FDA approval summary for lonafarnib (Zokinvy) for the treatment of Hutchinson-Gilford progeria syndrome and processing-deficient progeroid laminopathies.

The U.S. Food and Drug Administration recently approved lonafarnib as the first treatment for Hutchinson-Gilford progeria syndrome (HGPS) and processing-deficient progeroid laminopathies. This approval was primarily based on a comparison of patients with HGPS treated with lonafarnib in 2 open-label trials with an untreated patient cohort. With up to 11 years of follow-up, it was found that the lonafarnib treated patients with HGPS had a survival benefit of 2.5 years compared with the untreated patients with HGPS. This large treatment effect on the objective endpoint of mortality using a well-matched comparator group mitigated potential sources of bias and together with other evidence, established compelling evidence of a drug effect with benefits that outweighed the risks. This approval is an example of U.S. Food and Drug Administration's regulatory flexibility for a rare disease while ensuring that standards for drug approval are met.

Changes in phenology can alter patterns of natural selection: the joint evolution of germination time and postgermination traits.

The timing of a developmental transition (phenology) can influence the environment experienced by subsequent life stages. When phenology causes an organism to occupy a particular habitat as a consequence of the developmental cues used, it can act as a form of habitat tracking. Evolutionary theory predicts that habitat tracking can alter the strength, direction, and mode of natural selection on subsequently expressed traits. To test whether germination phenology altered natural selection on postgermination traits, we manipulated germination time by planting seedlings in seven germination cohorts spanning 2 yr. We measured selection on postgermination traits relating to drought, freezing, and heat tolerance using a diverse combination of Arabidopsis thaliana mutants and naturally occurring ecotypes. Germination cohorts experienced variable selection: when dry, cold, and hot environments were experienced by seedlings, selection was intensified for drought, freezing, and heat tolerance, respectively. Reciprocally, postgermination traits modified the optimal germination time; genotypes had maximum fitness after germinating in environments that matched their physiological tolerances. Our results support the theoretical predictions of feedbacks between habitat tracking and traits expressed after habitat selection. In natural populations, whether phenological shifts alter selection on subsequently expressed traits will depend on the effectiveness of habitat tracking through phenology.

Parental methylation mediates how progeny respond to environments of parents and of progeny themselves.

BACKGROUND AND AIMS: Environments experienced by both parents and offspring influence progeny traits, but the epigenetic mechanisms that regulate the balance of parental vs. progeny control of progeny phenotypes are not known. We tested whether DNA methylation in parents and/or progeny mediates responses to environmental cues experienced in both generations. METHODS: Using Arabidopsis thaliana, we manipulated parental and progeny DNA methylation both chemically, via 5-azacytidine, and genetically, via mutants of methyltransferase genes, then measured progeny germination responses to simulated canopy shade in parental and progeny generations. KEY RESULTS: We first found that germination of offspring responded to parental but not seed demethylation. We further found that parental demethylation reversed the parental effect of canopy in seeds with low (Cvi-1) to intermediate (Col) dormancy, but it obliterated the parental effect in seeds with high dormancy (Cvi-0). Demethylation did so by either suppressing germination of seeds matured under white-light (Cvi-1) or under canopy (Cvi-0), or by increasing the germination of seeds matured under canopy (Col). Disruption of parental methylation also prevented seeds from responding to their own light environment in one genotype (Cvi-0, most dormant), but it enabled seeds to respond to their own environment in another genotype (Cvi-1, least dormant). Using mutant genotypes, we found that both CG and non-CG DNA methylation were involved in parental effects on seed germination. CONCLUSIONS: Parental methylation state influences seed germination more strongly than does the progeny's own methylation state, and it influences how seeds respond to environments of parents and progeny in a genotype-specific manner.

The effect of seed-dispersal timing on seedling recruitment is modulated by environmental conditions that vary across altitude in a threatened palm.

