662. the Role of Npap1 Ancestral and Modern Variants on Circadian Rhythms and Lipid Metabolism in Prader-willi Syndrome
Year: 2025
Type: conference-abstract
Abstract: Background The migration of Homo sapiens out of Africa and into northern latitudes required significant genetic and behavioral adaptations for survival in new and challenging environments. Among the most critical challenges was the extreme variation in daylight exposure, which influenced circadian rhythms, metabolism, and sleep-wake cycles. Circadian entrainment, the process by which organisms synchronize their internal biological clocks with external environmental cues, plays a crucial role in regulating sleep, feeding, and overall energy balance. Disruptions in circadian regulation are associated with various metabolic and neurodevelopmental disorders, yet the evolutionary mechanisms underlying circadian adaptations in early humans remain underexplored. Aims & Objectives We explore the evolutionary history of the 15q11-q13 imprinted gene cluster, known for its involvement in Prader-Willi Syndrome (PWS), a neurodevelopmental disorder characterized by hyperphagia, obesity, and disrupted sleep-wake rhythms. In this study we aimed to identify genetic variants associated with circadian entrainment in early European populations, determine whether these genetic modifications represent convergent evolutionary adaptations, and examine the functional role of NPAP1 in lipid metabolism and sleep-wake regulation, with potential implications for PWS. Method We conducted a comprehensive paleogenomic analysis of ancient DNA from early northern European populations, utilizing whole-genome sequencing data to compare their genetic profiles with those of modern populations. Additionally, we performed a comparative analysis of the 15q11-q13 imprinted region, with a specific focus on NPAP1, to determine its role in lipid metabolism and circadian regulation. Results Our analysis revealed independent genetic changes in circadian entrainment pathways among early northern European settlers, suggesting a case of convergent evolution in response to extreme light cycles. These genetic adaptations were found in key regulators of circadian rhythms, which are involved in the synchronization of biological clocks. Furthermore, the paleogenetic analysis of the 15q11-q13 imprinted region revealed signatures of positive selection, with notable changes in NPAP1. Functional studies suggest that NPAP1 plays a novel role in lipid metabolism and circadian regulation, linking genetic adaptations in early humans to modern neurodevelopmental and metabolic disorders. Discussion & Conclusions The findings suggest that genetic adaptations in circadian entrainment pathways played a critical role in facilitating human survival in northern latitudes. These adaptations likely mitigated the physiological stress of seasonal variations in light exposure and food availability. The identification of positive selection within the 15q11-q13 locus, provides new insights into the evolutionary origins of metabolic and sleep-wake dysregulation observed in PWS. Overall, this study highlights the complex interplay between evolutionary genetics, circadian regulation, and neurodevelopmental disorders.
Author: V Tucci
Institution: Italian Institute of Technology
Language: English
Subfield: Endocrine and Autonomic Systems
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,693
OpenAlex ID: W4413284691