Free-running Circadian Period Research Articles

A conditional Smg6 mutant mouse model reveals circadian clock regulation through the nonsense-mediated mRNA decay pathway.

Nonsense-mediated messenger RNA (mRNA) decay (NMD) has been intensively studied as a surveillance pathway that degrades erroneous transcripts arising from mutations or RNA processing errors. While additional roles in physiological control of mRNA stability have emerged, possible functions in mammalian physiology in vivo remain unclear. Here, we created a conditional mouse allele that allows converting the NMD effector nuclease SMG6 from wild-type to nuclease domain-mutant protein. We find that NMD down-regulation affects the function of the circadian clock, a system known to require rapid mRNA turnover. Specifically, we uncover strong lengthening of free-running circadian periods for liver and fibroblast clocks and direct NMD regulation of Cry2 mRNA, encoding a key transcriptional repressor within the rhythm-generating feedback loop. Transcriptome-wide changes in daily mRNA accumulation patterns in the entrained liver, as well as an altered response to food entrainment, expand the known scope of NMD regulation in mammalian gene expression and physiology.

The regulation of circadian rhythm by insulin signaling in Drosophila

Circadian rhythm is well conserved across species and relates to numerous biological functions. Circadian misalignment impairs metabolic function. Insulin signaling is a key modulator of metabolism in the fruit fly as well as mammals and its defects cause metabolic disease. Daily diet timing affects both circadian rhythmicities of behavior and metabolism. However, the relationship between the circadian clock and insulin signaling is still elusive. Here, we report that insulin signaling regulates circadian rhythm in Drosophila melanogaster. We found the insulin receptor substrate mutant, chico1, showed a shorter free-running circadian period. The knockdown of insulin receptor (InR), or another signaling molecule downstream of InR, dp110, or the expression of a dominant-negative form of InR resulted in the shortening of the circadian period and diminished its amplitude. The impairment of insulin signaling both in all neurons and restricted circadian clock neurons altered circadian period length, indicating that the insulin signaling plays a role in the regulation of circadian rhythm in clock cells. Among 3 insulin-like ligands expressed in the brain, dilp5 showed the largest effect on circadian phenotype when deleted. These results suggested that insulin signaling contributes to the robustness of the circadian oscillation and coordinates metabolism and behavior.

Generation and Disruption of Circadian Rhythms in the Suprachiasmatic Nucleus: A Core-Shell Model.

We focus our research on how the core-shell organization controls behavior of the suprachiasmatic nucleus (SCN), how the core and shell are synchronized to the environment, what impact they have on the behavior of the SCN under different lighting conditions, and what mechanisms disrupt synchronization. To this end, we use a reduced Kuramoto model, with parameters inferred from experimental observations and calibrated for mice, and perform a detailed comparison between the model and experimental data under light-dark (LD), dark-dark (DD), and light-light (LL) conditions. The operating limits of free-running and entrained SCN activity under symmetric LD cycles are analyzed, with particular focus on the phenomena of anticipation and dissociation. Results reveal that the core-shell organization of the SCN enables anticipation of future events over circadian cycles. The model predicts the emergence of a second (dissociated) rhythm for large and small LD periods. Our results are in good qualitative and quantitative agreement with experimental observations of circadian dissociation. We further describe SCN activity under LL conditions and show that our model satisfies Aschoff’s first rule, according to which the endogenous free-running circadian period observed under complete darkness will shorten in diurnal animals and lengthen in nocturnal animals under constant light. Our results strongly suggest that the Kuramoto model captures essential features of synchronization and entrainment in the SCN. Moreover, our approach is easily extendible to an arbitrary number of groups, with dynamics described by explicit equations for the group phase and synchronization index. Viewed together, the reduced Kuramoto model presents itself as a useful tool for exploring open problems in the study of circadian rhythms, one that can account for evolving views of the circadian system’s organization, including peripheral clocks and inter-hemispheric interaction, and can be translated to other nocturnal and diurnal animals, including humans.

The Role of Race, Sex, and Age in Circadian Disruption and Metabolic Disorders.

