Scientists make progress in decoding the genetics of insomnia

Summary: Researchers identify the role that the Pig-Q gene plays in sleep regulation. Mutations in the Pig-Q gene increase sleep.

Source: Texas A&M

A research effort involving researchers from Texas A&M University, the University of Pennsylvania’s Perelman School of Medicine, and Children’s Hospital of Philadelphia (CHOP) used human genomics to identify a novel genetic pathway involved in the regulation of sleep from fruit flies to humans – a novel insight 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 and CHOP’s Struan Grant on the groundbreaking research, which is published in Scientific advances.

“There have been huge efforts to use human genomic studies to find sleep genes,” Keene said.

“Some studies involve hundreds of thousands of individuals. But validation and testing in animal models is key to understanding the function. We have succeeded here, in large part because we each bring a different area of ​​expertise that has enabled the ultimate effectiveness of this collaboration.

Keene says the most exciting thing about the team’s work is that they’ve developed a pipeline starting 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 a huge challenge. Our team used a genomic approach called variant-to-gene mapping to predict the genes impacted by each genetic variant. Next, we looked at the effect of these genes in fruit flies.

“Our studies showed that mutations in the Pig-Q gene, which is required for the biosynthesis of a protein function modifier, increased sleep. We then tested this in a vertebrate model, zebrafish, and found a similar effect.Therefore, in humans, flies, and zebrafish, Pig-Q is associated with sleep regulation.

Keene says the team’s next step is to investigate the role of a common protein modification, GPI anchor biosynthesis, on sleep regulation. Additionally, he notes that the human-fruit-fly-zebrafish pipeline the team has developed will allow them to functionally assess not only sleep genes, but also other commonly studied traits using human GWAS. , including neurodegeneration, aging and memory.

“Understanding how genes regulate sleep and the role of this pathway in sleep regulation can help unlock future discoveries about sleep and sleep disorders, such as insomnia,” said Gehrman, associate professor of psychology. clinic in psychiatry at Penn and clinical psychologist at the Penn Chronobiology and Sleep Institute.

This shows a drawing of a woman lying awake
Keene says the most exciting thing about the team’s work is that they’ve developed a pipeline starting not with a model organism, but with actual human genomic data. Image is in public domain

“In the future, we will continue to use and study this system to identify more sleep-regulating genes, which could point the way to new treatments for sleep disorders.”

Keene’s research in his laboratory affiliated with the Center for Biological Clocks Research lies at the intersection of evolution and neuroscience, with a primary focus on understanding neural mechanisms and the evolutionary underpinnings of sleep, formation of memory and other behavioral functions in fly and fish models.

Specifically, he is studying fruit flies (Drosophila melanogaster) and Mexican cavefish that have lost both sight and the ability to sleep with the goal of identifying the genetic basis for behavioral choices that influence human disease. , including obesity, diabetes and heart disease.

About this genetics and insomnia research news

Author: Shana K. Hutchins
Source: Texas A&M
Contact: Shana K. Hutchins – Texas A&M
Picture: Image is in public domain

See also

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Original research: Free access.
“Variant-to-gene mapping followed by cross-species genetic screening identifies GPI anchor biosynthesis as a novel regulator of sleep” by Justin Palermo et al. Scientists progress


Summary

Variant-gene mapping followed by cross-species genetic screening identifies GPI anchor biosynthesis as a novel regulator of sleep

Genome-wide association studies (GWAS) in humans have identified loci strongly associated with several diseases or inherited traits, but little is known about the functional roles of the underlying causative variants in the regulation sleep duration or quality.

We applied an ATAC-seq/promoter-driven Capture C strategy in human iPSC-derived neural progenitors to conduct a ‘variant-to-gene’ mapping campaign that identified 88 candidate sleep effector genes connected to relevant GWAS signals.

To functionally validate the role of effector genes involved in sleep regulation, we performed a neuron-specific RNA interference screen in the fruit fly, Drosophila melanogaster, followed by validation in zebrafish. This approach has identified a number of genes that regulate sleep, including an essential role for glycosylphosphatidylinositol (GPI) biosynthesis.

These results provide the first physical variant-gene mapping of human sleep genes, followed by model organism-based prioritization, revealing a conserved role for GPI anchor biosynthesis in sleep regulation.

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