David Clancy - Academia.edu (original) (raw)

Papers by David Clancy

Mitochondrion, 2019

Mitochondrial genetic variation can have profound effects on fitness, and the mitotype must inter... more Mitochondrial genetic variation can have profound effects on fitness, and the mitotype must interact with both the nuclear genes and the environment. We used Drosophila to investigate the extent to which mitotype effects on lifespan and activity are modulated by nucleotype and environmental variation. When nucleotype is varied, mitochondrial effects on lifespan persisted but were relatively small, and still male biased. Varying food as well, mitotype had substantial effects on male climbing speed, modifiable by nucleotype but less so by diet. Finally, mitotype affected fly lifespan much more in a cage environment compared with a vial, also modifiable by nucleotype and diet. The cage may represent a stressful environment. Mitochondrial genotype may affect fitness much more in conditions of stress, which may have implications for human health.

ABSTRACTA large body of studies has demonstrated that genetic variation that resides outside of t... more ABSTRACTA large body of studies has demonstrated that genetic variation that resides outside of the cell nucleus can affect the organismal phenotype. The cytoplasm is home to the mitochondrial genome and, at least in arthropods, often hosts intracellular endosymbiotic bacteria such asWolbachia. While numerous studies have implicated epistatic interactions between cytoplasmic and nuclear genetic variation as key to mediating patterns of phenotypic expression, two outstanding questions remain. Firstly, the relative contribution of mitochondrial genetic variation to other cytoplasmic sources of variation in shaping the phenotypic outcomes of cyto-nuclear interactions remains unknown. Secondly, it remains unclear whether the outcomes of cyto-nuclear interactions will manifest differently across the two sexes, as might be predicted given that cytoplasmic genomes are screened by natural selection only through females as a consequence of their maternal inheritance. Here, we address these q...

The Drosophila melanogaster gene chico encodes an insulin receptor substrate that functions in an... more The Drosophila melanogaster gene chico encodes an insulin receptor substrate that functions in an insulin/insulin-like growth factor (IGF) signaling pathway. In the nematode Caenorhabditis elegans, insulin/IGF signaling regulates adult longevity. We found that mutation of chico extends fruit fl y median life-span by up to 48% in homozygotes and 36% in heterozygotes. Extension of life-span was not a result of impaired oogenesis in chico females, nor was it consistently correlated with increased stress resistance. The dwarf phenotype of chico homozygotes was also unnecessary for extension of life-span. The role of insulin/IGF signaling in regulating animal aging is therefore evolutionarily conserved

Genetics, 1994

In Drosophila melanogaster, weak incompatibility in crosses between infected and uninfected strai... more In Drosophila melanogaster, weak incompatibility in crosses between infected and uninfected strains is associated with a Wolbachia microorganism. Crosses between infected males and uninfected females show a reduction (15-30%) in egg hatch. Progeny tests indicated that the infection is widespread in Australian D. melanogaster populations and that populations are polymorphic for the presence of the infection. The infection status of 266 lines from 12 populations along the eastern coast of Australia was determined by 4',6-diamidino-2-phenylindole (DAPI) staining of embryos. All populations contained both infected and uninfected flies. Infection frequencies varied between populations but there was no discernible geographical pattern. Laboratory experiments indicated that the infection was not associated with a reduction in fecundity as in Drosophila simulans. Incompatibility levels could not be increased by laboratory selection on isofemale lines. Factors contributing to the persist...

Philosophical Transactions of the Royal Society B: Biological Sciences, 2019

Evolutionary theory proposes that maternal inheritance of mitochondria will facilitate the accumu... more Evolutionary theory proposes that maternal inheritance of mitochondria will facilitate the accumulation of mitochondrial DNA (mtDNA) mutations that are harmful to males but benign or beneficial to females. Furthermore, mtDNA haplotypes sampled from across a given species distribution are expected to differ in the number and identity of these ‘male-harming’ mutations they accumulate. Consequently, it is predicted that the genetic variation which delineates distinct mtDNA haplotypes of a given species should confer larger phenotypic effects on males than females (reflecting mtDNA mutations that are male-harming, but female-benign), or sexually antagonistic effects (reflecting mutations that are male-harming, but female-benefitting). These predictions have received support from recent work examining mitochondrial haplotypic effects on adult life-history traits in Drosophila melanogaster . Here, we explore whether similar signatures of male-bias or sexual antagonism extend to a key phys...

