Biological clock varies due to gene expression, fruit fly study reveals

February 12, 2021

Your circadian rhythm may have a genetic connection. (Pixabay/congerdesign)

Whether someone is an “early bird” or a “night owl” depends in part on the pattern of expression of the genes connected to their body’s internal clock, according to a new study of day-night cycles in fruit flies.

A team led by Swiss researchers examined how gene expression varied in relation to fruit flies’ circadian rhythms, 24-hour cycles that function similarly in both that insect and humans. They also found several previously unstudied genes that could be crucial to the biological clock, and discovered that organs in a single fly are sometimes running on different clocks. If these features are confirmed to be in humans, they could improve understanding of disorders and treatments.

The findings were published in January in Science Advances.

Sharing about 60% of DNA with humans, fruit flies have played an outsized role in circadian rhythm investigations and genetics research more broadly. Six Nobel Prizes in physiology or medicine have been awarded on the back of Drosophila melanogaster, including the 2017 prize given to the discoverers of the genes and proteins that underlie the circadian rhythm.

In the recent study, scientists tracked the expression of fruit fly genes every two hours over two days to document how it changes over time. They studied tissues from four organs in 141 genetic lines of fruit flies, with each line containing practically identical individuals.

The results showed that the biological clocks of some flies were several hours apart because of differences in gene expression, akin to humans being hardwired to wake up at different times in the morning, according to co-author Bart Deplancke.

“Just like we know that there’s morning and evening people, so to speak, we also know that there's different kinds of flies, depending on their genotype,” said Deplancke, a professor of biology at the Swiss Federal Institute of Technology. “What was not known was how this is encoded at the molecular level in terms of gene expression. This is what we really now define for the first time.”

To avoid taking thousands of measurements, the researchers collected all samples for one fruit fly line and took a single sample from all the rest, using statistical estimates to extrapolate information about their circadian rhythms. The method had some blind spots, such as interpreting a fly’s dysfunctional biological clock as simply being shifted 10 hours from the reference fly’s clock, but it successfully generated the cycles of well-known clock genes.

Out of the 1,757 genes whose expression were found to cycle with the circadian rhythm,  the experiment identified only 14 that were active in all four organ tissues — the seven known core clock genes and seven poorly understood ones. Five of the mysterious genes have counterparts in mice, baboons and humans, implying that the proteins they encode could be crucial parts of the human circadian rhythm that have not yet been identified.

“I think they're very strong candidates for being central regulators that were so far going under the radar,” Deplancke said.

Major clock variations were also discovered between the brain, liver and other organs within individual flies of dozens of lines, a finding that “bewildered” Deplancke and his team. They tracked the expression of genes active in multiple organs to find that nearly one-third of the fruit fly lines had local circadian rhythms that were as much as multiple hours apart from one another.

Because the circadian rhythms of fruit flies and humans function similarly, people may also have out-of-sync organs, according to Deplancke. He said that could impact medications that are most effective at a particular time in the biological clock. It may also cause digestive problems and weight gain if appetite and digestion are desynchronized.

More studies in fruit flies are needed to understand clock misalignment in organs, such as the influence of diet, and similar studies would be difficult in humans because organ samples cannot be taken, according to the Swiss professor.

“I would be honored, in a way, if the circadian field at the human level would start to take this seriously, that, ‘OK, maybe we have to actually consider that there's this overall desynchrony, and how can we now approach this?’” Deplancke said.

The article, “Extensive tissue-specific expression variation and novel regulators underlying circadian behavior” was published Jan. 29 in Science Advances. The authors of the study were Maria Litovchenko, Antonio Meireles-Filho, Michael Frochaux, Roel Bevers, Alessio Prunotto, Brian Hollis, Vincent Gardeux, Virginie Braman, Julie Russeil, Matteo dal Peraro and Bart Deplancke, Swiss Federal Institute of Technology in Lausanne and Swiss Institute of Bioinformatics; and Ane Martin Anduaga and Sebastian Kadener, Brandeis University. The lead authors were Maria Litovchenko and Antonio Meireles-Filho.

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