BACKGROUND AND AIMS: The timing of seed dispersal determines the environmental conditions that plants face during early life stages. In seasonal environments, selection is expected to favour dispersal timing that is matched to environmental conditions suitable for successful recruitment. Our aim here was to test whether the timing of seed dispersal influences seedling establishment success in two populations of Euterpe edulis that are located at contrasting altitudes, have different seed-dispersal phenologies and are subjected to distinct climatic conditions. METHODS: We sowed E. edulis seeds in contrasting altitudes on different dates, and monitored seed germination, emergence and seedling establishment at each altitude over 4 years. At the high-altitude site, five seed-dispersal cohorts were established during the natural dispersal period. At the low-altitude site, three seed-dispersal cohorts were established during natural dispersal, and two were established either before or after natural dispersal. KEY RESULTS: At the high-altitude site, seed-dispersal timing did not affect seed germination, seedling emergence or seedling establishment success. In contrast, at the low-altitude site, late seed dispersal near the end of the wet season resulted in a lower probability of seedling establishment, possibly due to the exposure of seeds, germinants and seedlings to unfavourable drought conditions. In addition, at the low-altitude site, the natural seed-dispersal period was poorly matched to favourable environmental conditions for seedling establishment. CONCLUSIONS: The greater effect of seed-dispersal timing on seedling establishment at the low-altitude site is probably related to a more seasonal and drought-prone environment that favours a restricted period of seed dispersal. The magnitude of the effect of dispersal timing on seedling establishment success was modulated by environmental conditions that vary across altitude. Furthermore, reproductive phenology appears to be subject to more intense selection at the lower limit of the altitudinal range, due to a more restrictive window of opportunity for successful seedling establishment.

Genetic Consequences of Biologically Altered Environments.

Evolvable traits of organisms can alter the environment those organisms experience. While it is well appreciated that those modified environments can influence natural selection to which organisms are exposed, they can also influence the expression of genetic variances and covariances of traits under selection. When genetic variance and covariance change in response to changes in the evolving, modified environment, rates and outcomes of evolution also change. Here we discuss the basic mechanisms whereby organisms modify their environments, review how those modified environments have been shown to alter genetic variance and covariance, and discuss potential evolutionary consequences of such dynamics. With these dynamics, responses to selection can be more rapid and sustained, leading to more extreme phenotypes, or they can be slower and truncated, leading to more conserved phenotypes. Patterns of correlated selection can also change, leading to greater or less evolutionary independence of traits, or even causing convergence or divergence of traits, even when selection on them is consistent across environments. Developing evolutionary models that incorporate changes in genetic variances and covariances when environments themselves evolve requires developing methods to predict how genetic parameters respond to environments-frequently multifactorial environments. It also requires a population-level analysis of how traits of collections of individuals modify environments for themselves and/or others in a population, possibly in spatially explicit ways. Despite the challenges of elucidating the mechanisms and nuances of these processes, even qualitative predictions of how environment-modifying traits alter evolutionary potential are likely to improve projections of evolutionary outcomes.

The Snail's Charm.

In 2017, The American Naturalist celebrated its 150th anniversary. It was founded as a journal of natural history, yet it developed into an important vehicle of the evolutionary synthesis. During the early years of the journal and through much of the twentieth century, evolutionary theory was developed to explain the history of nature before humankind existed to alter it-when time was expansive and uncommon events, though rare, were frequent enough to effect evolutionary change. Today, with the influence of human activity, dispersal patterns are fundamentally altered, genetic variation is locally limiting in small and fragmented populations, and environments are changing so rapidly that time itself seems limited. How can we use this theory, which was built to explain the past and which depends on an excess of chances and time, to address the challenges of the present and the future when chances are fewer and time seems so short? And does the habit of naturalists to observe, describe, and cultivate a fascination with nature have a place in contemporary science?

Pleiotropy in developmental regulation by flowering-pathway genes: is it an evolutionary constraint?

Pleiotropy occurs when one gene influences more than one trait, contributing to genetic correlations among traits. Consequently, it is considered a constraint on the evolution of adaptive phenotypes because of potential antagonistic selection on correlated traits, or, alternatively, preservation of functional trait combinations. Such evolutionary constraints may be mitigated by the evolution of different functions of pleiotropic genes in their regulation of different traits. Arabidopsis thaliana flowering-time genes, and the pathways in which they operate, are among the most thoroughly studied regarding molecular functions, phenotypic effects, and adaptive significance. Many of them show strong pleiotropic effects. Here, we review examples of pleiotropy of flowering-time genes and highlight those that also influence seed germination. Some genes appear to operate in the same genetic pathways when regulating both traits, whereas others show diversity of function in their regulation, either interacting with the same genetic partners but in different ways or potentially interacting with different partners. We discuss how functional diversification of pleiotropic genes in the regulation of different traits across the life cycle may mitigate evolutionary constraints of pleiotropy, permitting traits to respond more independently to environmental cues, and how it may even contribute to the evolutionary divergence of gene function across taxa.

