Wednesday, April 28, 2021

Lack of transgenerational effects of ionizing radiation exposure from the Chernobyl accident

Lack of transgenerational effects of ionizing radiation exposure from the Chernobyl accident. Meredith Yeager et al. Science  Apr 22 2021:eabg2365. DOI: 10.1126/science.abg2365

Abstract: Effects of radiation exposure from the Chernobyl nuclear accident remain a topic of interest. We investigated whether children born to parents employed as cleanup workers or exposed to occupational and environmental ionizing radiation post-accident were born with more germline de novo mutations (DNMs). Whole-genome sequencing of 130 children (born 1987-2002) and their parents did not reveal an increase in the rates, distributions, or types of DNMs versus previous studies. We find no elevation in total DNMs regardless of cumulative preconception gonadal paternal (mean = 365 mGy, range = 0-4,080 mGy) or maternal (mean = 19 mGy, range = 0-550 mGy) exposure to ionizing radiation and conclude over this exposure range, evidence is lacking for a substantial effect on germline DNMs in humans, suggesting minimal impact on health of subsequent generations.


There was no evidence for a relationship between the total number of DNMs and preconception ionizing radiation dose (cumulative estimated gonadal dose at 38 weeks before birth) for maternal (−0.02 DNM per mGy, 95% CI: −0.04-0.007, p = 0.17) or paternal (−0.0007 DNM per mGy, 95% CI: −0.003-0.002, p = 0.56) exposures (Table 2 and fig. S2). In an analysis restricted to DNMs with known parent-of-origin (42%; Table 1), no effect of radiation was observed (table S4) whereas the effect of parental age remained robust; the parent-of-origin point estimates for paternal and maternal age effects were 0.71 and 0.28, respectively. Further investigation did not reveal evidence for an effect of preconception dose for any individual class of DNMs evaluated (table S5). Sensitivity analysis conducted with doses truncated at 1000 mGy or log transformed (ln(1+dose(mGy))) did not reveal an impact of maternal and paternal dose modeling on association with DNMs (Table 3). We further investigated categorical dose levels and found no increase in DNMs for any dose category, even 1000+mGy paternal dose (table S6). No effect of time since exposure was observed between parental preconception ionizing radiation exposure and DNM count for children born in the years immediately following the Chernobyl accident (Fig. 1). Moreover, when restricting to SNVs, there was no difference in the distribution of nucleotide substitutions based on quartile of maternal and paternal dose (fig. S3). Furthermore, the rates and types (molecular spectra) of DNMs observed in the current study were similar to those observed in prior studies conducted in general populations (Fig. 2 and fig. S4) (2468).

Since lifestyle exposures such as smoking have been associated with alterations of DNA (for example, mosaic loss of Y chromosome (32)), we also investigated possible effects of prenatal parental alcohol consumption and smoking on DNMs. We observed no association between the number of DNMs and either paternal tobacco smoking at conception (6.78, 95% CI = −16.62-14.87, p = 0.13, Table 2 and Fig. 1) or maternal tobacco smoking at conception (23.38, 95% CI = −2.00-48.77, p = 0.07, Table 2 and Fig. 1). Similarly, no effect was observed for increasing levels of paternal (p = 0.12) or maternal (p = 0.12) preconception alcohol consumption. In addition, sequencing batch had no impact on the number of DNMs (4.45, 95% CI = −5.07-13.97, p = 0.34).

Relative telomere length was measured by qPCR (33) in participants to investigate the potential transgenerational impact of parental ionizing radiation on leukocyte telomere length in children. As expected, an overall relationship was observed between increasing age at blood draw and shorter relative telomere length due to age-related telomere length attrition (p = 4.49×10−19, fig. S5). We did not observe an effect of paternal or maternal age at conception on relative telomere length in adult children (p = 0.95 and 0.06, respectively; table S7). While our analysis did not find evidence for an effect of total paternal preconception ionizing radiation exposure on relative leukocyte telomere length (p = 0.88), we did observe a possible effect of total maternal preconception exposure that requires confirmation (−2.75×10−4, 95% CI = −5.20×10−4 - −2.90×10−5, p = 0.03; table S7). There was no evidence for a transgenerational effect of paternal or maternal smoking on child’s telomere length (p = 0.91 and 0.22, respectively, table S7).