Circadian rhythms are 24-hour internal biological cycles that play an important role in metabolism, and their disruption has been implicated in the development of diseases such as diabetes mellitus type 2, obesity, coronary artery disease, hypertension, and metabolic syndrome. This phenomenon is illustrated by increased rates of risk factors for cardiovascular disease in night shift workers. Race, sex, and age are factors that play a role in circadian rhythms and metabolic disorders. The focus of this review article is to assess the link between circadian rhythm physiology and metabolic disorders from a race, sex, and age perspective. Black Americans were noted to have shorter free-running circadian periods, or tau, increased cortisol levels, and poorer sleep habits compared to white Americans, possibly contributing to increased rates of obesity, hypertension, and hyperlipidemia. Women were also noted to have shorter tau, increased levels of proinflammatory gut bacteria, and reduced sleep quality compared to men, possibly leading to higher rates of obesity, metabolic syndrome, hypertension (in postmenopausal women), and nonalcoholic fatty liver disease. Older people were noted to have decreased expression of anti-inflammatory clock genes compared to younger people, possibly leading to increased rates of obesity, diabetes, hyperlipidemia, and hypertension. Groups that are at a higher risk for metabolic disorders such as black Americans, women, and the elderly may have internal time keeping systems that place them at a higher risk for developing abnormal hormonal and/or inflammatory pathways.

Spontaneous Recovery of Circadian Organization in Mice Lacking a Core Component of the Molecular Clockwork.

Circadian rhythms are generated by interlocked transcriptional-translational feedback loops of circadian clock genes and their protein products. Mice homozygous for a functional deletion in the Period-2 gene (Per2m/m mice) exhibit short free-running circadian periods and eventually lose behavioral circadian rhythmicity in constant darkness (DD). We investigated Per2m/m mice in DD for several months and identified a categorical sex difference in the dependence on Per2 for maintenance of circadian rhythms. Nearly all female Per2m/m mice became circadian arrhythmic in DD, whereas free-running rhythms persisted in 37% of males. Remarkably, with extended testing, Per2m/m mice did not remain arrhythmic in DD, but after varying intervals spontaneously recovered robust, free-running circadian rhythms, with periods shorter than those expressed prior to arrhythmia. Spontaneous recovery was strikingly sex-biased, occurring in 95% of females and 33% of males. Castration in adulthood resulted in male Per2m/m mice exhibiting female-like levels of arrhythmia in DD, but did not affect spontaneous recovery. The circadian pacemaker of many gonad-intact males, but not females, can persist in DD for long intervals without a functional PER2 protein; their circadian clocks may be in an unstable equilibrium, incapable of sustaining persistent coherent circadian organization, resulting in transient cycles of circadian organization and arrhythmia.

Amplitude of circadian rhythms becomes weaken in the north, but there is no cline in the period of rhythm in a beetle.

Many species show rhythmicity in activity, from the timing of flowering in plants to that of foraging behavior in animals. The free-running periods and amplitude (sometimes called strength or power) of circadian rhythms are often used as indicators of biological clocks. Many reports have shown that these traits are highly geographically variable, and interestingly, they often show latitudinal or longitudinal clines. In many cases, the higher the latitude is, the longer the free-running circadian period (i.e., period of rhythm) in insects and plants. However, reports of positive correlations between latitude or longitude and circadian rhythm traits, including free-running periods, the power of the rhythm and locomotor activity, are limited to certain taxonomic groups. Therefore, we collected a cosmopolitan stored-product pest species, the red flour beetle Tribolium castaneum, in various parts of Japan and examined its rhythm traits, including the power and period of the rhythm, which were calculated from locomotor activity. The analysis revealed that the power was significantly lower for beetles collected in northern areas than southern areas in Japan. However, it is worth noting that the period of circadian rhythm did not show any clines; specifically, it did not vary among the sampling sites, despite the very large sample size (n = 1585). We discuss why these cline trends were observed in T. castaneum.

Juvenile hormone affects the development and strength of circadian rhythms in young bumble bee (Bombus terrestris) workers

The circadian and endocrine systems influence many physiological processes in animals, but little is known on the ways they interact in insects. We tested the hypothesis that juvenile hormone (JH) influences circadian rhythms in the social bumble bee Bombus terrestris. JH is the major gonadotropin in this species coordinating processes such as vitellogenesis, oogenesis, wax production, and behaviors associated with reproduction. It is unknown however, whether it also influences circadian processes. We topically treated newly-emerged bees with the allatoxin Precocene-I (P-I) to reduce circulating JH titers and applied the natural JH (JH-III) for replacement therapy. We repeated this experiment in three trials, each with bees from different source colonies. Measurements of ovarian activity suggest that our JH manipulations were effective; bees treated with P-I had inactive ovaries, and this effect was fully recovered by subsequent JH treatment. We found that JH augments the strength of circadian rhythms and the pace of rhythm development in individually isolated newly emerged worker bees. JH manipulation did not affect the free-running circadian period, overall level of locomotor activity, sleep amount, or sleep structure. Given that acute manipulation at an early age produced relatively long-lasting effects, we propose that JH effects on circadian rhythms are mostly organizational, accelerating the development or integration of the circadian system.

Home-cage hypoactivity in mouse genetic models of autism spectrum disorder.

Genome-wide association and whole exome sequencing studies from Autism Spectrum Disorder (ASD) patient populations have implicated numerous risk factor genes whose mutation or deletion results in significantly increased incidence of ASD. Behavioral studies of monogenic mutant mouse models of ASD-associated genes have been useful for identifying aberrant neural circuitry. However, behavioral results often differ from lab to lab, and studies incorporating both males and females are often not performed despite the significant sex-bias of ASD. In this study, we sought to investigate the simple, passive behavior of home-cage activity monitoring across multiple 24-h days in four different monogenic mouse models of ASD: Shank3b-/-, Cntnap2-/-, Pcdh10+/-, and Fmr1 knockout mice. Relative to sex-matched wildtype (WT) littermates, we discovered significant home-cage hypoactivity, particularly in the dark (active) phase of the light/dark cycle, in male mice of all four ASD-associated transgenic models. For Cntnap2-/- and Pcdh10+/- mice, these activity alterations were sex-specific, as female mice did not exhibit home-cage activity differences relative to sex-matched WT controls. These home-cage hypoactivity alterations differ from activity findings previously reported using short-term activity measurements in a novel open field. Despite circadian problems reported in human ASD patients, none of the mouse models studied had alterations in free-running circadian period. Together, these findings highlight a shared phenotype across several monogenic mouse models of ASD, outline the importance of methodology on behavioral interpretation, and in some genetic lines parallel the male-enhanced phenotypic presentation observed in human ASDs.

Exploring determinants of behavioral chronotype in a diurnal-rodent model of human physiology

Numerous studies conducted with human participants have shown that differences in chronotype, defined as individual patterns of early or late beginning of daily activity, have implications for many biobehavioral processes, such as cognitive performance, mood, impulsivity, academic achievement of college students, and mental health. However, the determinants of individual variation in chronotype have not been investigated. Basic research on circadian rhythms has provided a basis for investigating the causes of chronotype variation, but experimental tests of pertinent hypotheses are difficult to conduct with human subjects. This limitation can be overcome by use of animal models. This study was conducted with a rodent species, the antelope ground squirrel (Ammospermophilus leucurus), that, like humans, is active during the daytime, exhibits a spread of chronotypes, and has a similar average free-running circadian period. We found chronotype to be a stable trait within individuals based on strong consistency of separate determinations made six months apart (correlation r = 0.91). We also found a moderate correlation of chronotype with the duration of the active phase (r = −0.51) and with free running period (r = 0.34), but weak correlation with rhythm robustness (r = 0.16), and no correlation with photic responsiveness or with masking responses. The best multiple regression model, incorporating the duration of the active phase, free-running period, and rhythm robustness, explained 38% of the variance in chronotype. Although 62% of the variance in chronotype remained unaccounted for, the results are encouraging because they document the possibility of using a diurnal rodent as a model for the investigation of the determinants of chronotype variation in humans.

Paternal Cocaine Disrupts Offspring Circadian Clock Function in a Sex-Dependent Manner in Mice

The present study is the first to explore the multigenerational effects of mammalian paternal cocaine intake on offspring (F1) circadian clock regulation. Parental cocaine use poses significant health risks to the offspring, through both maternal and paternal drug influences. With respect to the latter, recent evidence suggests that a paternal mode of cocaine inheritance involves epigenetic germ line actions that can ultimately disrupt offspring behavior. Based on our previous report in mice that free-running circadian period (tau) is chronically lengthened following withdrawal from long-term cocaine treatment, the present study was undertaken to explore potential epigenetic effects of paternal exposure to cocaine over the ∼40-day murine spermatogenic cycle on F1 circadian regulatory functions. Here we show that, although withdrawal of sires from the cocaine treatment lengthened their tau, such an effect did not persist in adult F1 male or female offspring born from drug-naïve dams. Notably, however, there was a distinct deficit in the ability of F1 cocaine-sired males, but not females, to undergo light-induced phase delay shifts of the circadian clock. In contrast, F1 cocaine-sired females, but not males, had suppressed circadian phase advance shifting responses to two non-photic stimuli: acute i.p. injections of cocaine and the serotonin agonist ([+]8-OH-DPAT). The reduced cocaine shifting in females was not due to suppressed cocaine-induced behavioral arousal. Collectively, these results reveal that a father’s cocaine use can disrupt major circadian entrainment mechanisms in his adult progeny in a sex-dependent manner.

