| 1. |
- Iinatti Brengdahl, Martin, 1990-, et al.
(författare)
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Age-specific effects of deletions: Implications for ageing theories
- 2022
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Annan publikationabstract
- Evolution of ageing requires mutations with late-life deleterious effects. Classic theories assume these mutations either have neutral (Mutation Accumulation) or beneficial (Antagonistic Pleiotropy) effects early in life, but it is also possible that they start out as mildly harmful and gradually become more deleterious with age. Despite a wealth of studies on the genetics of ageing, we still have a poor understanding of how common mutations with age-specific effects are and what ageing theory they support. To advance our knowledge on this topic we measure a set of genomic deletions for their heterozygous effects on juvenile performance, fecundity at three ages, and adult survival. Most deletions have age-specific effects, and these are commonly harmful late in life. Many of the deletions assayed here would thus contribute to ageing if present in a population. Taking only age-specific fecundity into account, some deletions support Antagonistic Pleiotropy, but the majority of them better fit a scenario where their negative effects on fecundity become progressively worse with age. Most deletions have a negative effect on juvenile performance, a fact which strengthens the conclusion that deletions primarily contribute to ageing through negative effects that amplify with age.
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| 2. |
- Iinatti Brengdahl, Martin, et al.
(författare)
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Age-specific effects of deletions: implications for aging theories
- 2023
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Ingår i: Evolution. - : OXFORD UNIV PRESS. - 0014-3820 .- 1558-5646. ; 77:1, s. 254-263
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Tidskriftsartikel (refereegranskat)abstract
- The evolution of aging requires mutations with late-life deleterious effects. Classic theories assume these mutations either have neutral (mutation accumulation) or beneficial (antagonistic pleiotropy) effects early in life, but it is also possible that they start out as mildly harmful and gradually become more deleterious with age. Despite a wealth of studies on the genetics of aging, we still have a poor understanding of how common mutations with age-specific effects are and what aging theory they support. To advance our knowledge on this topic, we measure a set of genomic deletions for their heterozygous effects on juvenile performance, fecundity at 3 ages, and adult survival. Most deletions have age-specific effects, and these are commonly harmful late in life. Many of the deletions assayed here would thus contribute to aging if present in a population. Taking only age-specific fecundity into account, some deletions support antagonistic pleiotropy, but the majority of them better fit a scenario where their negative effects on fecundity become progressively worse with age. Most deletions have a negative effect on juvenile performance, a fact that strengthens the conclusion that deletions primarily contribute to aging through negative effects that amplify with age.
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| 3. |
- Iinatti Brengdahl, Martin, 1990-, et al.
(författare)
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Data from: Sex differences in lifespan: females homozygous for the X chromosome do not suffer the shorter lifespan predicted by the unguarded X hypothesis
- 2018
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Annan publikationabstract
- Lifespan differs between the sexes in many species. Three hypotheses to explain this interesting pattern have been proposed, involving different drivers: sexual selection, asymmetrical inheritance of cytoplasmic genomes, and hemizygosity of the X(Z) chromosome (the unguarded X hypothesis). Of these, the unguarded X has received the least experimental attention. This hypothesis suggests that the heterogametic sex suffers a shortened lifespan because recessive deleterious alleles on its single X(Z) chromosome are expressed unconditionally. In Drosophila melanogaster, the X chromosome is unusually large (~20% of the genome), providing a powerful model for evaluating theories involving the X. Here, we test the unguarded X hypothesis by forcing D. melanogaster females from a laboratory population to express recessive X-linked alleles to the same degree as males, using females exclusively made homozygous for the X chromosome. We find no evidence for reduced lifespan or egg-to-adult viability due to X homozygozity. In contrast, males and females homozygous for an autosome both suffer similar, significant reductions in those traits. The logic of the unguarded X hypothesis is indisputable, but our results suggest that the degree to which recessive deleterious X-linked alleles depress performance in the heterogametic sex appears too small to explain general sex differences in lifespan.
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| 4. |
- Iinatti Brengdahl, Martin, et al.
(författare)
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Deleterious mutations show increasing negative effects with age in Drosophila melanogaster
- 2020
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Ingår i: BMC Biology. - : BMC. - 1741-7007. ; 18:1
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Tidskriftsartikel (refereegranskat)abstract
- Background In order for aging to evolve in response to a declining strength of selection with age, a genetic architecture that allows for mutations with age-specific effects on organismal performance is required. Our understanding of how selective effects of individual mutations are distributed across ages is however poor. Established evolutionary theories assume that mutations causing aging have negative late-life effects, coupled to either positive or neutral effects early in life. New theory now suggests evolution of aging may also result from deleterious mutations with increasing negative effects with age, a possibility that has not yet been empirically explored. Results To directly test how the effects of deleterious mutations are distributed across ages, we separately measure age-specific effects on fecundity for each of 20 mutations inDrosophila melanogaster. We find that deleterious mutations in general have a negative effect that increases with age and that the rate of increase depends on how deleterious a mutation is early in life. Conclusions Our findings suggest that aging does not exclusively depend on genetic variants assumed by the established evolutionary theories of aging. Instead, aging can result from deleterious mutations with negative effects that amplify with age. If increasing negative effect with age is a general property of deleterious mutations, the proportion of mutations with the capacity to contribute towards aging may be considerably larger than previously believed.
