postreproductive survival is puzzling. Three biodemographic insights--concerning the correlation of death rates across age, individual differences in survival chances, and induced alterations in age patterns of fertility and mortality--offer clues and suggest research on the failure of complicated systems, on new demographic equations for evolutionary theory, and on fertility-longevity interactions. Nongenetic changes account for increases in human life-spans to date. Explication of these causes and the genetic license for extended survival, as well as discovery of genes and other survival attributes affecting longevity, will lead to even longer lives.

Aging↗
PubMed1998

Genetic analysis of extended life span in Drosophila melanogaster. II. Replication of the backcross test and molecular characterization of the N14 locus.

We are interested in localizing chromosomal regions that extend life span in Drosophila. Using stocks artificially selected for long life by Luckinbill and his colleagues, we have identified marker loci that are highly divergent in allelic frequencies between replicated long-lived lines and controls (Curtsinger et al., 1998). Several of the most divergent loci have been found to be associated with effects on life span in segregating backcross populations. Here we report an independent replication of the backcross test for the N14 marker locus, previously reported to extend male life spans by 12 days. The life span effect successfully replicates in males. N14 accounts for 30% of the total selection response in males. Life span extension occurs by a decrease in age-specific mortality rates at all ages, and is not attributable to modification of the slope of the age-specific mortality curve. The effect in females is small or nonexistent. Sequencing of the N14 locus shows that it is non-coding and not obviously regulatory, suggesting that the phenotypic effect arises from linkage disequilibrium with another locus or loci that directly affect life span. N14 DNA hybridizes to 63F/64A on the left arm of chromosome 3. The location is consistent with previous whole-chromosome substitution studies, and suggests new candidate genes for life span extension in Drosophila, including ras2.

Aging↗
PubMed1998

Genetic analysis of extended life span in Drosophila melanogaster. I. RAPD screen for genetic divergence between selected and control lines.

Using lines selected for long life by Luckinbil and his co-workers, we screened two selected and two control lines for allelic frequency differences at 1200 randomly chosen RAPD marker loci. Twenty-three marker loci showed frequency differences in excess of 80%, and five were greater than 90%. Age-specific effects of the five most differentiated loci were estimated by collecting complete survival data in segregating backcross populations. Alleles at four of the five marker loci were associated with significant extension of life span in males, while two marker loci had significant effects in females. Eighty percent of the total selection response in males can be explained by the identified QTL's, under the assumption of additivity. The N14+ marker allele accounted for a 12-day life span extension in males, but had little effect in females. Both sex-limited and sex-shared effects were observed. Analysis of age-specific mortality rates suggests that life span extension occurs by a combination of genetic factors that moderate both the level of mortality and the rate at which mortality increases with age.

Aging↗
PubMed1998

Age-specific properties of spontaneous mutations affecting mortality in Drosophila melanogaster.

An analysis of the effects of spontaneous mutations affecting age-specific mortality was conducted using 29 lines of Drosophila melanogaster that had accumulated spontaneous mutations for 19 generations. Divergence among the lines was used to estimate the mutational variance for weekly mortality rates and the covariance between weekly mortality rates at different ages. Significant mutational variance was observed in both males and females early in life (up to approximately 30 days of age). Mutational variance was not significantly different from zero for mortality rates at older ages. Mutational correlations between ages separated by 1 or 2 wk were generally positive, but they declined monotonically with increasing separation such that mutational effects on early-age mortality were uncorrelated with effects at later ages. Analyses of individual lines revealed several instances of mutation-induced changes in mortality over a limited range of ages. Significant age-specific effects of mutations were identified in early and middle ages, but surprisingly, mortality rates at older ages were essentially unaffected by the accumulation procedure. Our results provide strong evidence for the existence of a class of polygenic mutations that affect mortality rates on an age-specific basis. The patterns of mutational effects measured here relate directly to recently published estimates of standing genetic variance for mortality in Drosophila, and they support mutation accumulation as a viable mechanism for the evolution of senescence.

Age Factors↗
PubMed1997

Non-linear selection response in Drosophila: a strategy for testing the rare-alleles model of quantitative genetic variability.