Although it is reassuring that no transgenerational effects of ionizing radiation were observed in adult children of Chernobyl cleanup workers and evacuees in the current study, additional investigation is needed to address the effects of acute high-dose parental gonadal exposure closer to conception. The upper 95% confidence bound suggests the largest effect consistent with our data is <1 DNM per 100 mGy from paternal or maternal exposure (Table 3 and tables S8 and S9). Previously, Dubrova et al. (2229) reported a two-fold increase in mini-satellite mutations in children born to parents living in a highly exposed region of Belarus. Weinberg et al. (34) reported an increase in the mutation rate at microsatellite loci among children born to cleanup workers. Subsequent small studies have not reported an increased mini-satellite or microsatellite mutation rate in children of cleanup workers, including those with low doses (0.09-0.23 Gy) (213035) or in children of the atomic-bomb survivors of Hiroshima or Nagasaki (31).

Our study evaluated peripheral blood from adult children conceived months or years after the Chernobyl accident, which limited the ability to assess exposure closer to conception; however, there was no evidence of notable differences in DNMs in children born the following year (1987). Since these families were recruited several decades after the accident, we acknowledge potential survivor bias among sampled children, although this is unlikely since there is no consistent demonstration in humans of sustained clinical effects of preconception ionizing radiation exposure (36). The number of parental gonadal radiation-induced double strand breaks could be fewer than anticipated based on animal data, which often assesses acute exposure (as a single burst) at higher doses (2-4 Gy; (1337)). Doses to the Chernobyl liquidators were mostly lower and exposure was fractionated over an extended period of time, which could have decreased the probability of gonadal DNM events. Moreover, it is plausible that the balance between radiation-induced mutations and accurate repair over time favored the latter. Additionally, there could have been a loss of power due to dose errors. Further human studies are needed to investigate the frequency of radiation-induced mutations and the subsequent response to address both the accuracy and efficiency of DNA repair. In a genomic landscape analysis of 440 cases of papillary thyroid cancer following the Chernobyl accident, increased radiation exposure was associated with a shift in tumor drivers from point mutations to small indels and non-homologous end joining events underlying fusions and other structural variants (38). Notably, there was no evidence of a radiation-specific single base substitution signature, gene expression pattern or methylation profile in cases of thyroid cancer with comparable radiation exposure history; instead, these were strongly associated with the tumor driver.

The rate, class distribution, and SNV type distribution of DNMs in adult children born to parents exposed to ionizing radiation, specifically of the type and amount relevant to Chernobyl cleanup workers and evacuees, are comparable to those reported in the general population. No effect of radiation on the specific classes of DNMs (SNVs, indels, complex variants, or clusters) was observed (table S5). Paternal age remains the strongest contributor to DNMs, although with maternal age DNMs also increase albeit with lower magnitude (Table 2 and table S4; (12)). Our study sample did not include mothers with high exposure (>1 Gy), but lower maternal dose was not associated with elevated DNMs, consistent with animal studies (13). Furthermore, our analysis of 130 adult children from 105 couples using 80X coverage of short-read technology suggests that if such effects on human germline DNA occur, they are uncommon or of small magnitude. This is one of the first studies to systematically evaluate alterations in human mutation rates in response to a man-made disaster, such as accidental radiation exposure. Investigation of trios drawn from survivors of the Hiroshima atomic bomb could shed further light on this public health question. In conclusion, children of individuals exposed to either occupational or environmental radiation do not appear to experience elevated rates of DNMs from their parents’ exposure. Thus, our study does not provide support for a transgenerational effect of ionizing radiation on germline DNA in humans.

  • Ref31 M. Kodaira
  • H. Ryo
  • N. Kamada
  • K. Furukawa
  • N. Takahashi
  • H. Nakajima
  • T. Nomura
  • N. Nakamura
  • No evidence of increased mutation rates at microsatellite loci in offspring of A-bomb survivorsRadiat. Res.173205213 (2010). doi:10.1667/RR1991.1pmid:20095853

    Compared to controls, professional comedians had greater cortical surface area in brain regions that have been previously implicated in abstract, divergent thinking and the default-mode network

    Mapping the “Funny Bone”: Neuroanatomical Correlates of Humor Creativity in Professional Comedians. Jacob Brawer, Ori Amir. Social Cognitive and Affective Neuroscience, nsab049, April 28 2021.

