Age-specific effects of deletions: implications for aging theories.

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.

Ageing desexualizes the Drosophila brain transcriptome.

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.

Deleterious mutations show increasing negative effects with age in Drosophila melanogaster.

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 in Drosophila 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.

Incidence of gastro-intestinal anomalies and surgical outcome of fetuses diagnosed with echogenic bowel and bowel dilatation.

BACKGROUND: We aimed to evaluate the incidence of gastro-intestinal (GI) anomalies and surgical outcome in fetuses diagnosed with either echogenic bowel (EB) or EB plus bowel dilatation (BD) but no associated chromosomal, DNA and/or additional structural defects. METHODS: A 10-year (2008-2018) retrospective review was performed on all fetuses diagnosed with EB and EB+BD (RES-18-0000-072Q). Results are reported as number of cases (%) and mean ±SD. Fisher's exact test, Mann-Whitney U test and logistic regression were used to identify differences between groups and predisposing factors for gastro-intestinal anomalies. RESULTS: We identified 41 fetuses with EB and 14 fetuses with EB+BD. Post-natal surgical intervention was required in no patient of the EB group and in 7/14 (50%) of the EB+BD group, p<0.001. The risk of having a GI anomaly was higher in the EB+BD group (RR 42.0 [2.5-691.6]; p=0.009). Advanced maternal age (p=0.04), ascites (p=0.006) and polyhydramnios (p=0.007) were associated with a higher incidence of GI pathology. CONCLUSIONS: In fetuses with no associated chromosomal, DNA and/or additional structural defects, the finding of EB+BD is associated with 50% incidence of GI anomalies at birth. Advanced maternal age, ascites and polyhydramnios are also associated with higher incidence of GI pathology at birth.

Heightened condition-dependence of the sexual transcriptome as a function of genetic quality in Drosophila melanogaster head tissue.

Theory suggests sexual traits should show heightened condition-dependent expression. This prediction has been tested extensively in experiments where condition has been manipulated through environmental quality. Condition-dependence as a function of genetic quality has, however, only rarely been addressed, despite its central importance in evolutionary theory. To address the effect of genetic quality on expression of sexual and non-sexual traits, we here compare gene expression in Drosophila melanogaster head tissue between flies with intact genomes (high condition) and flies carrying a major deleterious mutation (low condition). We find that sex-biased genes show heightened condition-dependent expression in both sexes, and that expression in low condition males and females regresses towards a more similar expression profile. As predicted, sex-biased expression was more sensitive to condition in males compared to females, but surprisingly female-biased, rather than male-biased, genes show higher sensitivity to condition in both sexes. Our results thus support the fundamental predictions of the theory of condition-dependence when condition is a function of genetic quality.

Putatively adaptive genetic variation in the giant California sea cucumber (Parastichopus californicus) as revealed by environmental association analysis of restriction-site associated DNA sequencing data.

Understanding the spatial scale of local adaptation and the factors associated with adaptive diversity are important objectives for ecology and evolutionary biology, and have significant implications for effective conservation and management of wild populations and natural resources. In this study, we used an environmental association analysis to identify important bioclimatic variables correlated with putatively adaptive genetic variation in a benthic marine invertebrate-the giant California sea cucumber (Parastichopus californicus)-spanning coastal British Columbia and southeastern Alaska. We used a redundancy analysis (RDA) with 3,699 single nucleotide polymorphisms (SNPs) obtained using RAD sequencing to detect candidate markers associated with 11 bioclimatic variables, including sea bottom and surface conditions, across two spatial scales (entire study area and within subregions). At the broadest scale, RDA revealed 59 candidate SNPs, 86% of which were associated with mean bottom temperature. Similar patterns were identified when population structure was accounted for. Additive polygenic scores, which provide a measure of the cumulative signal across all candidate SNPs, were strongly correlated with mean bottom temperature, consistent with spatially varying selection across a thermal gradient. At a finer scale, 23 candidate SNPs were detected, primarily associated with surface salinity (26%) and bottom current velocity (17%). Our findings suggest that environmental variables may play a role as drivers of spatially varying selection for P. californicus. These results provide context for future studies to evaluate the genetic basis of local adaptation in P. californicus and help inform the relevant scales and environmental variables for in situ field studies of putative adaptive variation in marine invertebrates.