Multi-tasking as an ancient skill: When one gene does many things well.

Multi-tasking is in our DNA. Many genes perform more than one function, and the question is how well it can do them all. Pleiotropy is frequently considered to be an adaptive constraint that prevents optimal phenotypes from evolving because of antagonistic indirect selection acting on genetically correlated traits. However, as geneticists increasingly study the effects of genes under more realistic natural environments, even the most well studied genes are expressing fascinating pleiotropic effects. Pleiotropy appears to be utterly common. The genes involved in the regulation of flowering time in Arabidopsis thaliana, such as FLOWERING LOCUS C (FLC), offer case examples of such pleiotropy. Studying an ortholog of FLC in Arabis alpina, PERPETUAL FLOWERING 1 (PEP1), Hughes, Soppe and Albani (2019) present evidence that such pleiotropy in flowering-time genes persists through taxonomic diversification, albeit the precise function of the genes has evolved in response to taxon-specific natural selection. Their observation that trait-specific function can evolve even in highly pleiotropic genes suggests that pleiotropy may not constrain adaptation as much as is commonly assumed.

Effects of maternal source and progeny microhabitat on natural selection and population dynamics in Alliaria petiolata.

PREMISE: The success or failure of propagules in contrasting microhabitats may play a role in biological invasion. We tested for variation in demographic performance and phenotypic trait expression during invasion by Alliaria petiolata in different microhabitats. METHODS: We performed a reciprocal transplant experiment with Alliaria petiolata from edge, intermediate, and forest understory microhabitats to determine the roles of the environment and maternal source on traits, fecundity, population growth rates (λ), and selection. RESULTS: Observations of in situ populations show that edge populations had the highest density and reproductive output, and forest populations had the lowest. In experimental populations, population growth rates and reproductive output were highest in the edge, and the intermediate habitat had the lowest germination and juvenile survival. Traits exhibited phenotypic plasticity in response to microhabitat, but that plasticity was not adaptive. There were few effects of maternal source location on fitness components or traits. CONCLUSIONS: Alliaria petiolata appears to be viable, or nearly so, in all three microhabitat types, with edge populations likely providing seed to the other microhabitats. The intermediate microhabitat may filter propagules at the seed stage, but discrepancies between in situ observations and experimental transplants preclude clear conclusions about the role of each microhabitat in niche expansion. However, edge microhabitats show the highest seed output in both analyses, suggesting that managing edge habitats might reduce spread to the forest understory.

Can the Environment have a Genetic Basis? A Case Study of Seedling Establishment in Arabidopsis thaliana.

The timing of seed germination determines the environment experienced by a plant's most vulnerable life stage-the seedling. Germination is environmentally cued, and genotypes can differ in their sensitivity to environmental cues. When genotypes differ in their response to cues, and when cues accurately predict the postgermination environment, the postgermination environment experienced by seedlings can itself have a genetic basis and potential to evolve. We tested for genetic differences in the postgermination environment using Arabidopsis thaliana genotypes that vary in seed dormancy, a trait known to alter germination time. We dispersed seeds into the field in 5 seasonal cohorts over 1.5 years, observed germination timing for 5297 individuals, and measured the soil temperature and moisture experienced by individuals throughout their life cycle. We found that genotypes differed in the environments they experienced during seedling establishment. This environmental variation occurred because genotypes differed in their environmental sensitivity to germination cues, and pregermination cues were correlated with postgermination environments. Seeds exhibited temporal habitat selection by germinating into a nonrandom subset of environmental conditions available, and seed dormancy increased the consistency of habitat selection. Strikingly, the postgermination environment affected fitness by altering the probability of seedling survival such that genotypes that engaged in stronger habitat selection were less likely to reach reproduction. Our results suggest that environmentally cued development may be a widespread mechanism by which genotypes can differ in the environment they experience, introducing the possibility that the environment itself can be inherited and can evolve.

Hybridization can facilitate species invasions, even without enhancing local adaptation.

The founding population in most new species introductions, or at the leading edge of an ongoing invasion, is likely to be small. Severe Allee effects-reductions in individual fitness at low population density-may then result in a failure of the species to colonize, even if the habitat could support a much larger population. Using a simulation model for plant populations that incorporates demography, mating systems, quantitative genetics, and pollinators, we show that Allee effects can potentially be overcome by transient hybridization with a resident species or an earlier colonizer. This mechanism does not require the invocation of adaptive changes usually attributed to invasions following hybridization. We verify our result in a case study of sequential invasions by two plant species where the outcrosser Cakile maritima has replaced an earlier, inbreeding, colonizer Cakile edentula (Brassicaceae). Observed historical rates of replacement are consistent with model predictions from hybrid-alleviated Allee effects in outcrossers, although other causes cannot be ruled out.