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| 5. |
- Iinatti Brengdahl, Martin, 1990-
(författare)
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The effects of deleterious mutations on ageing
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Ageing is defined as the deterioration of an individual's physiological performance with advancing age, which leads to a decrease in reproduction and/or survival. The question why most organisms age has preoccupied humans for millennia and, over the last decades, resulted in an ever-increasing research effort to understand this phenomenon. The full explanation for why we age has, however, remained elusive. Evolutionary theories of ageing are based on two assumptions, which together inevitably result in organismal ageing, that the strength of selection declines with age and that mutations have age-specific effects. While a declining strength of selection with age naturally follows from external sources of death, the age-specific properties of mutations is a topic we only have a rudimentary understanding of. Established theories of ageing predict that mutations either have a beneficial or neutral effect early in life, and a deleterious effect later in life. New theory suggests that mutations with a small negative effect already early in life can also contribute to the evolution of ageing, a possibility that potentially explains empirical results that have been difficult to reconcile with current theories. Deleterious mutations may also directly or indirectly explain the sex differences in ageing and lifespan that are observed in many species.In this thesis, I investigate the age-specificity of deleterious mutations and test if they contribute to sex differences in ageing and lifespan. In paper I and II, I investigate the age-specificity of a set of supposedly deleterious mutations, by estimating their effect on fecundity in young, middle-aged and moderately old Drosophila melanogaster females. The majority of tested mutations show age-specific effects, with a detrimental effect that gradually increases with advancing age. These results thus support that mutations expressing a small negative effect already at an early age also can contribute to the evolution of ageing.In paper III, I manipulate the expression of autosomal deleterious mutations in D. melanogaster through inbreeding, and test if this has different effects on male and female ageing as predicted if sexual selection has shaped sex differences in ageing through condition-dependent investment in current reproduction. I find a sex difference in ageing in high condition, but not in low condition flies, suggesting that sexual selection indeed has shaped how resources are allocated between reproduction and somatic maintenance in relation to condition. I did not find a corresponding response for lifespan.In paper IV, I investigate if sex differences in lifespan are partly explained by the unconditional expression of recessive deleterious mutations on the single X-chromosome in males (the Unguarded X hypothesis). I test this hypothesis by forcing D. melanogaster females to express recessive mutations on the X-chromosome to the same extent as males do and assess their effect on female lifespan. This direct test did not show the expected reduction in female lifespan and thus fails to support the Unguarded X hypothesis as a major explanation of sex differences in lifespan.
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| 6. |
- Malacrino, Antonino, et al.
(författare)
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Ageing desexualizes the Drosophila brain transcriptome
- 2022
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Ingår i: Proceedings of the Royal Society of London. Biological Sciences. - London : The Royal Society Publishing. - 0962-8452 .- 1471-2954. ; 289:1980
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Tidskriftsartikel (refereegranskat)abstract
- General evolutionary theory predicts that individuals in low condition should invest less in sexual traits compared to individuals in high condition. Whether this positive association between condition and investment also holds between young (high condition) and senesced (low condition) individuals is however less clear, since elevated investment into reproduction may be beneficial when individuals approach the end of their life. To address how investment into sexual traits changes with age, we study genes with sex-biased expression in the brain, the tissue from which sexual behaviours are directed. Across two distinct populations of Drosophila melanogaster, we find that old brains display fewer sex-biased genes, and that expression of both male-biased and female-biased genes converges towards a sexually intermediate phenotype owing to changes in both sexes with age. We further find that sex-biased genes in general show heightened age-dependent expression in comparison to unbiased genes and that age-related changes in the sexual brain transcriptome are commonly larger in males than females. Our results hence show that ageing causes a desexualization of the fruit fly brain transcriptome and that this change mirrors the general prediction that low condition individuals should invest less in sexual phenotypes.
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| 7. |
- Naresh, Vinesh Shenoi, et al.