    Abstract: What are the neuroanatomical correlates of expertise in a specific creative domain? Professional comedians, amateurs, and controls underwent a T1 MRI anatomical scan. Measures of cortical surface area (gyrification and sulcal depth) and thickness were extracted for each participant. Compared to controls, professional comedians had greater cortical surface area in the left inferior temporal gyrus, angular gyrus, precuneus, and right medial prefrontal cortex. These regions have been previously implicated in abstract, divergent thinking and the default-mode network. The high degree of overlap between the regions of greater surface area in professional comedians with the regions showing greater activation in the same group during comedy improvisation in our previous work (particularly the temporal regions and angular gyrus), suggests these regions may be specifically involved in humor creativity.

    Keywords: Creativity, Expertise, Neuroanatomy, Comedians, Humor

    Science Skepticism Across 24 Countries: General faith in science was predicted by spirituality, suggesting that it, more than religiosity, may be the ‘enemy’ of science acceptance

    Science Skepticism Across 24 Countries. Bastiaan T. Rutjens et al. Social Psychological and Personality Science, April 28, 2021.

    Abstract: Efforts to understand and remedy the rejection of science are impeded by lack of insight into how it varies in degree and in kind around the world. The current work investigates science skepticism in 24 countries (N = 5,973). Results show that while some countries stand out as generally high or low in skepticism, predictors of science skepticism are relatively similar across countries. One notable effect was consistent across countries though stronger in Western, Educated, Industrialized, Rich, and Democratic (WEIRD) nations: General faith in science was predicted by spirituality, suggesting that it, more than religiosity, may be the ‘enemy’ of science acceptance. Climate change skepticism was mainly associated with political conservatism especially in North America. Other findings were observed across WEIRD and non-WEIRD nations: Vaccine skepticism was associated with spirituality and scientific literacy, genetic modification skepticism with scientific literacy, and evolution skepticism with religious orthodoxy. Levels of science skepticism are heterogeneous across countries, but predictors of science skepticism are heterogeneous across domains.

    Keywords: science skepticism, spirituality, ideology, climate change, vaccination, WEIRD, genetic modification, evolution, religion

    The extent to which science skepticism varies in degree and in kind around the world is not well understood. Up to now, a systematic cross-national investigation of the relative impact of various potential predictors of science skepticism across domains was lacking. This lacuna has obstructed efforts to understand and remedy the rejection of science—a phenomenon that is causing catastrophic health, economic, and environmental harms (Gallup, 2019World Health Organization, 2019). The current paper reports the results of the first large-scale effort to address this lacuna. In so doing, this work provides clear support for the heterogeneity of science skepticism, both in degree (levels of skepticism vary across domains but also across countries) and in kind (different predictors drive science skepticism in different domains). As formalized in our main hypotheses (Hypotheses 1–6), we expected different predictors to drive skepticism in different domains, within and across nations. All main hypotheses were supported, except for Hypothesis 2 (we did not find evidence that religious orthodoxy uniquely contributes to vaccine skepticism). We had also expected some heterogeneity to manifest between nations such that WEIRD and non-WEIRD nations would show systematic variation in patterns of science skepticism. These predictions were formalized in the country-level hypotheses (Hypotheses 1a, 2a, 2b, 6a, and 6b). It was indeed found that the impact of political conservatism on climate change skepticism was the strongest in the United States (Hypothesis 1a), but note that it was equally strong in Canada (followed by other WEIRD nations; Australia and the Netherlands). Evidence for the hypotheses that vaccine skepticism and low faith in science would be best predicted by spirituality in WEIRD nations (Hypotheses 2a–6a) and by orthodoxy in non-WEIRD nations (Hypotheses 2a and 2b) was found for faith in science but not for vaccine skepticism. Taken together, the results show that, of the various beliefs and ideologies examined as predictors of science skepticism, spirituality is among the most important.