Genetic Quality Affects the Rate of Male and Female Reproductive Aging Differently in Drosophila melanogaster.

Males and females often maximize fitness by pursuing different reproductive strategies, with males commonly assumed to benefit more from increased resource allocation into current reproduction. Such investment should trade off with somatic maintenance and may explain why males frequently live shorter than females. It also predicts that males should experience faster reproductive aging. Here we investigate whether reproductive aging and life span respond to condition differently in male and female Drosophila melanogaster, as predicted if sexual selection has shaped male and female resource-allocation patterns. We manipulate condition through genetic quality by comparing individuals inbred or outbred for a major autosome. While genetic quality had a similar effect on condition in both sexes, condition had a much larger general effect on male reproductive output than on female reproductive output, as expected when sexual selection on vigor acts more strongly on males. We find no differences in reproductive aging between the sexes in low condition, but in high condition reproductive aging is relatively faster in males. No corresponding sex-specific change was found for life span. The sex difference in reproductive aging appearing in high condition was specifically due to a decreased aging rate in females rather than any change in males. Our results suggest that females age slower than males in high condition primarily because sexual selection has favored sex differences in resource allocation under high condition, with females allocating relatively more toward somatic maintenance than males.

Sex differences in life span: Females homozygous for the X chromosome do not suffer the shorter life span predicted by the unguarded X hypothesis.

Life span 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 life span 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 life span 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 life span.

Mutation, condition, and the maintenance of extended lifespan in Drosophila.

The evolutionary theory of aging predicts that longevity will decline via drift or age-specific tradeoffs when selection favors early life fitness. Many Drosophila melanogaster populations continually terminated at young adult ages retain surprisingly long postselection lifespans. We compiled three decades of longevity data from the Ives population, demonstrating that postselective longevity was both substantial (30 days) and temporally stable over this period. Recently, alleles with positive pleiotropic effects between adjacent ages, particularly those affecting overall condition, have been integrated into the theory and may explain the extended longevity observed. We experimentally tested this hypothesis by isolating 20 hemiclones from Ives and allowing spontaneous mutations to accumulate (MA) for 35 generations. Fitness and longevity were positively genetically correlated in control females, and both traits declined due to MA. Crucially, MA induced a strong positive genetic correlation between the traits in both sexes, implying that mutations with early-life impacts also reduce late-life survival. Our results suggest that extended postreproductive longevity is actively maintained by selection for early-life fitness via positive pleiotropy and is not a merely a byproduct of exhaustion of genetic variation or weak drift. Thus mutation-selection balance for early fitness may govern variance in longevity in this system: a balance struck remarkably long after selection for continued survival ceases.

Minimally invasive adrenalectomy in children.

PURPOSE: Minimally invasive adrenalectomy (MIA) is the criterion standard for removal of small adrenal tumors in adults. The purpose of this review was to determine the place of MIA in children. METHODS: The authors conducted a systematic review of the pediatric and adult literature about MIA, focusing on the technique and indications. RESULTS: Minimally invasive adrenalectomy appears superior to open adrenalectomy for small tumors. The potential advantages of MIA are appealing for postoperative pain, risk of intestinal obstruction, and quality of scars. The most common approach is the transperitoneal lateral laparoscopy, which allows for a large working space. For small tumors or for bilateral adrenalectomy, the prone retroperitoneoscopy is a promising new technique. In children, the learning curve is an issue because the indications are rare. The most common indication is neuroblastoma without image-defined surgical risk factors. The incidence of local recurrence is low, but the follow-up is short in most cases. CONCLUSIONS: Minimally invasive adrenalectomy is promising for removal of small adrenal tumors. Long-term follow-up is required to evaluate the efficacy of MIA in neuroblastomas. Benign diseases are excellent candidates for this minimally invasive technique.

