Many human health conditions, such as sleep disorders, cardiovascular diseases, metabolic disorders, and even cancers can be the result of problems with circadian rhythm, our natural sleep-wake cycle. The circadian rhythm is one of the best-characterized mechanisms that mediates environmental signals on molecular, physiological and behavioral activities. But the process by which this rhythm gets in sync, or alignment, with regular daily light and dark cycles is not understood. Researchers from the NIH Common Fund Knockout Mouse Phenotyping Program (KOMP2)  are now shedding light on how mice align their circadian rhythms to these cycles.

The NIH Common Fund Knockout Mouse Phenotyping Program (KOMP2) is part of the International Mouse Phenotyping Consortium (IMPC) (link is external). This is a global effort to generate "knockout" mice for every protein coding gene in the mouse genome and then carry out a range of tests to understand each gene’s biological function. Studying the energy use of normal and different knockout mice in a well-controlled light and dark setting has now provided clues to some genetic underpinnings of circadian alignment. By collecting and studying indirect calorimetry (IC) data, a measure of energy use and activity levels, from more than 2000 normal mice, the researchers showed that onset time of peak activity and food intake rhythms are reliable parameters for screening defects of circadian alignment. Using a machine learning approach to look at the vast amount of data collected, they developed an algorithm for recognizing normal circadian parameters in mice. The algorithm was developed and validated and is available to use for future analysis of datasets. They then used this machine learning approach to look at a subset of 750 different knockout mice. They found five genes (Slc7a11, Rhbdl1, Spop, Ctc1 and Oxtr) potentially associated with altered patterns of activity or food intake, giving new insight into genes involved in circadian alignment. Because the IMPC researchers are still generating and phenotyping new knockout mice, this approach lays the foundation for a future larger and more comprehensive study of circadian behavior to uncover even more genes that help control circadian rhythm and its effects on health and disease.

Reference:

Zhang T, Xie P, Dong Y, Liu Z, Zhou F, Pan D, Huang Z, Zhai Q, Gu Y, Wu Q, Tanaka N, Obata Y, Bradley A, Lelliott CJ; Sanger Institute Mouse Genetics Project, Nutter LMJ, McKerlie C, Flenniken AM, Champy MF, Sorg T, Herault Y, Angelis MH, Durner VG, Mallon AM, Brown SDM, Meehan T, Parkinson HE, Smedley D, Lloyd KCK, Yan J, Gao X, Seong JK, Wang CL, Sedlacek R, Liu Y, Rozman J, Yang L, Xu Y. High-throughput discovery of genetic determinants of circadian misalignment (link is external). PLoS Genet. 2020 Jan 13;16(1):e1008577. doi: 10.1371/journal.pgen.1008577. PMID: 31929527; PMCID: PMC6980734.