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Gaucher disease (GD), the most common lysosomal storage disorder (LSD), is caused by autosomal recessive mutations of the glucocerebrosidase gene, GBA1. In the majority of cases, GD has a non-neuropathic chronic form with adult onset (GD1), while other cases are more acute and severer neuropathic forms with early onset (GD2/3). Currently, no radical therapies are established for GD2/3. Notably, GD1, but not GD2/3, is associated with increased risk of Parkinson’s disease (PD), the elucidation of which might provide a clue for novel therapeutic strategies. In this context, the objective of the present study is to discuss that the evolvability of α-synuclein (αS) might be differentially involved in GD subtypes. Hypothetically, aging-associated PD features with accumulation of αS, and the autophagy-lysosomal dysfunction might be an antagonistic pleiotropy phenomenon derived from αS evolvability in the development in GD1, without which neuropathies like GD2/3 might be manifested due to the autophagy-lysosomal dysfunction. Supposing that the increased severity of GD2/3 might be attributed to the decreased activity of αS evolvability, suppressing the expression of β-synuclein (βS), a potential buffer against αS evolvability, might be therapeutically efficient. Of interest, a similar view might be applicable to Niemann-Pick type C (NPC), another LSD, given that the adult type of NPC, which is comorbid with Alzheimer’s disease, exhibits milder medical symptoms compared with those of infantile NPC. Thus, it is predicted that the evolvability of amyloid β and tau, might be beneficial for the adult type of NPC. Collectively, a better understanding of amyloidogenic evolvability in the pathogenesis of LSD may inform rational therapy development.

Empirical evidence for declines in fitness components (survival and reproductive performance) with age has recently accumulated in wild populations, highlighting that the process of senescence is nearly ubiquitous in the living world. Senescence patterns are highly variable among species and current evolutionary theories of ageing propose that such variation can be accounted for by differences in allocation to growth and reproduction during early life. Here, we compiled 26 studies of free-ranging vertebrate populations that explicitly tested for a trade-off between performance in early and late life. Our review brings overall support for the presence of early-late life tradeoffs, suggesting that the limitation of available resources leads individuals to trade somatic maintenance later in life for high allocation to reproduction early in life. We discuss our results in the light of two closely related theories of ageing—the disposable soma and the antagonistic pleiotropy theories—and propose that the principle of energy allocation roots the ageing process in the evolution of life-history strategies. Finally, we outline research topics that should be investigated in future studies, including the importance of natal environmental conditions in the study of trade-offs between early-and late-life performance and the evolution of sex-differences in ageing patterns.

80 I. 80 II. 81 III. 83 IV. 83 84 References 84 SUMMARY: Floral traits often show correlated variation, both within and across species. One explanation for this pattern of floral integration is that different elements of floral phenotypes are controlled by the same genes, that is, that the genetic architecture is pleiotropic. Recent studies from a range of model systems suggest that the pleiotropy is common among the loci responsible for floral divergence. Moreover, the effects of allelic substitutions at these loci are overwhelmingly aligned with direction of divergence, suggesting that the nature of the pleiotropic effects was adaptive. Molecular genetic studies have revealed the functional basis for some of these effects, although much remains to be discovered with respect to the molecular, biochemical and developmental mechanisms underlying most quantitative trait loci (QTL) responsible for floral differences. Developing a detailed understanding of the nature of pleiotropic mutations and their phenotypic consequences is crucial for modeling how the genetic architecture of trait variation influences the tempo and trajectory of floral evolution.

Specialism is widespread in nature, generating and maintaining diversity, but recent work has demonstrated that generalists can be equally fit as specialists in some shared environments. This no-cost generalism challenges the maxim that ‘the jack of all trades is the master of none’, and requires evolutionary genetic mechanisms explaining the existence of specialism and no-cost generalism, and the persistence of specialism in the face of selection for generalism. Examining three well-described mechanisms with respect to epistasis and pleiotropy indicates that sign (or antagonistic) pleiotropy without epistasis cannot explain no-cost generalism and that magnitude pleiotropy without epistasis (including directional selection and mutation accumulation) cannot explain the persistence of specialism. However, pleiotropy with epistasis can explain all. Furthermore, epistatic pleiotropy may allow past habitat use to influence future use of novel environments, thereby affecting disease emergence and populations' responses to habitat change.

There is considerable interest in the occurrence and molecular mechanisms of phenotypic plasticity and genotype-by-environment interactions (G × E) in plant populations. The emergence of genomic tools, including quantitative trait locus (QTL) mapping and transcriptome studies, provides opportunities to identify G × E patterns and mechanisms across a diversity of phenotypes, species, and environments. We review progress in evaluating the presence and characterizing the mechanisms of G × E using genomic studies of abiotic responses in plants. Our review reveals that G × E is common, often caused by changes in the magnitude of genetic effects in response to the environment, and associated with diverse genetic factors and molecular variants. We illustrate this diversity with an examination of transcriptome studies and discussion of cloned genes underlying G × E. We discuss the caveats associated with existing studies and outline future directions for better understanding G × E and its impact on local adaptation and plant improvement.