Trends in Ecology & Evolution, 1996

In Drosophila simulans, cytoplasmically transmitted Wolbachia microbes cause reduced egg hatch wh... more In Drosophila simulans, cytoplasmically transmitted Wolbachia microbes cause reduced egg hatch when infected males mate with uninfected females. A Wolbachia infection and an associated mtDNA variant have spread northward through California since 1986. PCR assays show that Wolbachia infection is prevalent throughout the continental US and Central and South America, but some lines from Florida and Ecuador that are PCR-positive for Wolbachia do not cause incompatibility. We estimate from natural populations infection frequencies and the transmission and incompatibility parameter values that affect the spread of the infection. On average, infected females from nature produce 3-4% uninfected ova. Infected females with relatively low fidelity of maternal transmission show partial incompatibility with very young infected laboratory males. Nevertheless, crosses between infected flies in nature produce egg-hatch rates indistinguishable from those produced by crosses between uninfected individuals. Incompatible crosses in nature produce hatch rates 30-70% as high as those from compatible crosses. Wildcaught infected and uninfected females are equally fecund in the laboratory. Incompatibility decreases with male age, and age-specific incompatibility levels suggest that males mating in nature may often be 2 or 3 weeks old. Our parameter estimates accurately predict the frequency of Wolbachia infection in California populations. MM insect species harbor microbes related to Wolbachia pipientis that make infected males reproductively incompatible with uninfected females

Heredity, 1996

Microbes of the genus Wolbachia are transmitted by their hosts via the maternal parent and are re... more Microbes of the genus Wolbachia are transmitted by their hosts via the maternal parent and are responsible for cytoplasmic incompatibility among insect populations. This phenomenon can result in Wolbachia spreading through natural populations as previously demonstrated in Drosophila simulans. Here we describe another Wolbachia infection in D. simulans that does not cause cytoplasmic incompatibility. This is a property of the Wolbachia rather than the nuclear background. The infection occurs at a low frequency in natural populations from eastern Australia. The infection shows perfect maternal transmission in the field and does not cause any detectable deleterious effects on its host. These findings suggest that the Wolbachia infection behaves like a neutral variant in populations. The infection may represent an evolutionary outcome of interactions between Wolbachia infections and their hosts.

Experimental Gerontology, 2004

The link between resting metabolic rate and aging, measured as adult lifespan, was investigated i... more The link between resting metabolic rate and aging, measured as adult lifespan, was investigated in Drosophila melanogaster by (i) comparing lifespan and metabolic rate of individual flies, (ii) examining the effect of dietary-restriction on the metabolic rate of adult flies, and (iii) comparing the metabolic rate of wild-type and insulin/IGF-1 signalling mutant chico 1 flies. The resting oxygen consumption of 65 individually housed and fully fed Drosophila was measured weekly throughout their lifetime. There was no significant difference in the mass-specific rate of oxygen consumption between cohorts that differed in lifespan. Nor was there any statistical correlation between mass-specific oxygen consumption and lifespan of individual Drosophila. The average mass-specific rate of oxygen consumption at 25 8C was 3.52^0.07 ml O 2 mg 21 h 21. Variation in mass-specific metabolic rate explained only 4% of variation in individual life span in these flies. Contrary to predictions from the 'rate of living' theory of aging lifetime oxygen consumption was not constant and the lifespan of individual flies accounted for 91% of their lifetime oxygen consumption. An average Drosophila consumes about 3 ml O 2 during its adult life. Dietary-restriction had no effect on mass-specific resting metabolic rate both when measured as oxygen consumption by respirometry and when measured as heat production by microcalorimetry. The mass-specific resting heat production of fully fed adult flies at 25 8C averaged 17.3^0.3 mW mg 21. Similarly there was no difference in mass-specific metabolic rate of wild-type flies and longliving chico 1 insulin/IGF-1 signalling mutant flies, either when measured as oxygen consumption or heat production. Thus, individual variation in lifespan in wild-type flies, and life extension by dietary-restriction and reduced insulin/IGF-1 signalling is not attributable to differences in metabolic rate.