    Indeed, confirming previous results obtained in the Netherlands (Rutjens & van der Lee, 2020)—and providing strong support for Hypothesis 6—the current data speak to the crucial role of spirituality in fostering low faith in science, more generally, beyond its domain-specific effects on vaccine skepticism. This indicates that the negative impact of spirituality on faith in science represents a cross-national phenomenon that is more generalizable than might be expected based on the large variety (Muthukrishna et al., 2020) of countries included here. A possible explanation for the robustness of this effect may lie in the inherent irreconcilability of the intuitive epistemology of a spiritual belief system with science (Rutjens & van der Lee, 2020). (If so, then we might look at a potentially much larger problem that extends beyond spirituality and applies more generally to “post-truth” society, in which truth and perceptions of reality may be based on feelings rather than facts; Martel et al., 2020Rutjens & Brandt, 2018.) However, these results do not mean that traditional religiosity as a predictor of science skepticism (McPhetres & Zuckermann, 2018Rutjens, Heine, et al., 2018Rutjens, Sutton, & van der Lee, 2018) has now become irrelevant: Not only did religious orthodoxy significantly contribute to low faith in science, it was also found to be a very consistent cross-national predictor of evolution skepticism (but not of other forms of science skepticism included in the study).

    Research has started to challenge the widespread notion that science skepticism primarily results from a lack of knowledge.10 In the current work, scientific literacy was the main driver of science skepticism only in the domain of GM. This corroborates previous research and observations that suggest that merely addressing information deficits to combat science skepticism is in most cases not sufficient (McPhetres et al., 2019Rutjens, Heine, et al., 2018Rutjens & van der Lee, 2020).

    The cross-national approach of the current work is important because it provides support for the emerging theoretical understanding of what causes skepticism across different domains of science (Hornsey et al., 2018a2018bMcPhetres et al., 2019McPhetres & Zuckermann, 2018Rutjens, Heine, et al., 2018Rutjens & van der Lee, 2020) and does so by including various countries that have been virtually absent from the psychological science database (Apicella et al., 2020Hruschka et al., 2018Muthukrishna et al., 2020). The present results demonstrate that while predictors of science skepticism to some extent vary in predictable ways between countries, many of the hypothesized effects were observed across many of the included countries. Levels of skepticism showed more regional variation. This heterogeneity of science skepticism in degree is illustrated in Table 2 and Figure 1, with some countries standing out as being especially high or low on skepticism. For example, in Egypt, Romania, and Venezuela, science skepticism is much stronger than in Australia or Canada. Additionally, remarkable differences in science skepticism were observed within countries, depending on the domain (e.g., GM skepticism vs. skepticism in other domains in France, general faith in science vs. domain-specific skepticism in Turkey).

    One obvious and important limitation to the current work concerns the limited nature of the measures used. Many of the key measures employed were self-report single-item (i.e., most outcome variables) or two-item indices (i.e., most of the predictor variables). The brevity of the materials was necessary in order to keep study length constrained. Thus, the construct validity and (cross-cultural) reliability of these measures are necessarily limited, and we hope that future research will replicate and extend (some of) these results with better measures and extensive equivalence testing. That being said, the current measures have been used frequently in previous work; the single-item outcome measures have been shown to produce similar results as multi-item variants (Rutjens, Sutton, & van der Lee, 2018Rutjens & van der Lee, 2020), and the spirituality and religious orthodoxy indices consist of the items with the highest factor loadings (Rutjens, Sutton, & van der Lee, 2018Rutjens & van der Lee, 2020).

    In conclusion, the present results can support the further development of our understanding of the various causes of science skepticism in different domains and in different cultures and countries, which in turn may help support interventions and communication strategies. Indeed, these results may be particularly informative when the aim is to understand how trust in science and compliance with its recommendations vary across individuals and countries, for example, during a global pandemic like COVID-19. To illustrate, let us return to the more general problem of vaccine hesitancy as an example of how skepticism can pose serious risks to public health. The current results suggest that increasing scientific literacy might prove to be a more fruitful approach in some cultural contexts than in others (see Figure 3C). In contrast, a better understanding of the relation between spiritual beliefs and general science skepticism is likely to be extremely informative regardless of cultural context. Regardless, it is evident that any strategy aimed at combating science skepticism needs to be underpinned by a nuanced theoretical and empirical understanding of its causes across domains as well as cultural contexts.

