intersection of ribozyme folds and support for neutrality

    Though recently many authors have argued that molecular neutralism (ie. the position that the vast majority of changes at the molecular level occur due to genetic drift of selectively neutral mutations) is 'on the rocks', this study provides resounding evidence for the continued support for the viewpoint (or, at least, a balanced viewpoint such as the one addressed by Wagner (2008)).

    The authors examine two ribozymes (ribonucleic 'enzymes') with grossly differing sequence (<25% identity--the human hepatitis delta virus self-cleavage ribozyme and a class III self-ligating ribozyme) and folding, and, through a 'mutational walk', succeed in transforming them into one another.

    Furthermore, they show that through most of the 'walk' the enzymatic activity of the mutated molecules do not change dramatically.  This supports the contention that neutral mutations that have little effect on the molecular function of proteins can accumulate during 'neutral' evolutionary activity (through synonymous or nearly neutral alterations in nucleotide sequence, or, in the case of proteins, functional substitutions), allowing single polymorphisms to have drastic effects on structure and function when paired with said neutral alterations.

    Finally, the authors further create 'prototype' molecules of each 'fold'-type that share nearly 100% sequence identity (the shift in folding occurs through the changing of 2 nucleotides), demonstrating that, even with highly similar (near-identical) sequence identity, highly different functions can manifest.  Taken, together these results demonstrate how specific molecules (namely, robust proteins or ribozymes) can undergo a large number of neutral changes while retaining largely stable functionality.  It is only when these nearly-neutral changes are paired with a single (or few) highly structurally significant changes that large evolutionary/functional changes can occur.  This may explain how many multi-step evolutionary changes come about despite several neutral (or even mildly deleterious) intermediate states that would not be intuitively fixed through selection alone.


-Schultes E and Bartel D (2000) One Sequence, Two Ribozymes: Implications for the Emergence of New Ribozyme Folds . Science 289: 448-452.
-Wagner (2008) Neutralism and selectionism: a network-based reconciliation. Nature Reviews: Genetics 9:965-974