Between the 1930s and 1950s, scientists developed key principles of population genetics to try and explain the aging process. Almost a century later, these aging theories, including antagonistic pleiotropy and mutation accumulation, have been experimentally validated in animals. Although the theories have been much harder to test in humans despite research dating back to the 1970s, recent research is closing this evidence gap. Here we examine the strength of evidence for antagonistic pleiotropy in humans, one of the leading evolutionary explanations for the retention of genetic risk variation for non-communicable diseases. We discuss the analytical tools and types of data that are used to test for patterns of antagonistic pleiotropy and provide a primer of evolutionary theory on types of selection as a guide for understanding this mechanism and how it may manifest in other diseases. We find an abundance of non-experimental evidence for antagonistic pleiotropy in many diseases. In some cases, several studies have independently found corroborating evidence for this mechanism in the same or related sets of diseases including cancer and neurodegenerative diseases. Recent studies also suggest antagonistic pleiotropy may be involved in cardiovascular disease and diabetes. There are also compelling examples of disease risk variants that confer fitness benefits ranging from resistance to other diseases or survival in extreme environments. This provides increasingly strong support for the theory that antagonistic pleiotropic variants have enabled improved fitness but have been traded for higher burden of disease later in life. Future research in this field is required to better understand how this mechanism influences contemporary disease and possible consequences for their treatment.

Williams’ evolutionary theory of senescence based on antagonistic pleiotropy has become a landmark in evolutionary biology, and more recently in biogerontology and evolutionary medicine. In his original article, Williams launched a set of nine “testable deductions” from his theory. Although some of these predictions have been repeatedly discussed, most have been overlooked and no systematic evaluation of the whole set of Williams’ original predictions has been performed. For the sixtieth anniversary of the publication of the Williams’ article, we provide an updated evaluation of all these predictions. We present the pros and cons of each prediction based on recent accumulation of both theoretical and empirical studies performed in the laboratory and in the wild. From our viewpoint, six predictions are mostly supported by our current knowledge at least under some conditions (although Williams’ theory cannot thoroughly explain why for some of them). Three predictions, all involving the timing of senescence, are not supported. Our critical review of Williams’ predictions highlights the importance of William’s contribution and clearly demonstrates that, 60 years after its publication, his article does not show any sign of senescence.

The antagonistic pleiotropy theory of aging proposes that genes enhancing fitness in early life limit the lifespan, but the molecular evidence remains underexplored. By profiling translatome changes in Caenorhabditis elegans during starvation recovery, we find that an open reading frame (ORF) trl-1 “hidden” within an annotated pseudogene significantly translates upon refeeding. trl-1 mutant animals increase brood sizes but shorten the lifespan and specifically impair germline deficiency–induced longevity. The loss of trl-1 abnormally up-regulates the translation of vitellogenin that produces copious yolk to provision eggs, whereas vitellogenin overexpression is known to reduce the lifespan. We show that the TRL-1 protein undergoes liquid–liquid phase separation (LLPS), through which TRL-1 granules recruit vitellogenin messenger RNA and inhibit its translation. These results indicate that trl-1 functions as an antagonistic pleiotropic gene to regulate the reproduction–longevity tradeoff by optimizing nutrient production for the next generation.

Ageing is inherent to all human beings, yet why we age remains a hotly contested topic. Most mechanistic explanations of ageing posit that ageing is caused by the accumulation of one or more forms of molecular damage. Here, I propose that we age not because of inevitable damage to the hardware but rather because of intrinsic design flaws in the software, defined as the DNA code that orchestrates how a single cell develops into an adult organism. As the developmental software runs, its sequence of events is reflected in shifting cellular epigenetic states. Overall, I suggest that to understand ageing we need to decode our software and the flow of epigenetic information throughout the life course.

.— Most theoretical work on the evolution of senescence has assumed that all individuals within a population are equally susceptible to extrinsic sources of mortality. An influential qualitative prediction based on this assumption is Williams's hypothesis, which states that more rapid senescence is expected to evolve when the magnitude of such extrinsic mortality sources is increased. Much evidence suggests, however, that for many groups of organisms externally imposed mortality risk is a function of an organism's internal condition and hence susceptibility to such hazards. Here we use a model of antagonistic pleiotropy to investigate the consequences that such interactions (between environmental hazard and internal condition) can have for Williams's hypothesis. As with some previous theory examining nonin‐teractive extrinsic mortality sources, we find that an increase in interactive extrinsic sources of mortality makes it less likely that an individual will survive from birth to any given age, weakening selection against physiological deterioration at all ages and thus favoring more rapid senescence. However, an increase in interactive mortality sources also typically strengthens selection against physiological deterioration at any age, given an individual has survived to that age, because it reduces the fitness of poor‐condition individuals more than good‐condition individuals. These opposing effects are not felt equally at all ages, with the latter predominating at early ages. The combined effects can therefore result in the novel prediction that an increase in interactive extrinsic mortality sources can select for slower senescent deterioration early in life but more rapid deterioration late in life.