In 2017, the Nobel Prize in Physiology or Medicine was awarded to three scientists who discovered the molecular mechanisms that control circadian rhythm, also known as the “sleep-wake cycle”. To accomplish the task, the scientists used the common fruit fly Drosophila melanogaster, making it the sixth Nobel laureate of research involving it.
Fruitful fruit flies
Life scientists have been using Drosophila for over a hundred years now. Originally proposed by entomologist Charles W. Woodworth as an organism model, it was used in research initiated by geneticist Thomas H. Morgan who ran the famous Fly Room at Columbia University in the early 1900s.
Sharing about 60% of human DNA, the humble insect has been the baseline of countless scientific discoveries, from genetic inheritance and gene transfer to neurodegenerative disorders such as Alzheimer’s and Parkinson’s.
Circadian rhythms
Drosophila has also been widely used in the study of circadian rhythm, a process shared by almost all organisms, including animals, plants and even microbes. In addition to sleep and wakefulness, it affects many aspects of our bodies, including hormone release, eating and digestion, as well as body temperature.
Indeed, the study of circadian rhythms has become an area in itself: chronobiology. And because a person’s circadian rhythm seems to determine when certain drugs need to be taken to increase their effects, a new branch of medicine has also recently emerged: chronopharmacology.
Gene rhythms
Now, scientists led by Maria Litovchenko and Bart Deplancke at the EPFL School of Life Sciences have conducted an extensive study using Drosophila to study how different genes in different tissues of the animal are regulated so that they know when to turn it on and off during the course of a day, ie in the action of the circadian clock. “We wanted to assess how these molecular rhythms differ in the population of natural fruit flies and how genomic differences affect them,” Deplancke adds. The study is published in Advances in science.
The scientists turned to a fly facility called the Drosophila Genetic Reference Panel (DGRP), which contains more than 200 genetically differentiated lines of the insect. The genome of each line is followed in its entirety so that scientists can see differences between genotypes and then link them to differences between phenotypes, thus linking genes to their actions.
From the DGRP, the scientists sampled over 700 print-specific “transcripts”. In an organism or tissue or just a cell, genes are encoded or “transcribed” into mRNA, which is then used to synthesize proteins. Transcription is therefore a set of all RNA transcripts from DNA, organic coding or non-coding.
In this study, the scientists used the mRNA from reference, “control,” fly strain and then sampled the mRNA from 141 individual DGRP lines at high resolution – at nine-minute intervals between each line. The idea behind this was to see how the gene transcripts changed over time in different lines, and grasp how the genetic background of fruit flies and circadian rhythm combine to ‘affect the expression of different genes in specific differences.
“It allowed us to generate the first time series of a specific reference circadian gene expression in Drosophila; a broad atlas of circadian expression expression,” Litovchenko says. “But it will also allow us to gain unprecedented views on genome size and nature on circadian gene expression differentiation using an innovative approach that allowed the reconstruction of dynamic cycling patterns from collected samples. statistically. ”
The study revealed three main points about circadian rhythm.
The Clock rules over
Initially, the scientists found more than 1700 genes circulating according to the control of the circadian clock, and only fourteen of those genes were the same across all substances in the fruit fly.
“At least two of these fourteen were hitherto unidentified and significantly influenced several rhythm parameters of locomotor activity,” Litovchenko said, referring to the behavior patterns of the dependent fruit fly. to his circadian clock. “Because these genes have orthologs (similar genes) in mice, baboons, and humans, our findings strongly suggest that they are novel, fundamental regulators in mammals as well,” she says. add.
Morning man or night owl?
Second, that each person may have their own circadian rhythm, which may explain the wide range of human behavior, such as morning people, nappers, evening people, night owls and so on. The researchers used a state-of-the-art statistical method of calculating natural circadian rhythm for all tissues in all DGRP fruit fly transcripts.
What they found is that the physiological clock in about a third of Drosophila’s lines is significantly shifting from the “natural” time by more than three hours. And most of the lines showed only a change of circadian expression in one or two figs.
“People could be so affected by the difference,” says Deplancke. “There appears to be abundant, natural circadian asynchronization in molecular circadian rhythms between different tissues, something that we do not know before and that may exacerbate all kinds of psychological effects in metabolic patterns , digestion variables, etc. “
Light, dark, and muted
Finally, a small genetic mutation can disturb a person’s “photoentrainment”, which refers to the alignment of circadian rhythm with the light and dark pattern of the environment.
Focusing on the Drosophila line with the highest unnamed circadian rhythm (more than 10 hours), the researchers found that there is a novel, functional loss in Drosophila- clock and a lightly regulated cry gene (for “cryptochrome” ).
“This small deletion disturbs the light-guided FAD cofactor photoreduction,” Deplancke said. “It proves in vivo the importance of the conservative evolutionary imaging technique in the circadian pacemaker.”
From fly to human
The study also confirmed that Drosophila is an excellent model for studying circadian rhythm in humans, as it identified several new basic clock genes shared by both sexes. “We have gained unique insights into the extent to which the circadian clock is variable not only between individuals, but even between nappies of the same individual,” says Deplancke.
“Of course, we will not be able to realize such a vision in humans, because we can’t get a taste of human material over 24 hours,” he said. this variation is very wide. With the growing importance of chronopharmacology, it may be a good idea to find the circadian texture of individuals before embarking on important drug treatments. “
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Other donors
Swiss Institute of Bioinformatics
Brandeis University
Information
Maria Litovchenko, Antonio CA Meireles-Filho, Michael V Frochaux, Roel PJ Bevers, Alessio Prunotto, Ane Martin Anduaga, Brian Hollis, Vincent Gardeux, Virginie S Braman, Julie MC Russeil, Sebastian Kadener, Matteo dal Peraro, Bart Deplancke. Wide variation in specific expression and novel regulators underlying circadian behavior. Advances in science 7: eabc3781, 29 January 2021.