(författare)
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A genome-wide test for paternal indirect genetic effects on lifespan in Drosophila melanogaster
- 2022
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Ingår i: Proceedings of the Royal Society of London. Biological Sciences. - : The Royal Society. - 0962-8452 .- 1471-2954. ; 289:1974
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Tidskriftsartikel (refereegranskat)abstract
- Exposing sires to various environmental manipulations has demonstrated that paternal effects can be non-trivial also in species where male investment in offspring is almost exclusively limited to sperm. Whether paternal effects also have a genetic component (i.e. paternal indirect genetic effects (PIGEs)) in such species is however largely unknown, primarily because of methodological difficulties separating indirect from direct effects of genes. PIGEs may nevertheless be important since they have the capacity to contribute to evolutionary change. Here we use Drosophila genetics to construct a breeding design that allows testing nearly complete haploid genomes (more than 99%) for PIGEs. Using this technique, we estimate the variance in male lifespan due to PIGEs among four populations and compare this to the total paternal genetic variance (the sum of paternal indirect and direct genetic effects). Our results indicate that a substantial part of the total paternal genetic variance results from PIGEs. A screen of 38 haploid genomes, randomly sampled from a single population, suggests that PIGEs also influence variation in lifespan within populations. Collectively, our results demonstrate that PIGEs may constitute an underappreciated source of phenotypic variation.
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| 8. |
- Naresh, Vinesh Shenoi, et al.
(författare)
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On aging and age-specific effects of spontaneous mutations
- 2023
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Ingår i: Evolution. - : Oxford University Press. - 0014-3820 .- 1558-5646. ; 77:8, s. 1780-1790
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Tidskriftsartikel (refereegranskat)abstract
- Evolutionary theory assumes that mutations that cause aging either have beneficial early-life effects that gradually become deleterious with advancing age (antagonistic pleiotropy [AP]) or that they only have deleterious effects at old age (mutation accumulation [MA]). Mechanistically, aging is predicted to result from damage accumulating in the soma. While this scenario is compatible with AP, it is not immediately obvious how damage would accumulate under MA. In a modified version of the MA theory, it has been suggested that mutations with weakly deleterious effects at young age can also contribute to aging, if they generate damage that gradually accumulates with age. Mutations with increasing deleterious effects have recently gained support from theoretical work and studies of large-effect mutations. Here we address if spontaneous mutations also have negative effects that increase with age. We accumulate mutations with early-life effects in Drosophila melanogaster across 27 generations and compare their relative effects on fecundity early and late in life. Our mutation accumulation lines on average have substantially lower early-life fecundity compared to controls. These effects were further maintained throughout life, but they did not increase with age. Our results suggest that most spontaneous mutations do not contribute to damage accumulation and aging.
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| 9. |
- Shenoi Naresh, Vinesh, et al.
(författare)
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A genome-wide test for paternal indirect genetic effects on lifespan in Drosophila melanogaster
- 2022
-
Annan publikationabstract
- Exposing sires to various environmental manipulations has demonstrated that paternal effects can be non-trivial also in species where male investment in offspring is almost exclusively limited to sperm. Whether paternal effects also have a genetic component (i.e. paternal indirect genetic effects - PIGEs) in such species is however largely unknown, primarily because of methodological difficulties separating indirect from direct effects of genes. PIGEs may nevertheless be important, since they have the capacity to contribute to evolutionary change. Here we use Drosophila genetics to construct a breeding design that allows testing nearly complete haploid genomes (>99%) for PIGEs. Using this technique, we estimate the variance in male lifespan due to PIGEs among four populations and compare this to the total paternal genetic variance (the sum of paternal indirect and direct genetic effects). Our results indicate that a substantial part of the total paternal genetic variance results from PIGEs. A screen of 38 haploid genomes, randomly sampled from a single population, suggests that PIGEs also influence variation in lifespan within populations. Collectively, our results demonstrate that PIGEs may constitute an underappreciated source of phenotypic variation.
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| 10. |
- Shenoi, Vinesh, et al.
(författare)
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On ageing and age-specific effects of spontaneous mutations
- 2023
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Annan publikationabstract
- Evolutionary theories of ageing assume causal mutations either have beneficial early-life effects which gradually become deleterious with advancing age (antagonistic pleiotropy: AP) or mutations that only have deleterious effects at old age (mutation accumulation: MA). Mechanistically, ageing is predicted to result from damage accumulating in the soma. While this scenario is compatible with AP, it is not immediately obvious how damage would accumulate under MA. In a modified version of the MA theory, it has been suggested that mutations with weakly deleterious effects at young age can also contribute to ageing, if they generate damage that gradually accumulates with age. Mutations with increasing deleterious effects have recently gained support from theoretical work and studies of large-effect mutations. Here we address if spontaneous mutations also have negative effects that increase with age. We accumulate mutations with early-life effects in Drosophila melanogaster across 27 generations and compare their relative effects on fecundity early and late in life. Our mutation accumulation lines on average have substantially lower early-life fecundity compared to controls. These effects were further maintained throughout life, but they did not increase with age. Our results thus suggest that most spontaneous mutations do not contribute to damage accumulation and ageing.
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