Cross-species variant-to-function analyses implicate MEIS1 in conferring sleep abnormalities and impaired cerebellar...

Area of Science:

• Genetics
• Neuroscience
• Sleep Research

Background:

• Genome-wide association studies (GWAS) have identified genetic loci associated with insomnia.
• Functional validation of these loci is challenging due to variants in noncoding regions and unknown causal genes.

Purpose of the Study:

• To functionally validate potential insomnia effector genes using a zebrafish model.
• To identify the specific gene regulating sleep maintenance within a conserved human insomnia-associated locus.

Main Methods:

• Nomination of six insomnia effector genes based on human cell-based variant-to-gene mapping.
• CRISPR-based screening in zebrafish to assess gene function in sleep.
• Comparative chromatin analysis to investigate conserved regulatory architecture.
• Developmental profiling of gene expression in zebrafish.

Main Results:

• The zebrafish meis1b gene, an ortholog of human MEIS1, was identified as a regulator of sleep maintenance.
• meis1b disruption in zebrafish led to impaired nighttime sleep maintenance and increased sleep latency.
• Conserved regulatory elements implicate meis1b, while its ohnolog meis1a was not essential.
• meis1b is expressed in cerebellar granule progenitors, and its disruption affects cerebellar development.

Conclusions:

• Zebrafish serve as an effective vertebrate model for functional genomics of GWAS candidates.
• MEIS1 plays a conserved role in sleep maintenance, potentially through cerebellar pathways.
• This study provides functional evidence linking MEIS1 to insomnia.