Age-specific inbreeding depression and components of genetic variance in relation to the evolution of senescence

Two major theories of the evolution of senescence (mutation accumulation and antagonistic pleiotropy) make different predictions about the relationships between age, inbreeding effects, and the magnitude of genetic variance components of life-history components. We show that, under mutation accumulation, inbreeding decline and three major components of genetic variance are expected to increase with age in randomly mating populations. Under the simplest version of the antagonistic pleiotropy model, no changes in the severity of inbreeding decline, dominance variance, or the genetic variance of chromosomal homozygotes are expected, but additive genetic variance may increase with age. Age-specific survival rates and mating success were measured on virgin males, using lines extracted from a population of Drosophila melanogaster. For both traits, inbreeding decline and several components of genetic variance increase with age. The results are consistent with the mutation accumulation model, but can only be explained by antagonistic pleiotropy if there is a general tendency for an increase with age in the size of allelic effects on these life-history traits.     

Temporal and spatial expression patterns of two G-protein coupled receptors in Drosophila melanogaster

Mutations of the iduronate-2-sulfatase gene have been identified as responsible of Hunter syndrome or mucopolysaccharidosis type II. About 20% of the patients have deletions of the whole gene or other major structural alterations. The mutations found so far include: 34 missense, 8 nonsense, 11 small deletions from 1 to 3 bp, 2 deletions of 8 pb, 2 insertions of 1 bp and 2 insertions of 14 bp, with most leading to a frameshift and premature chain termination. Also 8 different splice-site mutations leading to insertions or deletions in the mRNA have been tabulated. Knowledge of the primary genetic defect allows insight into genotype-phenotype correlation and allows a better understanding of the structure and function of iduronate-2-sulfatase.     

Gene substitutions and geotaxis in Drosophila melanogaster.

Tightly linked gene markers at the white locus of Drosophila were placed, by repeated backcrossing, on each of 2 genetic backgrounds. 10 genotypes representing various combinations of homo- and heterozygosity were studied in a Hirsch-type geotactic maze. In general, the effects of genetic background, dominance, and epistasis were found to exceed the additive effects of gene substitutions. Results demonstrate the feasibility of analyzing the contributions of single genes to behaviors known to be polygenically determined. (29 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

A genetic analysis of the stoned locus and its interaction with dunce, shibire and Suppressor of stoned variants of Drosophila melanogaster

The genetic complementation patterns of both behavioral and lethal alleles at the stoned locus have been characterized. Mosaic analysis of a stoned lethal allele suggests that stoned functions either in the nervous system or in both the nervous system and musculature, but is not required for gross neural development. The behavioral alleles stnts and stnC, appear to be defective in a diametrically opposite sense, show interallelic complementation, and indicate distinct roles for the stoned gene product in the visual system and in motor coordination. A number of other neurological mutations have been investigated for their possible interaction with the viable stoned alleles. Mutations at two loci, dunce and shibire, act synergistically with the stnts mutations to cause lethality, but fail to interact with stnC. A third variant (Suppressor of stoned) has been identified which can suppress the debilitation associated with the stnts mutations. These data, together with a previously identified interaction between the stnts and tan mutants, indicate a central role for the stoned gene product in neuronal function, and suggests that the stoned gene product interacts, either directly or indirectly, with the neural cAMP second messenger system, with the synaptic membrane recycling pathway via dynamin, and with biogenic amine metabolism.     

Quantitative genetic variation of odor-guided behavior in a natural population of Drosophila melanogaster

Quantitative genetic variation in behavioral response to the odorant, benzaldehyde, was assessed among a sample of 43 X and 35 third chromosomes extracted from a natural population and substituted into a common inbred background. Significant genetic variation among chromosome lines was detected. Heritability estimates for olfactory response, however, were low, as is typical for traits under natural selection. Furthermore, the loci affecting naturally occurring variation in olfactory response to benzaldehyde were not the same in males and females, since the genetic correlation between the sexes was low and not significantly different from zero for the chromosome 3 lines. Competitive fitness, viability and fertility of the chromosome 3 lines were estimated using the balancer equilibrium technique. Genetic correlations between fitness and odor-guided behavior were not significantly different from zero, suggesting the number of loci causing variation in olfactory response is small relative to the number of loci causing variation in fitness. Since different genes affect variation in olfactory response in males and females, genetic variation for olfactory response could be maintained by genotype x sex environment interaction. This unusual genetic architecture implies that divergent evolutionary trajectories for olfactory behavior may occur in males and females.     