Comparative Biochemistry and Physiology Part D: Genomics and Proteomics, 2010

Here we report the sequence of three mitochondrial genomes from yeasts of the Nakaseomyces clade ... more Here we report the sequence of three mitochondrial genomes from yeasts of the Nakaseomyces clade that includes the pathogenic yeast Candida glabrata, namely, that of Kluyveromyces delphensis, Candida castellii and Kluyveromyces bacillisporus. The gene content is equivalent to that of C. glabrata, but reveals the existence of new group I introns in COX1 and CYTB and new potential intronic endonucleases. Gene order is highly rearranged in these genomes, which contain numerous palindromic GC clusters. The more GC nucleotides these elements contain, the longer and more AT-rich are the intergenes containing them, leading to a direct relationship between the number of Gs and Cs within the elements and the size of the genomes. Thus, there is a fivefold difference in size between the smallest and the largest mitochondrial genome, with the largest being the most AT-rich overall. Sequences are available under EMBL accession numbers FM995164, FM995165, and FM995166.

Aging Cell, 2008

Drosophila melanogaster is widely considered to be an attractive model organism for studying the ... more Drosophila melanogaster is widely considered to be an attractive model organism for studying the functions of the carbohydrate moieties of glycoconjugates produced by higher eukaryotes. However, the pathways of glycoconjugate biosynthesis are not as well defined in insects as they are in higher eukaryotes. One way to address this problem is to identify genes in the Drosophila genome that might encode relevant functions, express them, and determine the functions of the gene products by direct biochemical assays. In this study, we used this approach to identify a putative Drosophila β4-galactosyltransferase gene and determine the enzymatic activity of its product. Biochemical assays demonstrated that this gene product could transfer galactose from UDP-galactose to a β-xylosyl acceptor, but not to other acceptors in vitro. The apparent K m values for the donor and acceptor substrates indicated that this gene product is a functional galactosyltransferase. Additional assays showed that the enzyme is activated by manganese, has a slightly acidic pH optimum, and is localized in the insect cell Golgi apparatus. These results showed that Drosophila encodes an ortholog of human β4-galactosyltransferase-VII, also known as galactosyltransferase I, which participates in proteoglycan biosynthesis by transferring the first galactose to xylose in the linkage tetrasaccharide of glycosaminoglycan side chains.

Ageing Research Reviews, 2013

Drosophila and Caenorhabditis elegans have provided the largest body of evidence addressing the F... more Drosophila and Caenorhabditis elegans have provided the largest body of evidence addressing the Free Radical Theory of ageing, however the evidence has not been unequivocally supportive. Oxidative damage to DNA is probably not a major contributor, damage to lipids is assuming greater importance and damage to proteins probably the source of pathology. On balance the evidence does not support a primary role of oxidative damage in ageing in C. elegans, perhaps because of its particular energy metabolic and stress resistance profile. Evidence is more numerous, varied and consistent and hence more compelling for Drosophila, although not conclusive. However there is good evidence for a role of oxidative damage in later life pathology. Future work should: 1/ make more use of protein oxidative damage measurements; 2/ use inducible transgenic systems or pharmacotherapy to ensure genetic equivalence of controls and avoid confounding effects during development; 3/ to try to delay ageing, target interventions which reduce and/or repair protein oxidative damage.

The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 2006

Many studies demonstrate changes in physiology, biochemistry, or behavior with age, but almost no... more Many studies demonstrate changes in physiology, biochemistry, or behavior with age, but almost no studies demonstrate such changes being predictive of aging. We subsampled from 10 genetically distinct strains of Drosophila melanogaster as they aged, at three time points, measuring change over time of parameters related to water balance (water content, desiccation survival, and K þ , Mg 2þ , and Ca 2þ levels). We then determined whether the change over time in any parameters is predictive of mean life span or time of onset of aging. We observed a schedule of aging-related changes. Time of onset of aging was negatively correlated with decline in desiccation resistance and with decline in K þ between days 0 and 15, and was positively correlated with decline in Ca 2þ between days 15 and 24. We suggest that the potassium result, at least, may be due to loss of functional cytoplasm. We also discuss the use of different estimates of aging in the context of this study.

