Hidden Patterns Link Ribosomal RNAs to Genes of the Nervous System

Uncovering shared patterns between ribosomal RNAs and genes implicated in autism, bipolar disorder, ADHD, and schizophrenia.

Ribosomal RNA (rRNA) is a type of molecule and a key building block of the ribosome, the cell’s protein-making machinery. rRNA accounts for much of the RNA in a cell, and it’s crucial for life.

“It’s essentially one of the most important molecules that we have,” says Thomas Jefferson University researcher Isidore Rigoutsos, PhD, the Richard W. Hevner Professor in Computational Medicine. “But for nearly seven decades, we thought rRNA was only relevant to the ribosome.”

Now, a new study from Dr. Rigoutsos’ lab shows that the rRNA sequences of several organisms contain special patterns that are unique to each organism and shared primarily with genes of the nervous system. In humans, these patterns are found in genes with known links to brain conditions, including autism, attention deficit hyperactivity disorder (ADHD), bipolar disorder, and schizophrenia.

Genetic sequences, whether DNA or RNA, are made up of building blocks called nucleotides. Some RNAs will be used as templates to build proteins, whereas others will not. Because the composition of these genetic sequences determines how a cell functions, researchers have long sought patterns in them to uncover clues. Dr. Rigoutsos compares identifying these patterns to determining the words of an unknown language.

“If you consider each rRNA sequence to be a ‘sentence’ then nucleotides are the letters comprising that sentence,” says Dr. Rigoutsos. “If you can find a ‘motif,’ i.e., a combination of nucleotides that repeats frequently, it’s reasonable to assume that you have found a word, but you do not yet know the word’s meaning and its purpose in a sentence.”

Dr. Rigoutsos and his team analyzed the sequence of a newly released complete human genome and discovered ‘motifs’ in rRNA sequences that were most often repeated in genes of the nervous system. The genes that contained these motifs included considerably more risk genes for autism, ADHD, schizophrenia, and bipolar disorder than one would expect by chance. Moreover, several copies of these motifs across the human genome overlapped with risk variants for brain disorders that had been previously identified through genome-wide association studies.

“We were excited to have uncovered those logical linkages. But we wondered if what we were observing was confined to the human genome,” says Dr. Rigoutsos. So, the researchers performed the same analyses in the genomes of mice, fruit flies, and worms. The team found analogous motifs in the rRNAs of these organisms. While the actual motif sequences differed between the organisms, the motifs were repeated most often in each of the organism’s nervous system genes, just like in humans.

“rRNAs are carefully designed, optimized sequences, and all of a sudden we find pieces of them in places that we didn't expect,” Dr. Rigoutsos said. “It is remarkable to see the same setup repeat in different genomes across hundreds of millions of years of evolution.”

It’s not yet known how these rRNA sequences could influence these disorders. However, Dr. Rigoutsos says the results suggest the importance of casting a wider net. “In autism, for example, most of the work has focused on studying the function of risk genes that encode proteins,” he says. “Our analysis suggests that another source of disruption may be in the manner these genes are regulated by non-protein encoding genetic material like rRNA.” 

Furthermore, because the motifs are organism-specific, aspects of this regulation could be unique to humans, and, therefore, our understanding through animal models may be limited. “We hope our findings will offer a new vantage point from which to study the molecular processes that underlie these brain disorders.”

The results could also explain why schizophrenia, bipolar disorder, ADHD, and autism are often comorbid — they may be linked by the axis uncovered by this research that connects genomic architecture, rRNAs, and many risk genes for these conditions.

The work was supported by Thomas Jefferson University.