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bioRxiv · 10.64898/2026.04.23.720472

The Phenotypic Landscape of a Circadian Clock

Kim, S. J.·Schnitkey, D.·Andrews, B.·Ranganathan, R.·Rust, M.
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Abstract

Circadian clocks produce near-24-hour oscillations through biochemical feedback loops. To study their architecture, we developed a deep sequencing assay that measures the phenotypes of thousands of mutant clocks in parallel. We reveal a landscape where oscillator properties are factorized: mutations change period without decreasing amplitude and while maintaining a balanced waveform. Mutations that either shorten or lengthen period localize to specific protein-protein interaction surfaces, while a particularly sensitive region near the KaiC interdomain linker can cause extreme effects. After entrainment, high amplitude mutant oscillators form a tunable low-dimensional manifold in the period-phase plane, suggesting that most period mutations leave the coupling to the environment unchanged. In contrast, mutations that reduce amplitude are concentrated in a specific long period phenotype. This correlation structure may support the evolvability of this dynamical molecular system and is a powerful constraint on underlying mechanism.

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Kim, S. J., Schnitkey, D., Andrews, B., Ranganathan, R., Rust, M.. 2026-04-27. The Phenotypic Landscape of a Circadian Clock. https://doi.org/10.64898/2026.04.23.720472

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