Reliability and variability of sleep and activity as biomarkers of ageing in Drosophila

Biogerontology, 2012

There are currently no reliable biomarkers of ageing. A biomarker should indicate biological age,... more There are currently no reliable biomarkers of ageing. A biomarker should indicate biological age, that is, the amount of an animal's total lifespan it has lived and, therefore, the amount of time it has remaining. Some potential biomarkers cannot be validated as their measurement involves harm or death of the animal, such that its ultimate lifespan cannot be determined. A non-destructive biomarker would allow us to test molecular markers potentially involved directly in the ageing process, to monitor the effectiveness of therapeutic interventions to delay ageing, and provide a useful measure of general health of the organism. In the model organism Drosophila, various behavioural phenotypes change directionally with age, but we do not know whether they predict lifespan. Here we measure activity and sleep parameters in 64 wild type male flies from two recently wild-caught populations over the course of their natural lives, and determine whether such measures may predict biological age and ultimate lifespan. Indices of sleep fragmentation and circadian rhythm were the best predictors of lifespan, though population differences were evident. However, when used to predict a biological age of 50 % lifespan elapsed our best behavioural measure was slightly less accurate and less precise compared with using chronological age as predictor.

Cytoplasmic male sterility in Drosophila melanogaster associated with a mitochondrial CYTB variant

Heredity, 2011

Aging Cell, 2008

Mitochondria are thought to play a central role in aging. In humans, specific naturally occurring... more Mitochondria are thought to play a central role in aging. In humans, specific naturally occurring mitochondrial genetic variants are overrepresented among centenarians, but only in certain populations; therefore, we cannot tell whether this effect is due solely to mitochondrial genetics or to nuclear-mitochondrial gene complexes, nor do we know the magnitude of the effect in terms we can relate to, such as mean lifespan differences. To examine the effects of natural mitochondrial DNA (mtDNA) variation on lifespan, we need to vary the mitochondrial genotype while controlling the nuclear genotype. Here, nuclear genome replacement is achieved using strains of Drosophila melanogaster bearing multiply inverted 'balancer' chromosomes that suppress recombination, and an isogenic donor strain, thus forcing replacement of entire chromosomes in a single cross while suppressing recombination. Lifespans of wild-type mtDNA variants on the chromosome replacement background vary substantially, and sequencing of the entire protein coding mitochondrial genomes indicates that these lifespan differences are sometimes associated with single amino acid differences. On other nuclear genetic backgrounds, the magnitude and direction of these lifespan effects can change dramatically, and this can be due to changes in baseline mortality risk, rate of aging and/or time of onset of aging. The limited mtDNA variation in D. melanogaster makes it an ideal organism for biochemical studies to link genotype and aging phenotype.

Mitochondrion, 2019

Mitochondrial genetic variation can have profound effects on fitness, and the mitotype must inter... more Mitochondrial genetic variation can have profound effects on fitness, and the mitotype must interact with both the nuclear genes and the environment. We used Drosophila to investigate the extent to which mitotype effects on lifespan and activity are modulated by nucleotype and environmental variation. When nucleotype is varied, mitochondrial effects on lifespan persisted but were relatively small, and still male biased. Varying food as well, mitotype had substantial effects on male climbing speed, modifiable by nucleotype but less so by diet. Finally, mitotype affected fly lifespan much more in a cage environment compared with a vial, also modifiable by nucleotype and diet. The cage may represent a stressful environment. Mitochondrial genotype may affect fitness much more in conditions of stress, which may have implications for human health.

ABSTRACTA large body of studies has demonstrated that genetic variation that resides outside of t... more ABSTRACTA large body of studies has demonstrated that genetic variation that resides outside of the cell nucleus can affect the organismal phenotype. The cytoplasm is home to the mitochondrial genome and, at least in arthropods, often hosts intracellular endosymbiotic bacteria such asWolbachia. While numerous studies have implicated epistatic interactions between cytoplasmic and nuclear genetic variation as key to mediating patterns of phenotypic expression, two outstanding questions remain. Firstly, the relative contribution of mitochondrial genetic variation to other cytoplasmic sources of variation in shaping the phenotypic outcomes of cyto-nuclear interactions remains unknown. Secondly, it remains unclear whether the outcomes of cyto-nuclear interactions will manifest differently across the two sexes, as might be predicted given that cytoplasmic genomes are screened by natural selection only through females as a consequence of their maternal inheritance. Here, we address these q...