A genetic analysis of hermaphrodite, a pleiotropic sex determination gene in Drosophila melanogaster

Sex determination in Drosophila is controlled by a cascade of regulatory genes. Here we describe hermaphrodite (her), a new component of this regulatory cascade with pleiotropic zygotic and maternal functions. Zygotically, her+ function is required for female sexual differentiation: when zygotic her+ function is lacking, females are transformed to intersexes. Zygotic her+ function may also play a role in male sexual differentiation. Maternally, her+ function is needed to ensure the viability of female progeny: a partial loss of her+ function preferentially kills daughters. In addition, her has both zygotic and maternal functions required for viability in both sexes. Temperature sensitivity prevails for all known her alleles and for all of the her phenotypes described above, suggesting that her may participate in an intrinsically temperature-sensitive process. This analysis of four her alleles also indicates that the zygotic and maternal components of of her function are differentially mutable. We have localized her cytologically to 36A3-36A11.     

Age-specific incidence and prevalence rates of treated epilepsy in an unselected population of 2,052,922 and age-specific fertility rates of women with epilepsy

BACKGROUND: There are no data on prevalence or incidence of treated epilepsy, and no data on fertility of women with epilepsy from an unselected UK population. METHODS: We used the General Practice Research Database to ascertain the incidence and prevalence of people with treated epilepsy in an unselected population of 2,052,922 people in England and Wales, and also age-specific fertility rates. We defined period prevalence of treated epilepsy as the number of people with epilepsy taking an antiepileptic drug per 100,000 people during 1995. The incidence of treated epilepsy was defined as the number of new cases of treated epilepsy per 100,000 people during the same period. We calculated fertility rates among women with treated epilepsy between 1991 and 1995 and compared these rates with the population rates for England and Wales in 1993. FINDINGS: The period prevalence of treated epilepsy in 1995 was 5.15 per 1000 people (95% CI 5.05-5.25). The prevalence was lower in children (age 5-9 years 3.16 [2.86-3.48]; 10-14 years 4.05 [3.70-4.42]), and higher in older people (65-69 years 6.01 [5.50-6.57]; 70-74 years 6.53 [5.97-7.14]; 75-79 years 7.39 [6.73-8.11]); 80-84 years 7.54 [6.78-8.39]; 85 years and older 7.73 [6.98-8.66]). The incidence of treated epilepsy was 80.8 per 100,000 people (76.9-84.7). The incidence was lower in children (5-9 years 63.2 [50.5-79.1]; 10-14 years 53.8 [42.4-68.3]) and higher in older people (65-69 years 85.9 [68.5-107.3]; 70-74 years 82.8 [65.0-105.2]; 75-79 years 114.5 [116.9-179.2]; 80-84 years 159 [125.2-202.6]; > or = 85 years 135.4 [100.4-178.7]). Fertility was lower among women with treated epilepsy, with an overall rate of 47.1 livebirths per 1000 women aged 15-44 per year (42.3-52.2), compared with a national rate of 62.6 in the same age-group. The standardised fertility ratios were significantly lower between the ages of 25 and 39 years in women with epilepsy (p<0.001). INTERPRETATION: Compared with previous studies, we found that the incidence of epilepsy was higher in elderly people and lower in children. The prevalence rates also increase with age. Women aged 25-39 years with treated epilepsy have significantly lower fertility rates than those in the general population. Research is needed to identify any potentially preventable causes for the low fertility rates.     

Failure of 2- and 10-meter radio waves to induce genetic damage in Drosophila melanogaster

Over the past 20 years, more than 300 patients have been anesthetized in the lateral sitting position during neurosurgical procedures in the posterior fossa and the cervical and upper thoracic spine. Since the patient can be placed quickly and easily in the horizontal position, the lateral sitting position has a number of advantages over the conventional sitting position, particularly in the treatment of arterial hypotension and venous air embolism. Furthermore, with the patient in the lateral horizontal position, the surgical procedure can be completed satisfactorily.     

Spontaneous mutation for a quantitative trait in Drosophila melanogaster. II. Distribution of mutant effects on the trait and fitness

