Sewall Wright's genotypic fitness landscape makes explicit one mechanism by which epistasis for fitness can constrain evolution by natural selection. Wright distinguished between landscapes possessing multiple fitness peaks and those with only a single peak and emphasized that the former class imposes substantially greater constraint on natural selection. Here I present novel formalism that mor...

Bonhoeffer et al. (Reports, 26 November 2004, p. 1547) presented evidence for positive epistasis in a clinical data set of HIV-1 mutants and corresponding fitness values. We demonstrate that biases in the original and simulated data sets may lead to erroneous evidence for epistasis. More rigorous statistical tests must be used to account for such biases before one can infer epistasis.

Whether evolution is erratic due to random historical details, or is repeatedly directed along similar paths by certain constraints, remains unclear. Epistasis (i.e. non-additive interaction between mutations that affect fitness) is a mechanism that can contribute to both scenarios. Epistasis can constrain the type and order of selected mutations, but it can also make adaptive trajectories cont...

The extent and strength of epistasis is commonly unresolved in genetic studies, and observed epistasis is often difficult to interpret in terms of biological consequences or overall genetic architecture. We investigated the prevalence and consequences of epistasis by analyzing four body composition phenotypes--body weight, body fat percentage, femoral density, and femoral circumference--in a la...

Genotype-phenotype relationships are notoriously complicated. Idiosyncratic interactions between specific combinations of mutations occur, and are difficult to predict. Yet it is increasingly clear that many interactions can be understood in terms of global epistasis. That is, mutations may act additively on some underlying, unobserved trait, and this trait is then transformed via a nonlinear f...