The Drosophila melanogaster gene chico encodes an insulin receptor substrate that functions in an... more The Drosophila melanogaster gene chico encodes an insulin receptor substrate that functions in an insulin/insulin-like growth factor (IGF) signaling pathway. In the nematode Caenorhabditis elegans, insulin/IGF signaling regulates adult longevity. We found that mutation of chico extends fruit fl y median life-span by up to 48% in homozygotes and 36% in heterozygotes. Extension of life-span was not a result of impaired oogenesis in chico females, nor was it consistently correlated with increased stress resistance. The dwarf phenotype of chico homozygotes was also unnecessary for extension of life-span. The role of insulin/IGF signaling in regulating animal aging is therefore evolutionarily conserved

Genetics, 1994

In Drosophila melanogaster, weak incompatibility in crosses between infected and uninfected strai... more In Drosophila melanogaster, weak incompatibility in crosses between infected and uninfected strains is associated with a Wolbachia microorganism. Crosses between infected males and uninfected females show a reduction (15-30%) in egg hatch. Progeny tests indicated that the infection is widespread in Australian D. melanogaster populations and that populations are polymorphic for the presence of the infection. The infection status of 266 lines from 12 populations along the eastern coast of Australia was determined by 4',6-diamidino-2-phenylindole (DAPI) staining of embryos. All populations contained both infected and uninfected flies. Infection frequencies varied between populations but there was no discernible geographical pattern. Laboratory experiments indicated that the infection was not associated with a reduction in fecundity as in Drosophila simulans. Incompatibility levels could not be increased by laboratory selection on isofemale lines. Factors contributing to the persist...

Philosophical Transactions of the Royal Society B: Biological Sciences, 2019

Evolutionary theory proposes that maternal inheritance of mitochondria will facilitate the accumu... more Evolutionary theory proposes that maternal inheritance of mitochondria will facilitate the accumulation of mitochondrial DNA (mtDNA) mutations that are harmful to males but benign or beneficial to females. Furthermore, mtDNA haplotypes sampled from across a given species distribution are expected to differ in the number and identity of these ‘male-harming’ mutations they accumulate. Consequently, it is predicted that the genetic variation which delineates distinct mtDNA haplotypes of a given species should confer larger phenotypic effects on males than females (reflecting mtDNA mutations that are male-harming, but female-benign), or sexually antagonistic effects (reflecting mutations that are male-harming, but female-benefitting). These predictions have received support from recent work examining mitochondrial haplotypic effects on adult life-history traits in Drosophila melanogaster . Here, we explore whether similar signatures of male-bias or sexual antagonism extend to a key phys...

Trends in Ecology & Evolution, 1996

In Drosophila simulans, cytoplasmically transmitted Wolbachia microbes cause reduced egg hatch wh... more In Drosophila simulans, cytoplasmically transmitted Wolbachia microbes cause reduced egg hatch when infected males mate with uninfected females. A Wolbachia infection and an associated mtDNA variant have spread northward through California since 1986. PCR assays show that Wolbachia infection is prevalent throughout the continental US and Central and South America, but some lines from Florida and Ecuador that are PCR-positive for Wolbachia do not cause incompatibility. We estimate from natural populations infection frequencies and the transmission and incompatibility parameter values that affect the spread of the infection. On average, infected females from nature produce 3-4% uninfected ova. Infected females with relatively low fidelity of maternal transmission show partial incompatibility with very young infected laboratory males. Nevertheless, crosses between infected flies in nature produce egg-hatch rates indistinguishable from those produced by crosses between uninfected individuals. Incompatible crosses in nature produce hatch rates 30-70% as high as those from compatible crosses. Wildcaught infected and uninfected females are equally fecund in the laboratory. Incompatibility decreases with male age, and age-specific incompatibility levels suggest that males mating in nature may often be 2 or 3 weeks old. Our parameter estimates accurately predict the frequency of Wolbachia infection in California populations. MM insect species harbor microbes related to Wolbachia pipientis that make infected males reproductively incompatible with uninfected females

Heredity, 1996

Microbes of the genus Wolbachia are transmitted by their hosts via the maternal parent and are re... more Microbes of the genus Wolbachia are transmitted by their hosts via the maternal parent and are responsible for cytoplasmic incompatibility among insect populations. This phenomenon can result in Wolbachia spreading through natural populations as previously demonstrated in Drosophila simulans. Here we describe another Wolbachia infection in D. simulans that does not cause cytoplasmic incompatibility. This is a property of the Wolbachia rather than the nuclear background. The infection occurs at a low frequency in natural populations from eastern Australia. The infection shows perfect maternal transmission in the field and does not cause any detectable deleterious effects on its host. These findings suggest that the Wolbachia infection behaves like a neutral variant in populations. The infection may represent an evolutionary outcome of interactions between Wolbachia infections and their hosts.