Chronic social defeat stress suppresses locomotor activity but does not affect the free-running circadian period of the activity rhythm in mice

In mammals, daily rhythms in behavior and physiology are under control of an endogenous clock or pacemaker located in the suprachiasmatic nucleus (SCN) of the hypothalamus. The SCN assures an optimal temporal organization of internal physiological process and also synchronizes rhythms in physiology and behavior to the cyclic environment. The SCN receives direct light input from the retina, which is capable of resetting the master clock and thereby synchronizes internally driven rhythms to the external light-dark cycle. In keeping with its function as a clock and pacemaker, the SCN appears to be well buffered against influences by other stimuli and conditions that contain no relevant timing information, such as acute stressors. On the other hand, it has been suggested that chronic forms of stress may have gradually accumulating effects that can disturb normal clock function and thereby contribute to stress-related disorders. Therefore, in the present study we investigated whether chronic intermittent social stress affects the endogenous period and phase of the free-running activity rhythm in mice. Adult male mice were maintained in constant dim red light conditions and exposed to a daily 20 min social defeat stress session for 10 consecutive days, either during the first half of their activity phase or the first half of their resting phase. The overall amount of running wheel activity was strongly suppressed during the 10 days of social defeat, to about 50% of the activity in non-defeated control mice. Activity levels gradually normalized during post-defeat recovery days. Despite the strong suppression of activity in defeated animals, the endogenous free-running circadian period of the activity rhythm and the phase of activity onset were not affected. These findings are thus in agreement with earlier studies suggesting that the circadian pacemaker in the SCN that is driving the rhythmicity in activity is well-protected against stress. Even severe social defeat stress for 10 consecutive days, which has a major effect on the levels of activity, does not affect the pace of the endogenous clock.

Free-running circadian period in adolescents and adults.

Sleep timing shifts later during adolescence (second decade). This trend reverses at ~20years and continues to shift earlier into adulthood. The current analysis examined the hypothesis that a longer free-running circadian period during late adolescence (14-17years) compared with adulthood (30-45years) accounts for sleep timing differences. Sex and ancestry were also examined because previous reports find that women and those with African-American ancestry have shorter free-running periods. Circadian period was measured using an ultradian dark-light protocol (2hr dark/sleep, 2hr dim room light [~20 lux]/wake) over 3.4days. Dim light melatonin onsets were measured before and after the ultradian protocol, from which the circadian period was derived. In contrast to our hypothesis, we found that free-running circadian period was similar in adolescents and adults. African-American adults had shorter free-running circadian periods compared with adults of other ancestries. This ancestry difference was not seen in the adolescent group. Finally, we observed a non-significant trend for shorter free-running circadian periods in females compared with males. These data suggest that age-related changes in circadian period after late adolescence do not account for sleep timing differences. These data provide further support for ancestry-related differences in period, particularly in adults. Whether the large difference in circadian period between African-American and other ancestries emerges later in development should be explored.

Ovariectomy influences the circadian rhythm of locomotor activity and the photic phase shifts in the volcano mouse

Recently, the relationship between the circadian system and female reproduction has been of great interest; ovarian hormones can modify the amount and distribution of daily activity differently in rodent species. The volcano mouse Neotomodon alstoni is a species in which it is possible to study the circadian rhythm of locomotion, and it offers comparative information about the influence of ovaries on the circadian system. In this study, we used infrared crossings to compare free movement in intact and sham-operated or ovariectomized mice. We analyzed behavioral and endocrine changes related to the estrous cycle and locomotor circadian rhythm in free-running mice and photic phase shifting. Evidence shows that intact mice present a scalloped pattern of daily activity during the estrous cycle. In constant darkness, the ovariectomy reduces the total amount of activity, shortens the free-running circadian period of locomotion and increases photic phase shifts during the early subjective night. During entrainment, the ovariectomized mice increased the amplitude of total activity during the scotophase, and delay the time of activity onset. These results suggest that ovarian hormones in N. alstoni modulate the circadian rhythm of locomotor activity in a species-specific manner.