Exposure of the Chinese hamster ovarian AuxB1 cell line in vitro to fractionated X-irradiation generated sublines designated DXR-10, which proved resistant to multiple drugs and overexpressed P-glycoprotein (Pgp), as judged by Western blotting using the C219 monoclonal antibody. Further characterization of these irradiated DXR-10 sublines has provided evidence for: (i) the expression of cross-resistance to gramacidin D, taxol, puromycin and Navelbine, but not to daunomycin or mitoxantrone; (ii) overexpression of the class I Pgp, as judged by Western blotting using the C494 monoclonal antibody; (iii) decreased accumulation of 3H-vincristine, which could be enhanced by verapamil addition; (iv) unaltered accumulation and subcellular distribution of adriamycin; (v) significantly increased rhodamine 123 accumulation in the presence of verapamil; (vi) plasma-membrane ultrastructural modifications resulting in a significantly increased surface area; (vii) numerous clonal karyotypic alterations, with abnormalities involving the long arm of chromosome 1 being consistently identified; (viii) a lack of overexpression of sorcin; (ix) increased total glutathione levels and overexpression of glutathione S-transferase pi. The fact that only certain of these features are considered characteristic of the 'classic' multidrug-resistant CHRC5 cell line supports our earlier proposal that exposure to fractionated X-irradiation results in the expression of a unique drug-resistance phenotype.     

Polygenic mutation in Drosophila melanogaster: genetic interactions between selection lines and candidate quantitative trait loci

We have investigated genetic interactions between spontaneous mutations affecting abdominal and sternopleural bristle number that have accumulated in 12 long-term selection lines derived from an inbred strain, and mutations at 14 candidate bristle number quantitative trait loci. The quantitative test for complementation was to cross the selection lines to an inbred wild-type strain (the control cross) and to a derivative of the control strain into which the mutant allele at the candidate locus to be tested was substituted (the tester strain). Genetic interactions between spontaneous mutations affecting bristle number and the candidate locus mutations were common, and in several cases the interaction effects were different in males and females. Analyses of variance of the (tester- control) differences among and within groups of replicate lines selected in the same direction for the same trait showed significant group effects for several candidate loci. Genetically, the interactions could be caused by allelism of, and/ or epistasis between, spontaneous mutations in the selection lines and the candidate locus mutations. It is possible that much of the response to selection was from new mutations at candidate bristle number quantitative trait loci, and that for some of these loci, mutation rates were high.     

Characterization and cloning of tripeptidyl peptidase II from the fruit fly, Drosophila melanogaster

We describe the characterization, cloning, and genetic analysis of tripeptidyl peptidase II (TPP II) from Drosophila melanogaster. Mammalian TPP II removes N-terminal tripeptides, has wide distribution, and has been identified as the cholecystokinin-degrading peptidase in rat brain. Size exclusion and ion exchange chromatography produced a 70-fold purification of dTPP II activity from Drosophila tissue extracts. The substrate specificity and the inhibitor sensitivity of dTPP II is comparable to that of the human enzyme. In particular, dTPP II is sensitive to butabindide, a specific inhibitor of the rat cholecystokinin-inactivating activity. We isolated a 4309-base pair dTPP II cDNA which predicts a 1354-amino acid protein. The deduced human and Drosophila TPP II proteins display 38% overall identity. The catalytic triad, its spacing, and the sequences that surround it are highly conserved; the C-terminal end of dTPP II contains a 100-amino acid insert not found in the mammalian proteins. Recombinant dTPP II displays the predicted activity following expression in HEK cells. TPP II maps to cytological position 49F4-7; animals deficient for this interval show reduced TPP II activity.     

Mutation and evolution of microsatellites in Drosophila melanogaster

Levels of nucleotide polymorphism in the Drosophila melanogaster genome are correlated with rates of recombination. This relationship may be due to hitchhiking of advantageous mutations (selective sweeps) or to continual removal of deleterious mutations from the genome (background selection). One test of the relative contributions of selective sweeps and background selection to the observed levels of variation in the genome of D. melanogaster is to compare levels of nucleotide variability (with a mutation rate on the order of 10(-9) per nucleotide per generation) with more rapidly evolving DNA loci such as microsatellites. This test depends critically on details of the mutational process of microsatellites. In this paper, we summarize our studies of microsatellite characteristics and mutation rates in D. melanogaster. We find that D. melanogaster microsatellites are short and have a mutation rate (6.5 x 10(-6) per locus per generation) several orders of magnitude lower than mammals studied to date. We further show that genetic variation at 18 dinucleotide repeat microsatellites in a population of D. melanogaster from Maryland is correlated with regional rates of recombination. These and other microsatellite data suggest that both background selection and selective sweeps may contribute to the correlation between DNA sequence variation and recombination in Drosophila.     

A comparative genetic analysis of interlinear differences in intensity of lipid peroxidation and life span in Drosophila melanogaster. Inbred lines and hybrids

The interrelationship between the level of peroxidation lipid and longevity was studied as based on highly inbred lines of Drosophila melanogaster, bred for adaptively important characters. The concepts of the free-radical theory proved valid for the lines and failed to be supported for the crosses. The dominant role of heterosis in the protecting against the "aging action" of free radicals is postulated.     

