SIRT1, which requires NAD for its enzymatic activity, then uses increased NAD levels to suppress BMAL1 through deacetylation. This suppression results in less transcription of the NAMPT, less NAMPT protein, less NAD made, and therefore less SIRT1 and less suppression of the CLOCK-BMAL dimer. This dimer can again positively activate the "Nampt" gene transcription and the cycle continues, creating another oscillatory loop involving CLOCK-BMAL as positive elements. The key role that "Clock" plays in metabolic and circadian loops highlights the close relationship between metabolism and circadian clocks. "Clock" mutant organisms can either possess a null mutation or an antimorphic allele at the "Clock" locus that codes for an antagonist to the wild-type protein. The presence of an antimorphic protein downregulates the transcriptional products normally upregulated by "Clock". In "Drosophila", a mutant form of "Clock" ("Jrk") was identified by Allada, Hall, and Rosbash in 1998. The team used forward genetics to identify non-circadian rhythms in mutant flies. "Jrk" results from a premature stop codon that eliminates the activation domain of the CLOCK protein. This mutation causes dominant effects: half of the heterozygous flies with this mutant gene have a lengthened period of 24.8 hours, while the other half become arrhythmic. Homozygous flies lose their circadian rhythm. Furthermore, the same researchers demonstrated that these mutant flies express low levels of PER and TIM proteins, indicating that "Clock" functions as a positive element in the circadian loop. While the mutation affects the circadian clock of the fly, it does not cause any physiological or behavioral defects. The similar sequence between "Jrk" and its mouse homolog suggests common circadian rhythm components were present in both "Drosophila" and mice ancestors. A recessive allele of "Clock" leads to behavioral arrhythmicity while maintaining detectable molecular and transcriptional oscillations. This suggests that "Clk" contributes to the amplitude of circadian rhythms. The mouse homolog to the "Jrk" mutant is the "ClockΔ19" mutant that possesses a deletion in exon 19 of the "Clock" gene. This dominant-negative mutation results in a defective CLOCK-BMAL dimer, which causes mice to have a decreased ability to activate "per" transcription. In constant darkness, "ClockΔ19" mice heterozygous for the "Clock" mutant allele exhibit lengthened circadian periods, while "ClockΔ19/Δ19" mice homozygous for the allele become arrhythmic.