Quantitative genetic theory predicts that variation due to rare alleles at many loci will generate a transient acceleration in the response to directional selection. We have tested this prediction by constructing experimental lines of Drosophila melanogaster that carry positively selected ethanol resistance alleles at low frequencies, and then subjecting the lines to directional selection for ethanol resistance. Approximately 468,000 files were subjected to artificial selection over 30 generations. The predicted non-linear selection responses were observed in all experimental lines and replicates, on three genetic backgrounds. In contrast, un-selected controls and lines carrying random alleles at low frequencies on the same genetic backgrounds exhibited linear selection responses. These results demonstrate that non-linearities due to rare alleles are detectable and repeatable, provided that experiments are done on a sufficiently large scale. The results suggest that it may be possible to test for rare-alleles as a component of naturally occurring genetic variation by careful examination of selection response curves.

Alleles↗
PubMed1997

Heat-induced longevity extension in Drosophila. I. Heat treatment, mortality, and thermotolerance.

Survival data were collected on a total of 28,000 Drosophila melanogaster adults in order to investigate mortality patterns and induced physiological responses after a mild thermal stress. A brief, nonlethal heat treatment extends adult life span at normal temperatures by an average of 2 days (64), compared to nontreated controls of the same genotypes. Life expectancy is extended as a demographic consequence of reduced age-specific mortality over a period of up to several weeks after the heat treatment. Heat treatment also increases tolerance to subsequent, more severe thermal stress. Observations on single-sex populations suggest that heat-induced longevity extension is independent of the suppression of reproductive activity.

Acclimatization↗
PubMed1996

Effect of density on age-specific mortality in Drosophila: a density supplementation experiment.

Age-specific mortality rates were studied at two adult density levels in four inbred lines of Drosophila melanogaster. In experimental populations, adult densities were maintained at constant levels throughout the experiment by replacing dead flies with live, marked mutants. In control populations, densities declined naturally as the cohorts aged. For all experimental populations the best mortality model is the two-stage Gompertz model, with slower mortality acceleration at older ages. Flies in the experimental populations generally lived longer than flies in control populations, regardless of sex, genotype, or initial density level. The data demonstrate that deceleration of age-specific mortality rates at older ages is not caused by declining cohort densities. Mortality deceleration is a real phenomenon that raises serious questions about the evolution of senescence.

Age Factors↗
PubMed1996

Age-specific patterns of genetic variance in Drosophila melanogaster. I. Mortality.

PETER MEDAWAR proposed that senescence arises from an age-related decline in the force of selection, which allows late-acting deleterious mutations to accumulate. Subsequent workers have suggested that mutation accumulation could produce an age-related increase in additive genetic variance (VA) for fitness traits, as recently found in Drosophila melanogaster. Here we report results from a genetic analysis of mortality in 65,134 D. melanogaster. Additive genetic variance for female mortality rates increases from 0.007 in the first week of life to 0.325 by the third week, and then declines to 0.002 by the seventh week. Males show a similar pattern, though total variance is lower than in females. In contrast to a predicted divergence in mortality curves, mortality curves of different genotypes are roughly parallel. Using a three-parameter model, we find significant VA for the slope and constant term of the curve describing age-specific mortality rates, and also for the rate at which mortality decelerates late in life. These results fail to support a prediction derived from MEDAWAR's "mutation accumulation" theory for the evolution of senescence. However, our results could be consistent with alternative interpretations of evolutionary models of aging.

Aging↗
PubMed1996

Age-specific patterns of genetic variance in Drosophila melanogaster. II. Fecundity and its genetic covariance with age-specific mortality.

Under the mutation accumulation model of senescence, it was predicted that the additive genetic variance (VA) for fitness traits will increase with age. We measured age-specific mortality and fecundity from 65,134 Drosophila melanogaster and estimated genetic variance components, based on reciprocal crosses of extracted second chromosome lines. Elsewhere we report the results for mortality. Here, for fecundity, we report a bimodal pattern for VA with peaks at 3 days and at 17-31 days. Under the antagonistic pleiotropy model of senescence, it was predicted that negative correlations will exist between early and late life history traits. For fecundity itself we find positive genetic correlations among age classes > 3 days but negative nonsignificant correlations between fecundity at 3 days and at older age classes. For fecundity vs. age-specific mortality, we find positive fitness correlations (negative genetic correlations) among the traits at all ages > 3 days but a negative fitness correlation between fecundity at 3 days and mortality at the oldest ages (positive genetic correlations). For age-specific mortality itself we find overwhelmingly positive genetic correlations among all age classes. The data suggest that mutation accumulation may be a major source of standing genetic variance for senescence.

Aging↗