Timeless genes and jetlag

It has been 35 years since Konopka and Benzer (1) published their landmark paper in PNAS documenting the discovery of three lines of Drosophila with aberrant circadian rhythms. One strain was governed by a clock that ran faster than wild type, one harbored a slower-than-normal clock, and one was arrhythmic. These mutations equivalently affected two different rhythms, in the timing of adult emergence from the pupal case and the flies' rhythms of locomotion, suggesting that they affected a general circadian clock mechanism rather than the observed behaviors per se. The genetic analysis of these mutants, however, is what made this discovery so powerful: By meiotic recombination mapping, analysis of small chromosome deletions, and complementation, the genetic etiology of the rhythm anomalies in all three lines mapped to the same gene, dubbed period, creating an allelic series with the arrhythmic allele (per⁰) appearing to be a null allele. The remarkable implication of this discovery, that there are specific genes whose functions specifically subserve a general circadian timekeeping mechanism, has been spectacularly borne out with the discovery of at least a half-dozen other such “clock factors” in forward genetic screens and the ensuing construction of a coherent molecular model for circadian clock function. In a recent issue of PNAS, Peschel et al. (2) showed that, 35 years later, classical forward genetic studies continue to yield important insights into the mechanisms of the circadian clock.

As currently understood, the Drosophila circadian clock mechanism consists primarily of a time-delayed transcription-translation feedback loop (3) (Fig. 1). Two positive transcription factors, encoded by Clock (Clk) and cycle (cyc), drive the transcription of the per locus as well as the clock gene timeless (tim). PER and TIM proteins heterodimerize, accumulate in the cytoplasm, undergo orchestrated translocation to the nucleus, and ultimately repress the CLK–CYC …

*E-mail: vangelder{at}vision.wustl.edu