Base pairing constraints drive structural epistasis in ribosomal RNA sequences

Area of Science:

• Molecular Biology
• Evolutionary Biology
• Bioinformatics

Background:

• Ribosomal RNA (rRNA) structural constraints are thought to drive coevolutionary changes.
• Current coevolutionary detection methods excel at identifying Watson-Crick (WC) pairs in secondary structures but struggle with tertiary interactions in 3D structures.

Purpose of the Study:

• To investigate why coevolutionary methods fail to detect tertiary interactions in rRNA 3D structures.
• To analyze the differences in coevolution patterns between WC and non-WC base pairs in rRNA.

Main Methods:

• Analysis of 2,682 interacting sites from high-resolution rRNA structures across Archaea and Bacteria.
• Derivation of fitness landscapes from base pairing geometry and construction of neutral networks.
• Estimation of evolutionary constraint and substitution rates for different base pair types.

Main Results:

• A striking difference in coevolution was observed between WC and non-WC pairs.
• WC pairs exhibit fitness valleys, leading to coevolution, while non-WC pairs do not.
• Non-WC pairs show a negative correlation between constraint and substitution rate, with WC pairs being outliers.

Conclusions:

• Coevolutionary signals in rRNA are predominantly detected in 2D secondary structures (WC pairs) rather than 3D tertiary interactions.
• Biochemical knowledge of structural organization, particularly within helical stems, is crucial for understanding molecular variation patterns.
• Current coevolutionary analyses provide limited insight into the 3D structural dynamics of rRNA.