Fitness effects of mutations: An assessment of PROVEAN predictions using mutation accumulation data

Predicting fitness in natural populations is a major challenge in biology. It may be possible to leverage fast-accumulating genomic datasets to infer the fitness effects of mutant alleles, allowing evolutionary questions to be addressed in any organism. In this paper, we investigate the utility of one such tool, called PROVEAN. This program compares a query sequence with existing data to provide an alignment-based score for any protein variant, with scores categorized as neutral or deleterious based on a preset threshold. PROVEAN has been used widely in evolutionary studies, e.g., to estimate mutation load in natural populations, but has not been formally tested as a predictor of aggregate mutational effects on fitness. Using three large, published datasets on the genome sequences of laboratory mutation accumulation lines, we assessed how well PROVEAN predicted the actual fitness patterns observed, relative to other metrics. In most cases, we find that a simple count of the total number...