    Privacy intuitions evolved in an environment that was radically different from the one found online; this evolved privacy psychology leaves people disconnected from the consequence of online privacy threats

    The Privacy Mismatch: Evolved Intuitions in a Digital World. Azim Shariff, Joe Green, William Jettinghoff. Current Directions in Psychological Science, April 14, 2021.

    Abstract: Although people report grave concern over their data privacy, they take little care to protect it. We suggest that this privacy paradox can be understood in part as the consequence of an evolutionary mismatch: Privacy intuitions evolved in an environment that was radically different from the one found online. This evolved privacy psychology leaves people disconnected from the consequence of online privacy threats.

    Keywords: emotion, evolution, Internet, privacy, technology

    “You have zero privacy anyway,” declared Scott McNealy, CEO of Sun Microsystems in 1999. “Get over it” (quoted in Sprenger, 1999, paras. 1–2). Two decades later, the amount of public data vacuumed up by social networks, geolocalized cell phones, and other smart devices makes those early days seem quaint. Yet polling indicates that people remain strongly—indeed, increasingly—concerned about online privacy (Pew Research Center, 2019). They have not “gotten over it.” Or at least, they say they have not. Though people express serious concerns about their privacy, these same people do little to protect it (Gerber et al., 2018). This inconsistency—now extensively documented (Kokolakis, 2017)—is known as the privacy paradox.

    As more of people’s lives moves online and falls under increasingly sophisticated surveillance technologies, these gaps between the public’s professed desire for privacy and their behavior will become more consequential. We argue here that understanding privacy psychology in modern online environments requires looking back to the evolutionary roots of privacy concern. The privacy paradox, we submit, is the consequence of an evolutionary mismatch (Li et al., 2018). Human privacy intuitions emerged in an ancestral environment that differed radically from the digital environment in which those intuitions are now being tested.

    For privacy psychology, the past three decades have seen an environmental change that is arguably larger than even the Neolithic revolution 12,000 years ago. In this current environment, online interfaces befuddle intuitions that have otherwise allowed people to adaptively decide what to share, how much, and with whom. The mass, permanent record of online behavior leaves access to people’s information—and thus control over their reputations and decisions—to the whims of online power brokers. This leaves users vulnerable to coercive persecution by dissent-averse governments, commercial manipulation by profit-seeking corporations, and criminal exploitation by tech-savvy ne’er-do-wells (Zuboff, 2019).

    Examples of the consequences of privacy erosion are accumulating. Data breaches have taken a substantial psychological and human toll (the leaking of account information from adulterous match-making site Ashley Madison provoked divorces, resignations, and suicides). The easily accessed digital footprints people leave online can often return to sabotage other aspects of their life (e.g., Sherman, 2013, found that one in ten 16- to 34-year-olds reported being rejected from a job because of something they had posted online). Surreptitiously acquired personal data on Facebook can be used to sway an electorate (as happened in the 2016 U.S. election with the political consulting firm Cambridge Analytica and the Trump campaign). Perhaps the most large-scale example is the broad use of online data that powers China’s Social Credit System, which has already been used to regulate millions of citizens’ travel options, apartment rents, medical wait times, and even education quality.

    However, people’s reactions to privacy violations are tied not to these grave consequences, but to their evolved intuitions. This disconnect between reaction and consequence exposes how privacy psychology can be exploited for power and profit. For instance, even though technology companies soberly and technically explain their privacy policies, they can nonetheless easily coax data from people by burying the cues that would trigger evolved privacy concerns. In exchange, companies offer returns—for example, the connection of social networks or the titillation of online pornography—that powerfully appeal to evolved desires. Both corporations and governments often appease citizens’ civil-liberty concerns by removing the triggers of, rather than the actual intrusions behind, privacy concern. These types of solutions exploit humans’ mismatched psychology, quelling immediate emotional reactions while leaving the deeper, more rational concerns unaddressed.