PHYD prevents secondary dormancy establishment of seeds exposed to high temperature and is associated with lower PIL5 accumulation.

Dormancy cycling controls the seasonal conditions under which seeds germinate, and these conditions strongly influence growth and survival of plants. Several endogenous and environmental signals affect the dormancy status of seeds. Factors such as time, light, and temperature influence the balance between abscisic acid (ABA) and gibberellic acid (GA), two phytohormones that play a key role in seed dormancy and germination. High temperatures have been shown to increase ABA level and prevent seed germination, a process known as thermoinhibition. High temperature can also cause the acquisition of secondary dormancy, preventing germination of seeds upon their return to favorable germination conditions. The mechanisms and conditions linking thermoinhibition and secondary dormancy remain unclear. Phytochromes are photoreceptors known to promote seed germination of many plant species including Arabidopsis thaliana. Here, we demonstrate a role for PHYD in modulating secondary dormancy acquisition in seeds exposed to high temperature. We found that a functional PHYD gene is required for the germination of seeds that experienced high temperature, and that ABA- and GA-related gene expression during and after pre-incubation at high temperatures was altered in a phyD mutant. We further show that the level of PHYD mRNA increased in seeds pre-incubated at high temperature and that this increase correlates with efficient removal of the germination repressor PIL5.

The autonomous flowering-time pathway pleiotropically regulates seed germination in Arabidopsis thaliana.

Background and Aims: Two critical developmental transitions in plants are seed germination and flowering, and the timing of these transitions has strong fitness consequences. How genetically independent the regulation of these transitions is can influence the expression of life cycles. Method: This study tested whether genes in the autonomous flowering-time pathway pleiotropically regulate flowering time and seed germination in the genetic model Arabidopsis thaliana, and tested whether the interactions among those genes are concordant between flowering and germination stages. Key Results: Several autonomous-pathway genes promote flowering and impede germination. Moreover, the interactions among those genes were highly concordant between the regulation of flowering and germination. Conclusions: Despite some degree of functional divergence between the regulation of flowering and germination by autonomous-pathway genes, the autonomous pathway is highly functionally conserved across life stages. Therefore, genes in the autonomous flowering-time pathway are likely to contribute to genetic correlations between flowering and seed germination, possibly contributing to the winter-annual life history.

The fitness benefits of germinating later than neighbors.

PREMISE OF THE STUDY: Phenology, the seasonal timing of development, can alter biotic interactions. Emergence from dormant or quiescent stages often occurs earlier when neighbors are present, which may reduce the neighbors' competitive effects. Delayed emergence in response to neighbors also has been observed, but the potential benefits of such delays are unclear. Further, emergence time may respond to neighbors experienced by parents, which may predict future competition in offspring. METHODS: In the annual plant Arabidopsis thaliana (Brassicaceae), we quantified seed germination responses to neighbors in parental and offspring (seed) environments. To examine how observed changes in germination affect interactions with neighbors, we performed an outdoor experiment using neighbors of different sizes to represent different germination times. KEY RESULTS: Seeds were more likely to germinate if their parent had neighbors, but they were less likely to germinate if they themselves experienced a neighbor cue (canopy). As seeds lost dormancy over time, they gained the ability to germinate under a canopy, which suggests that they germinate later in the presence of neighbors. Neighbors of both sizes reduced growth, survival to reproduction, fecundity, and total fitness, but large neighbors increased seedling survival. Smaller neighbors provided no such benefit and had stronger negative effects. CONCLUSIONS: Delayed germination in response to neighbors can reduce negative interactions and promote positive ones if it occurs late enough to expose seedlings to larger neighbors. By altering relative phenologies and, in turn, the outcomes of biotic interactions, phenological responses to environmental change may influence species interactions and community dynamics.

Adjusting phenotypes via within- and across-generational plasticity.