0710 REPRODUCIBILITY OF CIRCADIAN VARIABLES (MEQ, MSF, DLMO, PHASE ANGLE, AND CIRCADIAN PERIOD) OVER MONTHS

We conducted two studies that were similar for the first 10 days (nature.com/articles/srep08381, nature.com/articles/srep36716), and determined each subject’s morningness-eveningness score (MEQ), Mid-sleep on Free Days (MSF) from the MCTQ, baseline dim light melatonin onset (DLMO), phase angle of entrainment, and free-running circadian period. Ten African-Americans (6 women, 4 men) and 8 European-Americans (2 women, 6 men) participated in both studies separated by 9 to 33 months (mean ± SD = 16 ± 7). They were 32.2 ± 6.7 years old at the first study. The purpose of this report is to examine the reproducibility of these circadian variables. Subjects slept in the lab on a fixed 8-h sleep schedule similar to their usual sleep schedule for 4 days, followed by a circadian phase assessment with 30 min saliva samples to calculate baseline DLMO. Phase angle was the interval from DLMO to bedtime. There were also 3 days of ultradian LD cycles producing forced desynchrony. Circadian period was determined from phase assessments before and after the days of ultradian LD cycles. For each circadian variable, we made scatter plots with identical x and y axes. Lines of unity showed when the variable was exactly the same in both studies. Lines parallel to and on each side of the line of unit showed how much the variable differed between the studies. We also calculated Pearson correlations for each variable. The MEQ score differed by less than 10 points between the two studies; MSF by 1 h or less, except for 2 subjects, baseline DLMO by 1 h or less except for 3 subjects, phase angle by 2 h or less, and circadian period by 0.3 h or less except for 2 subjects. All correlations were significant (p≤.0001), MEQ r=.85, MSF r=.78, baseline DLMO r=.81, phase angle r=.80, circadian period r=.78. A longer time between the two studies did not make the variables more different. In this small sample, there were no differences between men and women or between European and African-Americans in the stability of these variables. Circadian parameters were relatively stable over months. NIHR01NR007677.

Sex and ancestry determine the free-running circadian period.

The endogenous, free-running circadian period (τ) determines the phase relationship that an organism assumes when entrained to the 24-h day. We found a shorter circadian period in African Americans compared to non-Hispanic European Americans (24.07 versus 24.33h). We speculate that a short circadian period, closer to 24h, was advantageous to humans living around the equator, but when humans migrated North out of Africa, where the photoperiod changes with seasons, natural selection favoured people with longer circadian periods. Recently, in evolutionary terms, immigrants came from Europe and Africa to America ('the New World'). The Europeans were descendents of people who had lived in Europe for thousands of years with changing photoperiods (and presumably longer periods), whereas Africans had ancestors who had always lived around the equator (with shorter periods). It may have been advantageous to have a longer circadian period while living in Europe early in the evolution of humans. In our modern world, however, it is better to have a shorter period, because it helps make our circadian rhythms earlier, which is adaptive in our early-bird-dominated society. European American women had a shorter circadian period than men (24.24 versus 24.41), but there was no sex difference in African Americans (24.07 for both men and women). We speculate that selection pressures in Europe made men develop a slightly longer period than women to help them track dawn which could be useful for hunters, but less important for women as gatherers.

Differential Sensitivity to Ethanol-Induced Circadian Rhythm Disruption in Adolescent and Adult Mice.

Growing evidence supports a central role for the circadian system in alcohol use disorders, but few studies have examined this relationship during adolescence. In mammals, circadian rhythms are regulated by the suprachiasmatic nucleus, a biological clock whose timing is synchronized (reset) to the environment primarily by light (photic) input. Alcohol (ethanol [EtOH]) disrupts circadian timing in part by attenuating photic phase-resetting responses in adult rodents. However, circadian rhythms change throughout life and it is not yet known whether EtOH has similar effects on circadian regulation during adolescence. General circadian locomotor activity was monitored in male C57BL6/J mice beginning in adolescence (P27) or adulthood (P61) in a 12-hour light, 12-hour dark photocycle for ~2weeks to establish baseline circadian activity measures. On the day of the experiment, mice received an acute injection of EtOH (1.5g/kg, i.p.) or equal volume saline 15minutes prior to a 30-minute light pulse at Zeitgeber Time 14 (2hours into the dark phase) and then were released into constant darkness (DD) for ~2weeks to assess phase-resetting responses. Control mice of each age-group received injections but no light pulse prior to DD. While adults showed the expected decrease in photic phase-delays induced by acute EtOH, this effect was absent in adolescent mice. Adolescents also showed baseline differences in circadian rhythmicity compared to adults, including advanced photocycle entrainment, larger photic phase-delays, a shorter free-running (endogenous) circadian period, and greater circadian rhythm amplitude. Collectively, our results indicate that adolescent mice are less sensitive to the effect of EtOH on circadian photic phase-resetting and that their daily activity rhythms are markedly different than those of adults.