    Evolutionary mismatches tend to resolve via subsequent evolution, environmental change, or behavioral adaptation (Lloyd et al., 2014. The glacial pace of genetic evolution precludes subsequent evolution from being a reasonable solution for this issue. Environmental change, in this context, would entail changing how people experience the Internet. Europe’s General Data Protection Regulation was aimed at such user-level changes, but its contractual legalese bloodlessly appealed only to abstract concerns, failing to ignite emotional privacy intuitions. Privacy alerts could be reimagined to more viscerally trigger people’s social intuitions (Calo, 2012), and researchers should measure the effectiveness of such changes for aligning preferences and behavior. However, we are pessimistic.

    The sheer scale of privacy management online makes putting the behavioral onus on individual users—even with the help of alerts and pop-ups on websites—unrealistic. The problems are similar, if even more formidable, for bottom-up behavioral adaptations that require individual users to simply edit their privacy settings themselves. Even scholars who are themselves skeptical of the existence of a privacy paradox (e.g., Solove, 2020) recognize that when it comes to privacy, the online environment is too vast to be individually managed given humans’ psychological limitations. People were not built for it.

    Given the privacy mismatch, efforts to align users’ preferences and behavior may prove futile. A more tractable solution could focus on mitigating the negative consequences of people’s loose privacy behavior, but data-protection efforts face resistance from powerful government and corporate interests. Challenging those interests would require rousing public interest in, and changing social norms about, data privacy. Psychologically, one strategy for lifting an issue to sociopolitical importance is via “moral piggybacking”—tying privacy to other areas of existing moral concern (Feinberg et al., 2019). Privacy could be piggybacked on fairness concerns, by highlighting the injustice of corporations extracting personal data for profit, or onto liberty concerns, by reminding people that their data fuel mass manipulation through personalization algorithms. Moralizing privacy via piggybacking may rally greater political will to support privacy rights.

    Obviously, the online environment is vast and diverse. Not all domains will lead to poorly calibrated oversharing. In fact, certain technologies may provoke mismatches that err in the other direction, affording novel but self-defeating motivations for social withdrawal. For instance, videoconferencing enables asymmetric visibility whereby students, patients, or audience members can unilaterally disable their webcams—rendering themselves seeing, but unseen. This protects privacy, but may undermine other goals by degrading a traditional social experience.

    In either case, for something so morally complex, culturally ubiquitous, and increasingly topical, privacy somehow remains understudied in psychology. We hope that the functionalist approach we have outlined here can help close the gap between the paucity of psychological research on privacy and the important, pervasive, and ever-widening public discussion of it. There are few topics for which the gap is so large.

    Selling well even when there is no gain... Trigger warning efficacy/impact: Warnings had no significant effect on changes to affect or test scores but did significantly increase perceptions of warnings as necessary

    Boysen, G. A., Isaacs, R. A., Tretter, L., & Markowski, S. (2021). Trigger warning efficacy: The impact of warnings on affect, attitudes, and learning. Scholarship of Teaching and Learning in Psychology, 7(1), 39–52, Apr 2021.

    Abstract: The purpose of trigger warnings is to prevent distress by giving prior notice about sensitive topics, but there is little empirical evidence to support their effectiveness in psychology education. The current research examined the effects of trigger warnings on affect, learning, and attitudes. Study 1 (N = 353) presented an online sample of adults with a video lecture about sexual assault, and participants reported their positive and negative affect before and after the video. They also took a test on the content and reported their attitudes about the necessity of warnings. Learning about sexual assault led to significant changes in affect for participants with and without personal experience related to the topic. Trigger warnings had no significant impact on changes in affect or test scores. However, participants who received a trigger warning had significantly increased belief that warnings are necessary for the topic of sexual assault. Study 2 (N = 412) replicated Study 1 using the topic of suicide. Trigger warnings had no significant effect on changes to affect or test scores but did significantly increase perceptions of warnings as necessary. Study 3 examined a sample of college students (N = 105) learning about sexual assault, and it also showed no significant effect of trigger warnings on changes to affect or test scores but a significant effect on belief that warnings are necessary. Overall, trigger warnings appear to have little impact on affect or learning, but they do increase people’s belief that warnings are necessary for sensitive topics.

