Triallelic population genomics for inferring correlated fitness effects of same site nonsynonymous mutations

Aaron P. Ragsdale, Alec J. Coffman, Pinghsun Hsieh, Travis J. Struck, Ryan N. Gutenkunst

Research output: Contribution to journalArticlepeer-review

9 Scopus citations


The distribution of mutational effects on fitness is central to evolutionary genetics. Typical univariate distributions, however, cannot model the effects of multiple mutations at the same site, so we introduce a model in which mutations at the same site have correlated fitness effects. To infer the strength of that correlation, we developed a diffusion approximation to the triallelic frequency spectrum, which we applied to data from Drosophila melanogaster. We found a moderate positive correlation between the fitness effects of nonsynonymous mutations at the same codon, suggesting that both mutation identity and location are important for determining fitness effects in proteins. We validated our approach by comparing it to biochemical mutational scanning experiments, finding strong quantitative agreement, even between different organisms. We also found that the correlation of mutational fitness effects was not affected by protein solvent exposure or structural disorder. Together, our results suggest that the correlation of fitness effects at the same site is a previously overlooked yet fundamental property of protein evolution.

Original languageEnglish (US)
Pages (from-to)513-523
Number of pages11
Issue number1
StatePublished - May 2016


  • Diffusion approximation
  • Distribution of fitness effects
  • Drosophila melanogaster
  • Nonsynonymous mutations
  • Triallelic sites

ASJC Scopus subject areas

  • Genetics


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