Joanna Masel

Molecular errors, cryptic genetic variation, and evolvability

Making genes into gene products is subject to predictable errors, each with a phenotypic effect that depends on a normally cryptic sequence. The distribution of fitness effects of these cryptic sequences, like that of new mutations, is bimodal. For example, a cryptic sequence might be strongly deleterious if it causes protein misfolding, or it might have only a minor effect if it preserves the protein fold and tweaks function. Few sequences have effect sizes that fall in between.

Strongly deleterious sequences can be subject to some selection even while they are cryptic, and expressed only at low levels that depend on a molecular error. Strongly deleterious effects can be avoided globally by avoiding making errors (e.g., via proofreading machinery) or locally by ensuring that each error has a relatively benign effect. The local solution requires powerful selection acting on every cryptic site, and so evolves only in large populations. Small populations with less effective selection evolve global proofreading solutions. However, we also find that for a large range of realistic intermediate population sizes, the evolutionary dynamics are bistable and either solution may result. The local solution, which does not occur in very small populations, facilitates the co-option of cryptic sequences and therefore substantially increases evolvability.  This can occur even in genetically uniform populations.
Purging selection due to translational errors can likely explain how noncoding sequences can be converted to coding during evolution. Examples will be given both for C-terminal protein sequences that evolved from 3'UTRs, and of a new 28 amino acid polypeptide in Saccharomyces cerevisiae. The latter was detected from ribosomal profiling data, which also shows that many “noncoding” transcripts show extensive physical association with ribosomes. This association allows for purging selection to operate on translational errors. Time permitting, I will also discuss evolutionary capacitors, which can switch “on” previously cryptic stocks of variation. Molecular switches that do this, such as the yeast prion [PSI+], can be favored by natural selection. In other words, evolvability can evolve.

Joanna Masel is Associate Professor of Ecology and Evolutionary Biology at the University of Arizona.  For more information, please visit: