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Changes in DNA methylation with age are observed across the tree of life. The stereotypical nature of these changes can be modeled to produce epigenetic clocks capable of predicting chronological age with unprecedented accuracy. Despite the predictive ability of epigenetic clocks and their utility as biomarkers in clinical applications, the underlying processes that produce clock signals are not fully resolved, which limits their interpretability. Here, we develop a computational approach to spatially resolve the within read variability or “disorder” in DNA methylation patterns and test if age-associated changes in DNA methylation disorder underlie signals comprising epigenetic clocks. We find that epigenetic clock loci are enriched in regions that both accumulate and lose disorder with age, suggesting a link between DNA methylation disorder and epigenetic clocks. We then develop epigenetic clocks that are based on regional disorder of DNA methylation patterns and compare their performance to other epigenetic clocks by investigating the influences of development, lifespan interventions, and cellular dedifferentiation. We identify common responses as well as critical differences between canonical epigenetic clocks and those based on regional disorder, demonstrating a fundamental decoupling of epigenetic aging processes. Collectively, we identify key linkages between epigenetic disorder and epigenetic clocks and demonstrate the multifaceted nature of epigenetic aging in which stochastic processes occurring at non-random loci produce predictable outcomes. 

Abstract Epigenetic drift or “disorder” increases across the mouse lifespan and is suggested to underlie epigenetic clock signals. While the role of epigenetic drift in determining maximum lifespan across species has been debated, robust tests of this hypothesis are lacking. Here, we test if epigenetic disorder at various levels of genomic resolution explains maximum lifespan across four mammal species. We show that epigenetic disorder increases with age in all species and at all levels of genomic resolution tested. The rate of disorder accumulation occurs faster in shorter lived species and corresponds to species adjusted maximum lifespan. While the density of cytosine-phosphate-guanine dinucleotides (“CpGs”) is negatively associated with the rate of age-associated disorder accumulation, it does not fully explain differences across species. Our findings support the hypothesis that the rate of epigenetic drift explains maximum lifespan and provide partial support for the hypothesis that CpG density buffers against epigenetic drift. 

Abstract Maternal provisioning and the developmental environment are fundamental determinants of offspring traits, particularly in oviparous species. However, the extent to which embryonic responses to these factors differ across populations to drive phenotypic variation is not well understood. Here, we examine the contributions of maternal provisioning and incubation temperature to hatchling morphological and metabolic traits across four populations of the American alligator (Alligator mississippiensis), encompassing a large portion of the species' latitudinal range. Our results show that whereas the influence of egg mass is generally consistent across populations, responses to incubation temperature show population‐level variation in several traits, including mass, head length, head width, and residual yolk mass. Additionally, the influence of incubation temperature on developmental rate is greater at northern populations, while the allocation of maternal resources toward fat body mass is greater at southern populations. Overall, our results suggest that responses to incubation temperature, relative to maternal provisioning, are a larger source of interpopulation phenotypic variation and may contribute to the local adaptation of populations. 

ABSTRACT Considerations of the impact climate change has on reptiles are typically focused on habitat change or loss, range shifts and skewed sex ratios in species with temperature-dependent sex determination. Here, we show that incubation temperature alters stripe number and head colouration of hatchling American alligators (Alligator mississippiensis). Animals incubated at higher temperatures (33.5°C) had, on average, one more stripe than those at lower temperatures (29.5°C), and also had significantly lighter heads. These patterns were not affected by estradiol-induced sex reversal, suggesting independence from hatchling sex. Therefore, increases in nest temperatures as a result of climate change have the potential to alter pigmentation patterning, which may have implications for offspring fitness. 