Contents 343 I. 343 II. 343 III. 347 IV. 348 348 References 348 SUMMARY: There is renewed interest in how transgenerational environmental effects, including epigenetic inheritance, contribute to adaptive evolution. The contribution of across-generation plasticity to adaptation, however, needs to be evaluated within the context of within-generation plasticity, which is often proposed to contribute more efficiently to adaptation because of the potentially greater accuracy of progeny than parental cues to predict progeny selective environments. We highlight recent empirical studies of transgenerational plasticity, and find that they do not consistently support predictions based on the higher predictive ability of progeny environmental cues. We discuss these findings within the context of the relative predictive ability of maternal and progeny cues, costs and constraints of plasticity in parental and progeny generations, and the dynamic nature of the adaptive value of within- and across-generation plasticity that varies with the process of adaptation itself. Such contingent and dynamically variable selection could account for the diversity of patterns of within- and across-generation plasticity observed in nature, and can influence the adaptive value of the persistence of environmental effects across generations.

Maternal vernalization and vernalization-pathway genes influence progeny seed germination.

Different life stages frequently respond to the same environmental cue to regulate development so that each life stage is matched to its appropriate season. We investigated how independently each life stage can respond to shared environmental cues, focusing on vernalization, in Arabidopsis thaliana plants. We first tested whether effects of rosette vernalization persisted to influence seed germination. To test whether genes in the vernalization flowering pathway also influence germination, we assessed germination of functional and nonfunctional alleles of these genes and measured their level of expression at different life stages in response to rosette vernalization. Rosette vernalization increased seed germination in diverse ecotypes. Genes in the vernalization flowering pathway also influenced seed germination. In the Columbia accession, functional alleles of most of these genes opposed the germination response observed in the ecotypes. Some genes influenced germination in a manner consistent with their known effects on FLOWERING LOCUS C gene regulation during the transition to flowering. Others did not, suggesting functional divergence across life stages. Despite persistent effects of environmental conditions across life stages, and despite pleiotropy of genes that affect both flowering and germination, the function of these genes can differ across life stages, potentially mitigating pleiotropic constraints and enabling independent environmental regulation of different life stages.

Photoperiod throughout the maternal life cycle, not photoperiod during seed imbibition, influences germination in Arabidopsis thaliana.

PREMISE OF THE STUDY: Plants adjust their phenology in response to seasonal cues experienced both by their parents and by themselves, and coordinating responses to these cues is necessary for expressing adaptive phenology. We investigated how cues are integrated across time to influence an important progeny phenotype, i.e., seed germination. METHODS: We used Arabidopsis thaliana to investigate how the photoperiod experienced by maternal parents and by progeny influences seed germination. We examined when maternal photoperiod effects on germination are imposed and how long they persist in progeny. KEY RESULTS: The photoperiod experienced by maternal plants more strongly influenced germination than the photoperiod experienced during seed imbibition. In addition, the photoperiod experienced at the prereproductive stage frequently influenced germination as strongly as that experienced during reproduction. In general, seeds from plants grown under short days had higher seed germination percentages than seeds from plants grown in longer days. These maternal effects diminished with after-ripening, but reappeared in seeds induced into secondary dormancy. CONCLUSIONS: We found no evidence that the effect of photoperiod systematically attenuates in proportion to the time that elapsed between the cue and the timing of seed germination. Moreover, more recently experienced cues did not override the effects of cues experienced previously. Instead, specific sequences of photoperiods experienced at the prereproductive and reproductive stages appear to influence germination behavior.

Multiple paths to similar germination behavior in Arabidopsis thaliana.

Germination timing influences plant fitness, and its sensitivity to temperature may cause it to change as climate shifts. These changes are likely to be complex because temperatures that occur during seed maturation and temperatures that occur post-dispersal interact to define germination timing. We used the model organism Arabidopsis thaliana to determine how flowering time (which defines seed-maturation temperature) and post-dispersal temperature influence germination and the expression of genetic variation for germination. Germination responses to temperature (germination envelopes) changed as seeds aged, or after-ripened, and these germination trajectories depended on seed-maturation temperature and genotype. Different combinations of genotype, seed-maturation temperature, and after-ripening produced similar germination envelopes. Likewise, different genotypes and seed-maturation temperatures combined to produce similar germination trajectories. Differences between genotypes were most likely to be observed at high and low germination temperatures. The germination behavior of some genotypes responds weakly to maternal temperature but others are highly plastic. We hypothesize that weak dormancy induction could synchronize germination of seeds dispersed at different times. By contrast, we hypothesize that strongly responsive genotypes may spread offspring germination over several possible germination windows. Considering germination responses to temperature is important for predicting phenology expression and evolution in future climates.