Organism-Specific Sequence Motifs Link Ribosomal RNAs to Brain Disorders.

Researchers found special genetic patterns in human cells that connect the protein-making machinery (ribosomes) to brain genes. These patterns are strongly linked to genes involved in autism and other brain conditions. In brain tissue from people with autism, these patterns were found mainly in genes that weren't working properly in areas of the brain that control language, hearing, and sight. This discovery could help develop better ways to diagnose and treat autism.

This evolutionary genomics study identified 1,723 organism-specific sequence motifs in human ribosomal RNAs that are predominantly shared with 3,430 nervous system genes, including 1,046 genes associated with brain disorders such as autism spectrum disorder and schizophrenia. These motifs, unique to primates, appear to function as regulatory contact points for RNA interactions and are found in RNA-binding protein sites. Analysis of brain tissue from autism patients revealed that specific motif combinations are enriched only among downregulated genes in cortical areas responsible for language, hearing, and vision. The study suggests these motifs represent an extensive regulatory layer linking ribosomal function to nervous system gene expression, potentially offering new avenues for molecular diagnostics and treatments.

Findings suggest a novel regulatory mechanism linking ribosomal function to nervous system gene expression that could inform new diagnostic approaches and therapeutic targets for autism and other neurodevelopmental disorders, particularly those affecting language, hearing, and visual processing.

Sample size not reported. Study type unclear. Limited to bulk brain tissue analysis rather than single-cell resolution. Expression data analysis appears restricted to autism patients versus controls without broader validation across other neurodevelopmental conditions.

We report that in humans, mice, fruit flies, and worms, the ribosomal RNAs and the transcribed spacers of 45S are densely packed with organism-specific sequence motifs that are primarily shared with nervous system genes. The human ribosomal RNAs and 45S spacers contain 1,723 such motifs. Specific combinations of these motifs are predominantly found in 3,430 human nervous system genes, of which 1,046 are genes associated with brain disorders, including autism spectrum disorder and schizophrenia. The sequences of the 1,723 motifs and their locations in the introns and exons of nervous system genes are unique to primates.

Experimental evidence indicates that the motifs are contact points for ribosomal-RNA|messenger-RNA and messenger-RNA|messenger-RNA heteroduplexes, present in the binding sites of many RNA-binding proteins, and carried by endogenous small noncoding RNAs. Moreover, several of the motifs' intergenic copies overlap genome-wide association-study-determined polymorphisms associated with brain disorders and other conditions. Lastly, based on expression data from bulk brain samples from autism spectrum disorder patients and controls, specific combinations of these motifs are enriched only among genes that are downregulated in the patients and only in the cortical areas that are responsible for language, hearing, and vision. This study shows that genomic architecture, the sequences of ribosomal RNAs/spacers, and the sequences of nervous system genes have remained interlocked across 600 million years of evolution through organism-specific motifs.

The findings suggest an extensive regulatory layer and can aid in developing new molecular diagnostics and treatments for disorders considered typically human.