A National Institutes of Health-funded project involving researchers from Texas A&M University, the Perelman School of Medicine at the University of Pennsylvania and the Children’s Hospital of Philadelphia (CHOP) has used human genomics to identify a new genetic pathway involved in regulating sleep in fruit flies to humans – a novel finding that could pave the way for new treatments for insomnia and other sleep-related disorders.
Texas A&M geneticist and evolutionary biologist Alex Keene collaborated with Penn’s Allan Pack and Philip Gehrman’s and CHOP’s Struan Grant on the groundbreaking research, which is published in scientific advances.
“There has been a tremendous effort to use human genomic studies to find sleep genes,” Keene said. “Some studies involve hundreds of thousands of people. But validation and testing in animal models are critical to understanding how it works. We have achieved that here, largely because we each bring a different area of expertise that has enabled the ultimate effectiveness of this collaboration.”
According to Keene, the most exciting thing about the team’s work is that they have developed a pipeline that starts not with a model organism but with actual human genomic data.
“There is an abundance of human genome-wide association studies (GWAS) that identify genetic variants associated with sleep in humans,” Keene said. “However, validating them was an enormous challenge. Our team used a genomic approach called variant-to-gene mapping to predict which genes are affected by each genetic variant. Then we looked at the effect of these genes in fruit flies.
“Our studies have found that mutations in the Pig-Q gene, which is required for the biosynthesis of a protein function modifier, increase sleep. We then tested this in a vertebrate model, the zebrafish, and found a similar effect. So in humans.” , flies and zebrafish, Pig-Q has been implicated in sleep regulation.”
According to Keene, the team’s next step is to study the role of a common protein modification, GPI anchor biosynthesis, in sleep regulation. In addition, he notes that the human-to-fruit, fly-to-zebrafish pipeline the team is developing will enable them to functionalize not only sleep genes but also other traits commonly studied with human GWAS, including neurodegeneration, aging and memory to rate.
“Understanding how genes regulate sleep and the role this pathway plays in sleep regulation may help inform future insights about sleep and sleep disorders such as insomnia,” said Gehrman, associate professor of clinical psychology in psychiatry at Penn University and clinical psychologist at the University of Pennsylvania Penn Chronobiology and Sleep Institute. “In the future, we will continue to use and study this system to identify additional genes that regulate sleep, which could point in the direction of new treatments for sleep disorders.”
Keene’s research within his laboratory attached to the Center for Biological Clocks Research lies at the intersection of evolution and neuroscience, with a focus on understanding the neural mechanisms and evolutionary basis of sleep, memory formation and other behavioral functions in fly and fish models. In particular, he studies fruit flies (Drosophila melanogaster) and Mexican cavefish, who have lost both their eyesight and the ability to sleep, with the goal of identifying the genetic basis of behavioral decisions that contribute to human diseases, including obesity, diabetes and heart disease.
Materials provided by Texas A&M University. Originally written by Shana K Hutchins. Note: Content can be edited for style and length.