    Hydras, without a central nervous system, seem to have a sleep-like state; seems a conserved sleep mechanisms during the evolutionary development of the central nervous system

    A sleep-like state in Hydra unravels conserved sleep mechanisms during the evolutionary development of the central nervous system. Hiroyuki J. Kanaya et al. Science Advances Oct 7 2020:Vol. 6, no. 41, eabb9415. DOI: 10.1126/sciadv.abb9415

    Abstract: Sleep behaviors are observed even in nematodes and arthropods, yet little is known about how sleep-regulatory mechanisms have emerged during evolution. Here, we report a sleep-like state in the cnidarian Hydra vulgaris with a primitive nervous organization. Hydra sleep was shaped by homeostasis and necessary for cell proliferation, but it lacked free-running circadian rhythms. Instead, we detected 4-hour rhythms that might be generated by ultradian oscillators underlying Hydra sleep. Microarray analysis in sleep-deprived Hydra revealed sleep-dependent expression of 212 genes, including cGMP-dependent protein kinase 1 (PRKG1) and ornithine aminotransferase. Sleep-promoting effects of melatonin, GABA, and PRKG1 were conserved in Hydra. However, arousing dopamine unexpectedly induced Hydra sleep. Opposing effects of ornithine metabolism on sleep were also evident between Hydra and Drosophila, suggesting the evolutionary switch of their sleep-regulatory functions. Thus, sleep-relevant physiology and sleep-regulatory components may have already been acquired at molecular levels in a brain-less metazoan phylum and reprogrammed accordingly.


    Our demonstration of the sleep-like state in Hydra and the commonality of sleep-regulatory genes, neurotransmitters, and physiology provide important insights into how ancestral sleep has evolved with developing CNS and how sleep-regulatory pathways have been reorganized accordingly. While the two-process model for shaping daily sleep has been widely accepted (12), free-running circadian rhythms are not readily detectable in Hydra behaviors. This observation contrasts with circadian control of the quiescence state in the cnidarian jellyfish (5). Circadian clocks are not an essential prerequisite for sleep behaviors because animal species with no overt circadian rhythms (e.g., Caenorhabditis elegans) or circadian clock mutants in Drosophila and mammals exhibit sleep. Circadian rhythms have also been observed widely in nonanimal kingdoms, where sleep-like states are not recognized. Nonetheless, our discovery of 4-hour free-running rhythms in Hydrasleep may reflect an evolutionary intermediate for circadian clock-dependent sleep given that circadian rhythms emerge from coupled ultradian oscillators (33). We also reason that the ultradian rhythms in Hydra sleep could be an ancestral form of the sleep-stage cycling in mammals. In this sense, Hydra may represent one of the most primitive animal models for sleep.

    Dopamine is a wake-promoting molecule conserved across animal species (1). We, however, showed that dopamine promotes Hydra sleep. This unexpected finding suggests that dopamine’s sleep-regulatory function may depend on how dopaminergic circuits are incorporated into sleep-regulatory pathways of the developing CNS. Consistent with this idea, dopamine is one of the major arousal neurotransmitters in adult flies, whereas it is dispensable for sleep in developing larvae (31). We speculate that the functional flipping of specific sleep-regulatory pathways (e.g., dopamine and ornithine) may have occurred during the evolutionary development of CNS. On the other hand, sleep-promoting pathways involving melatonin, GABA, or PRKG1 may have persisted in this process.

    Our evidence does not necessarily exclude the possible contribution of the diffuse nerve net to Hydra sleep. Emerging evidence, however, indicates the presence of sleep-wake cycles of cell-autonomous nature and sleep-regulatory mechanisms of non-neuronal origin in mammals and Drosophila (1). Likewise, dopamine may contribute to Hydra sleep via its indirect effects on peripheral tissues (e.g., metabolism, cell growth, and oxidative stress) (34). We predict that essential metabolism (e.g., ornithine-derived metabolic pathways) would play a key role in shaping these ancestral forms of sleep, and Hydra would act as an important node in the phylogenetic tree of sleep for validating this hypothesis. Future studies should further mine phylogenetic nodes to illustrate the evolutionary trace of sleep-regulatory mechanisms at high resolution and elucidate the origin of sleep.