Experimental Gerontology, 2004

The link between resting metabolic rate and aging, measured as adult lifespan, was investigated i... more The link between resting metabolic rate and aging, measured as adult lifespan, was investigated in Drosophila melanogaster by (i) comparing lifespan and metabolic rate of individual flies, (ii) examining the effect of dietary-restriction on the metabolic rate of adult flies, and (iii) comparing the metabolic rate of wild-type and insulin/IGF-1 signalling mutant chico 1 flies. The resting oxygen consumption of 65 individually housed and fully fed Drosophila was measured weekly throughout their lifetime. There was no significant difference in the mass-specific rate of oxygen consumption between cohorts that differed in lifespan. Nor was there any statistical correlation between mass-specific oxygen consumption and lifespan of individual Drosophila. The average mass-specific rate of oxygen consumption at 25 8C was 3.52^0.07 ml O 2 mg 21 h 21. Variation in mass-specific metabolic rate explained only 4% of variation in individual life span in these flies. Contrary to predictions from the 'rate of living' theory of aging lifetime oxygen consumption was not constant and the lifespan of individual flies accounted for 91% of their lifetime oxygen consumption. An average Drosophila consumes about 3 ml O 2 during its adult life. Dietary-restriction had no effect on mass-specific resting metabolic rate both when measured as oxygen consumption by respirometry and when measured as heat production by microcalorimetry. The mass-specific resting heat production of fully fed adult flies at 25 8C averaged 17.3^0.3 mW mg 21. Similarly there was no difference in mass-specific metabolic rate of wild-type flies and longliving chico 1 insulin/IGF-1 signalling mutant flies, either when measured as oxygen consumption or heat production. Thus, individual variation in lifespan in wild-type flies, and life extension by dietary-restriction and reduced insulin/IGF-1 signalling is not attributable to differences in metabolic rate.

Comparative Biochemistry and Physiology Part D: Genomics and Proteomics, 2010

Here we report the sequence of three mitochondrial genomes from yeasts of the Nakaseomyces clade ... more Here we report the sequence of three mitochondrial genomes from yeasts of the Nakaseomyces clade that includes the pathogenic yeast Candida glabrata, namely, that of Kluyveromyces delphensis, Candida castellii and Kluyveromyces bacillisporus. The gene content is equivalent to that of C. glabrata, but reveals the existence of new group I introns in COX1 and CYTB and new potential intronic endonucleases. Gene order is highly rearranged in these genomes, which contain numerous palindromic GC clusters. The more GC nucleotides these elements contain, the longer and more AT-rich are the intergenes containing them, leading to a direct relationship between the number of Gs and Cs within the elements and the size of the genomes. Thus, there is a fivefold difference in size between the smallest and the largest mitochondrial genome, with the largest being the most AT-rich overall. Sequences are available under EMBL accession numbers FM995164, FM995165, and FM995166.

Aging Cell, 2008

Drosophila melanogaster is widely considered to be an attractive model organism for studying the ... more Drosophila melanogaster is widely considered to be an attractive model organism for studying the functions of the carbohydrate moieties of glycoconjugates produced by higher eukaryotes. However, the pathways of glycoconjugate biosynthesis are not as well defined in insects as they are in higher eukaryotes. One way to address this problem is to identify genes in the Drosophila genome that might encode relevant functions, express them, and determine the functions of the gene products by direct biochemical assays. In this study, we used this approach to identify a putative Drosophila β4-galactosyltransferase gene and determine the enzymatic activity of its product. Biochemical assays demonstrated that this gene product could transfer galactose from UDP-galactose to a β-xylosyl acceptor, but not to other acceptors in vitro. The apparent K m values for the donor and acceptor substrates indicated that this gene product is a functional galactosyltransferase. Additional assays showed that the enzyme is activated by manganese, has a slightly acidic pH optimum, and is localized in the insect cell Golgi apparatus. These results showed that Drosophila encodes an ortholog of human β4-galactosyltransferase-VII, also known as galactosyltransferase I, which participates in proteoglycan biosynthesis by transferring the first galactose to xylose in the linkage tetrasaccharide of glycosaminoglycan side chains.

