High-throughput discovery of genetic determinants of “circadian misalignment”

This topic is “made for” these GEITP pages, i.e. the gene-environment interactions theme leaps out. The environmental signal is “light” or “absence of light” (i.e. day vs night, light-dark cycles called circadian rhythm), and virtually all animals “sense” these signals; their response then comprises multiple genetic networks (encoded by their genomes), which regulate physiological and critical life functions. This “circadian clock” is one of the best-characterized mechanisms” studied — that can mediate effects of “environmental cues” on molecular, physiological and behavioral activities.

The suprachiasmatic nucleus (SCN) is the central circadian pacemaker in mammals; the SCN receives photic information via the retina, integrates time-related information of tissues and organs, and then transmits timing information to cells and tissues, which in turn regulate physiology and behavior to cause animals to respond to daily changes of environmental cues. Chronic misalignment between the circadian clock and the environment — has been implicated in many pathological processes (e.g. sleep disorders, cardiovascular diseases, metabolic disorders, and cancer).

In humans, dysfunction or misalignment of the circadian clock with environmental cues — can alter timing of the sleep-wake cycle. Mice with mutations orthologous to human mutations (PER2*Ser662Gly, CK1*δT44A) recapitulate human phase-advanced behavioral rhythms. Transgenic mice carrying the Per1*Ser714Gly mutation affects feeding behavior, indicating that mice are a good model for human circadian functions. In addition, activity, feeding, temperature, and glucocorticoid signals — can also affect circadian rhythmicity. These are all zeitgebers (rhythmically occurring natural phenomena that act as cues to regulate the body’s circadian rhythms) and will impart phase information on their target tissues; circadian misalignment is therefore a consequence of conflicting signals of these zeitgebers.

Authors collected and analyzed indirect calorimetry data from >2000 wild-type mice available from the International Mouse Phenotyping Consortium (IMPC); authors demonstrated that onset time & peak phase of activity, and food intake rhythms — are reliable parameters for screening defects of circadian misalignment. Authors then developed a machine-learning algorithm to quantify these parameters in their screen of 750 mutant mouse lines from five IMPC phenotyping centers. Mutations in five genes [Slc7a11 (solute carrier 7A11), Rhbdl1 (rhomboid-like-1), Spop (speckle-type BTB/POZ protein), Ctc1 (CST telomere replication complex component-1) and Oxtr (oxytocin receptor)] were shown to be associated with altered patterns of activity or food intake. By further studying the Slc7a11 transgenic mouse, authors comfirmed its advanced-activity-phase phenotype — in response to simulated jetlag and skeleton photoperiod stimuli. Disruption of the Slc7a11 gene affected the intercellular communication within the SCN, suggesting a defect in synchronization of clock neurons. This herculean study has established a systematic phenotype analysis approach that should be useful for uncovering mechanisms of circadian entrainment in mice. 😊


PLoS Genet Jan 2020; 16: e1008577

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