Background: Reptiles and amphibians provide untapped potential for discovering how a diversity of genetic pathways and environmental conditions are incorporated into developmental processes that can lead to similar functional outcomes. These groups display a multitude of reproductive strategies, and whereas many attributes are conserved within groups and even across vertebrates, several aspects of sexual development show considerable variation. Summary: In this review, we focus our attention on the development of the reptilian and amphibian ovary. First, we review and describe the events leading to ovarian development, including sex determination and ovarian maturation, through a comparative lens. We then describe how these events are influenced by environmental factors, focusing on temperature and exposure to anthropogenic chemicals. Lastly, we identify critical knowledge gaps and future research directions that will be crucial to moving forward in our understanding of ovarian development and the influences of the environment in reptiles and amphibians. Key Messages: Reptiles and amphibians provide excellent models for understanding the diversity of sex determination strategies and reproductive development. However, a greater understanding of the basic biology of these systems is necessary for deciphering the adaptive and potentially disruptive implications of embryo-by-environment interactions in a rapidly changing world. 

Abstract Conservation of thermally sensitive species depends on monitoring organismal and population‐level responses to environmental change in real time. Epigenetic processes are increasingly recognized as key integrators of environmental conditions into developmentally plastic responses, and attendant epigenomic data sets hold potential for revealing cryptic phenotypes relevant to conservation efforts. Here, we demonstrate the utility of genome‐wide DNA methylation (DNAm) patterns in the face of climate change for a group of especially vulnerable species, those with temperature‐dependent sex determination (TSD). Due to their reliance on thermal cues during development to determine sexual fate, contemporary shifts in temperature are predicted to skew offspring sex ratios and ultimately destabilize sensitive populations. Using reduced‐representation bisulphite sequencing, we profiled the DNA methylome in blood cells of hatchling American alligators ( Alligator mississippiensis ), a TSD species lacking reliable markers of sexual dimorphism in early life stages. We identified 120 sex‐associated differentially methylated cytosines (DMCs; FDR < 0.1) in hatchlings incubated under a range of temperatures, as well as 707 unique temperature‐associated DMCs. We further developed DNAm‐based models capable of predicting hatchling sex with 100% accuracy (in 20 training samples and four test samples) and past incubation temperature with a mean absolute error of 1.2°C (in four test samples) based on the methylation status of 20 and 24 loci, respectively. Though largely independent of epigenomic patterning occurring in the embryonic gonad during TSD, DNAm patterns in blood cells may serve as nonlethal markers of hatchling sex and past incubation conditions in conservation applications. These findings also raise intriguing questions regarding tissue‐specific epigenomic patterning in the context of developmental plasticity. 

The environment experienced during embryonic development is a rich source of phenotypic variation, as environmental signals have the potential to both inform adaptive plastic responses and disrupt normal developmental programs. Environment-by-embryo interactions are particularly consequential for species with temperature-dependent sex determination, a mode of sex determination common in non-avian reptiles and fish, in which thermal cues during a discrete period of development drive the formation of either an ovary or a testis. Here we examine the impact of thermal variation during incubation in combination with developmental exposure to a common endocrine-disrupting contaminant on fitness-related hatchling traits in the American alligator (Alligator mississippiensis), a species with temperature-dependent sex determination. Using a factorial design, we exposed field-collected eggs to five thermal profiles (three constant temperatures, two fluctuating temperatures) and two environmentally relevant doses of the pesticide metabolite dichlorodiphenyldichloroethylene; and we quantified incubation duration, sex ratios, hatchling morphometric traits, and growth (9–10 days post-hatch). Whereas dichlorodiphenyldichloroethylene exposure did not generally affect hatchling traits, constant and fluctuating temperatures produced diverse phenotypic effects. Thermal fluctuations led to subtle changes in incubation duration and produced shorter hatchlings with smaller heads when compared to the constant temperature control. Warmer, male-promoting incubation temperatures resulted in larger hatchlings with more residual yolk reserves when compared to cooler, female-promoting temperatures. Together, these findings advance our understanding of how complex environmental factors interact with developing organisms to generate phenotypic variation and raise questions regarding the mechanisms connecting variable thermal conditions to responses in hatchling traits and their evolutionary implications for temperature-dependent sex determination.