Summary: Researchers have identified a conserved role for the Pig-Q gene in sleep regulation. Mutations in Pig-Q increase sleep across species, from fruit flies to zebrafish, and the finding links human genomics to model-organism validation.
Source: Texas A&M
Researchers from Texas A&M University, the Perelman School of Medicine at the University of Pennsylvania, and Children’s Hospital of Philadelphia (CHOP) have combined human genomic data and cross-species experiments to reveal a new genetic pathway that regulates sleep. Their work, which traces mechanisms from humans to fruit flies and zebrafish, offers a fresh direction for understanding insomnia and other sleep disorders.
The study was led by Texas A&M geneticist and evolutionary biologist Alex Keene in collaboration with Penn’s Allan Pack and Philip Gehrman, and Struan Grant from CHOP. The research appears in Science Advances and uses a human-first pipeline that maps genetic variants to genes and then tests those candidate genes in animal models.
Large human genome-wide association studies (GWAS) have identified many genetic variants associated with sleep traits, but linking those variants to specific genes and functions has been challenging. To bridge that gap, the team applied a variant-to-gene mapping strategy using ATAC-seq and promoter-focused Capture C in human induced pluripotent stem cell (iPSC)-derived neural progenitors. This approach identified 88 candidate genes potentially affected by sleep-associated human variants.
To validate and prioritize these candidates, the researchers performed a neuron-specific RNA interference screen in Drosophila melanogaster (fruit flies). Hits from the fly screen were then tested in a vertebrate model, zebrafish, to assess conservation of function. This cross-species pipeline allowed the team to move from human genetic signals to experimentally validated regulators of sleep.
Among the validated genes, Pig-Q emerged as a strong regulator of sleep. Pig-Q is required for the biosynthesis of glycosylphosphatidylinositol (GPI) anchors, a common protein modification that tethers certain proteins to the cell membrane and can influence protein function. The researchers found that mutations in Pig-Q increased sleep in fruit flies and produced a similar effect in zebrafish, indicating a conserved role for GPI-anchor biosynthesis in sleep regulation across species.
Alex Keene highlighted the novelty of starting with human genomics rather than a traditional model-organism screen. By predicting effector genes from human GWAS signals and then testing them in animals, the team demonstrated a powerful route for functional genomics: identify human-associated variants, map them to likely target genes, and validate those genes through model organisms. This pipeline accelerates discovery and provides biologically relevant candidates for follow-up in human studies.
Philip Gehrman, an associate professor of clinical psychology in psychiatry at Penn and a clinician with the Penn Chronobiology and Sleep Institute, emphasized the translational value: understanding how Pig-Q and GPI-anchor biosynthesis affect sleep may reveal mechanisms relevant to insomnia and other sleep disorders and point toward potential therapeutic targets.
The team plans to probe the specific role of GPI-anchor biosynthesis in neural circuits that control sleep, and to continue using the human-to-fly-to-fish pipeline to functionally assess other candidate genes from human GWAS. Beyond sleep, the same strategy could be applied to human traits such as neurodegeneration, aging, and memory, improving our understanding of the genetic bases of diverse brain-related phenotypes.
Keene’s laboratory at the Center for Biological Clocks Research focuses on the intersection of evolutionary biology and neuroscience, using fly and fish models to study neural mechanisms underlying sleep, memory formation, and behavior. By studying species such as Drosophila melanogaster and Mexican cavefish—models that vary naturally in sleep and sensory traits—his team seeks genetic insights that have relevance to human health, including conditions associated with sleep disruption like 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
Image: Image in the public domain
Original Research: Open access. “Variant-to-gene-mapping followed by cross-species genetic screening identifies GPI-anchor biosynthesis as novel regulator of sleep” by Justin Palermo et al., Science Advances.
Abstract
Variant-to-gene-mapping followed by cross-species genetic screening identifies GPI-anchor biosynthesis as novel regulator of sleep
Human GWAS have revealed loci associated with sleep duration and quality, but the causal genes and mechanisms remain largely unknown. The authors applied ATAC-seq and promoter-focused Capture C in human iPSC-derived neural progenitors to map GWAS variants to 88 candidate sleep effector genes. A neuron-specific RNA interference screen in Drosophila followed by zebrafish validation identified multiple genes that influence sleep, highlighting a conserved requirement for glycosylphosphatidylinositol (GPI)–anchor biosynthesis. These findings constitute the first physical variant-to-gene mapping for human sleep traits followed by model-organism prioritization, and they reveal GPI-anchor biosynthesis as a conserved regulator of sleep.