Susceptibility of the male fitness phenotype to spontaneous mutation.

Adult reproductive success can account for a large fraction of male fitness, however, we know relatively little about the susceptibility of reproductive traits to mutation-accumulation (MA). Estimates of the mutational rate of decline for adult fitness and its components are controversial in Drosophila melanogaster, and post-copulatory performance has not been examined. We therefore separately measured the consequences of MA for total male reproductive success and its major pre-copulatory and post-copulatory components: mating success and sperm competitive success. We also measured juvenile viability, an important fitness component that has been well studied in MA experiments. MA had strongly deleterious effects on both male viability and adult fitness, but the latter declined at a much greater rate. Mutational pressure on total fitness is thus much greater than would be predicted by viability alone. We also noted a significant and positive correlation between all adult traits and viability in the MA lines, suggesting pleiotropy of mutational effect as required by 'good genes' models of sexual selection.

Experimental mutation-accumulation on the X chromosome of Drosophila melanogaster reveals stronger selection on males than females.

BACKGROUND: Sex differences in the magnitude or direction of mutational effect may be important to a variety of population processes, shaping the mutation load and affecting the cost of sex itself. These differences are expected to be greatest after sexual maturity. Mutation-accumulation (MA) experiments provide the most direct way to examine the consequences of new mutations, but most studies have focused on juvenile viability without regard to sex, and on autosomes rather than sex chromosomes; both adult fitness and X-linkage have been little studied. We therefore investigated the effects of 50 generations of X-chromosome mutation accumulation on the fitness of males and females derived from an outbred population of Drosophila melanogaster. RESULTS: Fitness declined rapidly in both sexes as a result of MA, but adult males showed markedly greater fitness loss relative to their controls compared to females expressing identical genotypes, even when females were made homozygous for the X. We estimate that these mutations are partially additive (h ~ 0.3) in females. In addition, the majority of new mutations appear to harm both males and females. CONCLUSIONS: Our data helps fill a gap in our understanding of the consequences of sexual selection for genetic load, and suggests that stronger selection on males may indeed purge deleterious mutations affecting female fitness.

Prognostic factors of severe foetal megacystis.

BACKGROUND: At antenatal ultrasound, severe megacystis implies high foetal mortality rate. Traditionally, many of these foetuses undergo termination of pregnancy. We undertook a study to investigate the prognostic factor(s) for megacystis foetuses. METHODS: 61 consecutive cases of antenatally diagnosed severe megacystis between 1988 to 2008 were reviewed from a statewide tertiary referral centre for major foetal abnormalities. The data included the ultrasonic measurements and post-mortem pathologies. RESULTS: Mean gestational age (GA) at diagnosis was 17.0 weeks (range 11 to 39). The average bladder diameters for GA 10 to 14 weeks, 15 to 26 weeks, and 27 to 39 weeks were 32.5 mm, 45.7 mm, and 57.2 mm respectively. In males the most common cause of megacystis was posterior urethral valves in 32.6% (n = 17). The most common cause in females was urethral stenosis in 33% (n = 3). We compared the relative bladder size (as a percentage of normal for that gestational age) between the survivor group (n = 14) and the foetal/neonatal death group (n = 17). All terminations (n = 20) were excluded. The bladder sizes of the two groups were almost identical (310.2 ± 108% vs. 309.8 ± 120%). We analysed various prognostic factors. Megacystis foetuses with oligohydramnios had an increased risk of death compared to those who had megacystis without oligohydramnios (OR = 6.0; 95% CI 1.26 - 28.5, Chi-square: P = 0.019). CONCLUSION: Relative bladder size alone does not predict survival. The combination of severe megacystis and oligohydramnios implies complete obstruction of bladder outlet and is associated with high mortality rate. This provides clinicians with measurable evidence to predict survival. It also gives parents the option of avoiding unnecessary termination of pregnancy.