Ageing Research Reviews, 2013

Drosophila and Caenorhabditis elegans have provided the largest body of evidence addressing the F... more Drosophila and Caenorhabditis elegans have provided the largest body of evidence addressing the Free Radical Theory of ageing, however the evidence has not been unequivocally supportive. Oxidative damage to DNA is probably not a major contributor, damage to lipids is assuming greater importance and damage to proteins probably the source of pathology. On balance the evidence does not support a primary role of oxidative damage in ageing in C. elegans, perhaps because of its particular energy metabolic and stress resistance profile. Evidence is more numerous, varied and consistent and hence more compelling for Drosophila, although not conclusive. However there is good evidence for a role of oxidative damage in later life pathology. Future work should: 1/ make more use of protein oxidative damage measurements; 2/ use inducible transgenic systems or pharmacotherapy to ensure genetic equivalence of controls and avoid confounding effects during development; 3/ to try to delay ageing, target interventions which reduce and/or repair protein oxidative damage.

The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 2006

Many studies demonstrate changes in physiology, biochemistry, or behavior with age, but almost no... more Many studies demonstrate changes in physiology, biochemistry, or behavior with age, but almost no studies demonstrate such changes being predictive of aging. We subsampled from 10 genetically distinct strains of Drosophila melanogaster as they aged, at three time points, measuring change over time of parameters related to water balance (water content, desiccation survival, and K þ , Mg 2þ , and Ca 2þ levels). We then determined whether the change over time in any parameters is predictive of mean life span or time of onset of aging. We observed a schedule of aging-related changes. Time of onset of aging was negatively correlated with decline in desiccation resistance and with decline in K þ between days 0 and 15, and was positively correlated with decline in Ca 2þ between days 15 and 24. We suggest that the potassium result, at least, may be due to loss of functional cytoplasm. We also discuss the use of different estimates of aging in the context of this study.

Reliability and variability of sleep and activity as biomarkers of ageing in Drosophila

Biogerontology, 2012

There are currently no reliable biomarkers of ageing. A biomarker should indicate biological age,... more There are currently no reliable biomarkers of ageing. A biomarker should indicate biological age, that is, the amount of an animal's total lifespan it has lived and, therefore, the amount of time it has remaining. Some potential biomarkers cannot be validated as their measurement involves harm or death of the animal, such that its ultimate lifespan cannot be determined. A non-destructive biomarker would allow us to test molecular markers potentially involved directly in the ageing process, to monitor the effectiveness of therapeutic interventions to delay ageing, and provide a useful measure of general health of the organism. In the model organism Drosophila, various behavioural phenotypes change directionally with age, but we do not know whether they predict lifespan. Here we measure activity and sleep parameters in 64 wild type male flies from two recently wild-caught populations over the course of their natural lives, and determine whether such measures may predict biological age and ultimate lifespan. Indices of sleep fragmentation and circadian rhythm were the best predictors of lifespan, though population differences were evident. However, when used to predict a biological age of 50 % lifespan elapsed our best behavioural measure was slightly less accurate and less precise compared with using chronological age as predictor.

Cytoplasmic male sterility in Drosophila melanogaster associated with a mitochondrial CYTB variant

Heredity, 2011

Aging Cell, 2008

Mitochondria are thought to play a central role in aging. In humans, specific naturally occurring... more Mitochondria are thought to play a central role in aging. In humans, specific naturally occurring mitochondrial genetic variants are overrepresented among centenarians, but only in certain populations; therefore, we cannot tell whether this effect is due solely to mitochondrial genetics or to nuclear-mitochondrial gene complexes, nor do we know the magnitude of the effect in terms we can relate to, such as mean lifespan differences. To examine the effects of natural mitochondrial DNA (mtDNA) variation on lifespan, we need to vary the mitochondrial genotype while controlling the nuclear genotype. Here, nuclear genome replacement is achieved using strains of Drosophila melanogaster bearing multiply inverted 'balancer' chromosomes that suppress recombination, and an isogenic donor strain, thus forcing replacement of entire chromosomes in a single cross while suppressing recombination. Lifespans of wild-type mtDNA variants on the chromosome replacement background vary substantially, and sequencing of the entire protein coding mitochondrial genomes indicates that these lifespan differences are sometimes associated with single amino acid differences. On other nuclear genetic backgrounds, the magnitude and direction of these lifespan effects can change dramatically, and this can be due to changes in baseline mortality risk, rate of aging and/or time of onset of aging. The limited mtDNA variation in D. melanogaster makes it an ideal organism for biochemical studies to link genotype and aging phenotype.