Western diet affects the murine circadian system possibly through the gastrointestinal microbiota

Consumption of a high-fat diet characteristic of human Western diet has been shown to affect the circadian system of laboratory rodents. The present study confirms an effect of Western diet on the circadian system of mice, specifically a shortening of the free-running circadian period of running-wheel activity, in addition to increased weight gain. Decimation of the gut microbiota by broad spectrum antibiotic treatment reversed the effect of Western-diet feeding on the free-running period, which suggests that the effect of Western-diet feeding on the circadian system is mediated by the gastrointestinal microbiota. This finding is particularly relevant in view of recent studies describing a relationship between gut microbes, circadian clock function, and obesity.

Circadian rhythms of European and African-Americans after a large delay of sleep as in jet lag and night work.

Jet travel and night shift work produce large changes in when people sleep, work and eat; a challenge that was not encountered during most of our evolution. Successful adaptation would require the internal, master, circadian clock to make large phase shifts to reduce the circadian misalignment between circadian rhythms and the times for sleep, work and meals. We compared African-Americans and non-Hispanic European-Americans in how much their circadian clocks shifted after a 9 hour phase delay of the light/dark, sleep/wake and meal schedule, which has similarities to flying west or sleeping in the daytime after night shifts. We also measured their free-running circadian periods using a forced desynchrony protocol with a 5-h day. European-Americans had longer free-running periods and larger phase delays than African-Americans. Correlations (among all subjects, just African-Americans and just European-Americans) showed that longer circadian periods were associated with larger phase delays. Larger phase delays, facilitated by longer circadian periods, reduce jet lag after westward travel and make it easier to work night shifts and sleep during the daytime after night work. On the other hand, a shorter circadian period, which makes one more of a morning-type person, is better for most people given our early-bird dominated society.

Circadian and Geotactic Behaviors: Genetic Pleiotropy in Drosophila Melanogaster.

Data presented in this paper test the hypotheses that Hirsch’s positive geotaxis (Lo) and negative geotaxis (Hi5) strains of Drosophila melanogaster (fruit fly) differ in length of the free-running circadian activity period (tau) as well as adult geotaxis.Several genes have been shown to alter geotaxis in Drosophila. Two of these genes, cryptochrome (cry) and Pigment-dispersing-factor (Pdf) are integral to the function of biological clocks. Pdf plays a crucial role in maintaining free-running circadian periods. The cry gene alters blue-light (<420 nm) phototransduction which affects biological clocks, spatial orientation and taxis relative to gravity, magnetic fields, solar, lunar, and celestial radiation in several species. The cry gene is involved in phase resetting (entrainment) of the circadian clock by blue light (<420 nm).Geotaxis involves spatial orientation, so it might be expected that geotaxis is linked genetically with other forms of spatial orientation. The association between geotaxis and biological clocks is less intuitive. The data and the literature presented here show that genes, physiology and behavioural aspects of geotaxis, biological clocks, magnetosensitivity and other types of spatial orientation, are complex, intriguing and interrelated.

Circadian rhythm phase shifts and endogenous free-running circadian period differ between African-Americans and European-Americans.

Successful adaptation to modern civilization requires the internal circadian clock to make large phase shifts in response to circumstances (e.g., jet travel and shift work) that were not encountered during most of our evolution. We found that the magnitude and direction of the circadian clock's phase shift after the light/dark and sleep/wake/meal schedule was phase-advanced (made earlier) by 9 hours differed in European-Americans compared to African-Americans. European-Americans had larger phase shifts, but were more likely to phase-delay after the 9-hour advance (to phase shift in the wrong direction). The magnitude and direction of the phase shift was related to the free-running circadian period, and European-Americans had a longer circadian period than African-Americans. Circadian period was related to the percent Sub-Saharan African and European ancestry from DNA samples. We speculate that a short circadian period was advantageous during our evolution in Africa and lengthened with northern migrations out of Africa. The differences in circadian rhythms remaining today are relevant for understanding and treating the modern circadian-rhythm-based disorders which are due to a misalignment between the internal circadian rhythms and the times for sleep, work, school and meals.