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Abstract Loss-of-function alleles are a pertinent source of genetic variation with the potential to contribute to adaptation. Cave-adapted organisms exhibit striking loss of ancestral traits such as eyes and pigment, suggesting that loss-of-function alleles may play an outsized role in these systems. Here, we leverage 141 whole genome sequences to evaluate the evolutionary history and adaptive potential of single nucleotide premature termination codons (PTCs) in Mexican tetra. We find that cave populations contain significantly more PTCs at high frequency than surface populations. We also find that PTCs occur more frequently in genes with inherent relaxed evolutionary constraint relative to the rest of the genome. Using SLiM to simulate PTC evolution in a cavefish population, we show that the smaller population size and increased genetic drift is sufficient to account for the observed increase in PTC frequency in cave populations without positive selection. Using CRISPR-Cas9, we show that mutation of one of these genes, pde6c, produces phenotypes in surface Mexican tetra that mimic cave-derived traits. Finally, we identify a small subset of candidate genes that contain high-frequency PTCs in cave populations, occur within selective sweeps, and may contribute to beneficial traits such as reduced energy expenditure, suggesting that a handful of PTCs may be adaptive. Overall, our work provides a rare characterization of PTCs across wild populations and finds that they may have an important role in loss-of-function phenotypes, contributing to a growing body of literature showing genome evolution through relaxed constraint in subterranean organisms. 

Circadian rhythms are nearly ubiquitous throughout nature, suggesting they are critical for survival in diverse environments. Organisms inhabiting largely arrhythmic environments, such as caves, offer a unique opportunity to study the evolution of circadian rhythms in response to changing ecological pressures. Populations of the Mexican tetra, Astyanax mexicanus , have repeatedly invaded caves from surface rivers, where individuals must contend with perpetual darkness, reduced food availability, and limited fluctuations in daily environmental cues. To investigate the molecular basis for evolved changes in circadian rhythms, we investigated rhythmic transcription across multiple independently-evolved cavefish populations. Our findings reveal that evolution in a cave environment has led to the repeated disruption of the endogenous biological clock, and its entrainment by light. The circadian transcriptome shows widespread reductions and losses of rhythmic transcription and changes to the timing of the activation/repression of core-transcriptional clock. In addition to dysregulation of the core clock, we find that rhythmic transcription of the melatonin regulator aanat2 and melatonin rhythms are disrupted in cavefish under darkness. Mutants of aanat2 and core clock gene rorca disrupt diurnal regulation of sleep in A . mexicanus , phenocopying circadian modulation of sleep and activity phenotypes of cave populations. Together, these findings reveal multiple independent mechanisms for loss of circadian rhythms in cavefish populations and provide a platform for studying how evolved changes in the biological clock can contribute to variation in sleep and circadian behavior.