Infant and child mortality in Bangladesh: age-specific effects of previous child''s death

In the first part of three overviews on recognition memory in the rat, we discussed the tasks employed to study recognition memory. In the second part, we discussed the neuroanatomical systems thought to be of importance for the mediation of recognition memory in the rat. In particular, we delineated two parallel-distributed neuronal networks, one that is essential for the processing of non-spatial/item recognition memory processes and incorporates the cortical association areas such as TE1, TE2 and TE3, the rhinal cortices, the mediodorsal thalamic nucleus and prefrontal cortical areas (Network 1), the other comprising of the hippocampus, mamillary bodies, anterior thalamic nuclei and medial prefrontal areas (Network 2), suggested to be pivotal for the processing of spatial recognition memory. The next step will progress to the level of the neurotransmitters thought to be involved. Current data suggest that the majority of drugs have non-specific, i.e. delay-independent effects in tasks measuring recognition memory. This may be due to attentional, motivational or motoric changes. Alternatively, delay-independent effects may result from altered acquisition/encoding rather than from altered retention. Furthermore, the neurotransmitter systems affected by these drugs could be important as modulators rather than as mediators of recognition memory per se. It could, of course, also be the case that systemic treatment induces non-specific effects which overshadow any specific, delay-dependent, effect. This possibility receives support from lesion experiments (for example, of the septohippocampal cholinergic system) or studies employing local intracerebral infusion techniques. However, it is evident that those delay-dependent effects are relatively subtle and more readily seen in delayed response paradigms, which tax spatial recognition memory. One interpretation of these results could be that some neurotransmitter systems are more involved in spatial than in item recognition memory processes. However, performance in delayed response tasks can be aided by mediating strategies. Drugs or lesions can alter those strategies, which could equally explain some of the (delay-dependent) drug effects on delayed responding. Thus, it is evident that neither of the neurotransmitter systems reviewed (glutamate, GABA, acetylcholine, serotonin, dopamine and noradrenaline) can be viewed as being directly and exclusively concerned with storage/retention. Rather, our model of recognition memory suggests that information about previously encountered items is differentially processed by distinct neural networks and is not mediated by a single neurotransmitter type.     

Geographic variations of life history strategies in Drosophila melanogaster. III. New data

A crucial assumption of evolutionary theories of aging is that age-specific differences of life history traits may have genetic causes. The present study focuses on the existence of such differences between eight freshly caught populations of Drosophila melanogaster. A highly significant differentiation of the populations is observed, yet it accounts for a relatively small part of the variance. It is also shown that large discrepancies may be found between the estimations of fitness based, on the one hand, on data for egg production and, on the other hand, on fertility data. This stresses the need for accurate measurements of fitness for the assessment of evolutionary theories. Finally, the results suggest that neither of the current evolutionary theories of aging is generally valid. Indeed, the age-specific differences that are found between the populations match either the antagonistic pleiotropy mechanism, or the concordant pleiotropy mechanism, or none of them.     

Trends and patterns of mortality associated with birth defects and genetic diseases in the United States, 1979-1992: an analysis of multiple-cause mortality data

Contemporary information on the trends and patterns of mortality associated with birth defects and genetic diseases is lacking in the United States. To study these trends and patterns, we used the Multiple-Cause Mortality Files of the National Center for Health Statistics. From 1979 through 1992, 320,208 deaths in the United States were associated with birth defects and genetic diseases. The age-adjusted mortality rates for people with birth defects declined from about 8.2/100,000 in 1979 to about 6.7/100,000 in 1992, and the mortality rates for people with genetic diseases increased from 2.2/100,000 in 1979 to 2.5/100,000 in 1992. The mortality rate was higher among men than among women and higher among blacks than among whites or other races for both birth defect- and genetic disease-associated deaths. The rate among infants with birth defects was more than 25 times higher than that among other age groups. About half of the children whose deaths were associated with birth defects had cardiovascular system defects, 15% had central nervous system defects, and 12% had chromosomal defects. For deaths associated with genetic diseases, hereditary neurologic or storage disorders were the most common genetic diseases (38%), followed by metabolic disorders (21%), sickle cell and thalassemia (12%). The decline in the rate of mortality from birth defects in the United States probably reflects improvements in medical and surgical care and other factors. Most of the mortality associated with birth defects remains in the pediatric age group (less than 15 years old). The upward trend we detected for the deaths with genetic diseases was most likely related to improved recognition and reporting of some genetic diseases rather than to the increased prevalence.