Circadian clocks can be reset by light stimulation. To investigate the mechanism of this phase shifting, the effects of light pulses on the protein and messenger RNA products of the Drosophila clock gene period (per) were measured. Photic stimuli perturbed the timing of the PER protein and messenger RNA cycles in a manner consistent with the direction and magnitude of the phase shift. In addition, the recently identified clock protein TIM (for timeless) interacted with PER in vivo, and this association was rapidly decreased by light. This disruption of the PER-TIM complex in the cytoplasm was accompanied by a delay in PER phosphorylation and nuclear entry and disruption in the nucleus by an advance in PER phosphorylation and disappearance. These results suggest a mechanism for how a unidirectional environmental signal elicits a bidirectional clock response.

Circadian (Х24-h) rhythms are governed by endogenous biochemical oscillators (clocks) that in a wide variety of organisms can be phase shifted (i.e., delayed or advanced) by brief exposure to light and changes in temperature. However, how changes in temperature reset circadian timekeeping mechanisms is not known. To begin to address this issue, we measured the effects of short-duration heat pulses on the protein and mRNA products from the Drosophila circadian clock genes period (per) and timeless (tim). Heat pulses at all times in a daily cycle elicited dramatic and rapid decreases in the levels of PER and TIM proteins. PER is sensitive to heat but not light, indicating that individual clock components can markedly differ in sensitivity to environmental stimuli. A similar resetting mechanism involving delays in the per-tim transcriptional-translational feedback loop likely underlies the observation that when heat and light signals are administered in the early night, they both evoke phase delays in behavioral rhythms. However, whereas previous studies showed that the light-induced degradation of TIM in the late night is accompanied by stable phase advances in the temporal regulation of the PER and TIM biochemical rhythms, the heat-induced degradation of PER and TIM at these times in a daily cycle results in little, if any, long-term perturbation in the cycles of these clock proteins. Rather, the initial heat-induced degradation of PER and TIM in the late night is followed by a transient and rapid increase in the speed of the PER-TIM temporal program. The net effect of these heat-induced changes results in an oscillatory mechanism with a steady-state phase similar to that of the unperturbed control situation. These findings can account for the lack of apparent steady-state shifts in Drosophila behavioral rhythms by heat pulses applied in the late night and strongly suggest that stimulus-induced changes in the speed of circadian clocks can contribute to phase-shifting responses.Circadian (Х24-h) rhythms are governed by endogenous biochemical oscillators, or clocks (reviewed in references 18 and 46). Although these rhythms persist under constant environmental conditions, they can be entrained (synchronized) by external time cues (zeitgebers), most notably the daily light/ dark and temperature cycles. The adaptive ability of circadian clocks to be reset by external cues enables organisms to maintain temporal alignment between their endogenously driven rhythms and biologically advantageous times in a daily cycle. A powerful strategy for probing this resetting feature is based on the ability of short pulses of environmental stimuli or other agents to elicit phase shifts in circadian pacemakers. These perturbation experiments revealed that the direction (i.e., delay or advance) and magnitude of a phase shift are functions of the time in a daily cycle that the zeitgeber is administered. Plotting the average phase shift as a function of time that the stimulus was applied yields a phase-response curve (PRC) that describes...

Strabismus has been known to have a significant genetic component, but the mode of inheritance and the identity of the relevant genes have been enigmatic. This paper reports linkage analysis of nonsyndromic strabismus. The principal results of this study are: (i) the demonstrated feasibility of identifying and recruiting large families in which multiple members have (or had) strabismus; (ii) the linkage in one large family of a presumptive strabismus susceptibility locus to 7p22.1 with a multipoint logarithm of odds score of 4.51 under a model of recessive inheritance; and (iii) the failure to observe significant linkage to 7p in six other multiplex families, consistent with genetic heterogeneity among families. These findings suggest that it will be possible to localize and ultimately identify strabismus susceptibility genes by linkage analysis and mutation screening of candidate genes.linkage ͉ whole genome scan ͉ complex trait ͉ ophthalmic genetics S trabismus (misalignment of the eyes; also referred to as ''squint'') is one of the most common ocular disorders in humans, affecting 1-4% of the population (1). It is frequently associated with amblyopia (uniocular visual neglect), a leading cause of visual impairment in children and young adults. The familial clustering of strabismus has been recognized since antiquity. For example, Hippocrates stated that ''children of parents having distorted eyes squint also for the most part'' (1).Numerous twin and family studies point to a significant genetic component in the etiology of strabismus (summarized in refs. 1-4). Summing the data from 11 published twin studies shows that, among 206 monozygotic and 130 dizygotic twin pairs in which one member of the twin pair had strabismus, 73% of monozygotic twin pairs were concordant for strabismus, whereas only 35% of dizygotic twin pairs were concordant for strabismus. We note that the degree of concordance among dizygotic twin pairs is higher than the Ϸ10-15% typically reported for siblings; this may reflect the overall higher incidence of strabismus among premature and low-birth-weight infants.The overall incidence of strabismus and the incidence of specific types of strabismus show appreciable differences between racial groups, further supporting the relevance of genetic factors. Two studies have documented a lower incidence of all types of strabismus among Africans or African Americans (0.5% and 0.6%, respectively) relative to Americans of European ancestry (2.5%; refs. 5 and 6). Moreover, the majority of African, African American, and Asian strabismics are exotropes, whereas the majority of Caucasian strabismics are esotropes (5-7).With respect to overall heritability, the relative risk for first degree relatives of an affected individual is estimated to be between 3 and 5. Crone and Vezeboer (8) found that 13% of parents of strabismic probands had strabismus vs. a 3% incidence in the general population. Hu (9) found a 9% incidence among first-degree relatives and a 2.2% incidence among second degree relatives, versus ...