Characterizing Amino Acid Substitution with Complete Linkage of Sites on a Lineage.

Amino acid substitution models are commonly used for phylogenetic inference, for ancestral sequence reconstruction, and for the inference of positive selection. All commonly used models explicitly assume that each site evolves independently, an assumption that is violated by both linkage and protein structural and functional constraints. We introduce two new models for amino acid substitution which incorporate linkage between sites, each based on the (population-genetic) Moran model. The first model is a generalized population process tracking arbitrarily many sites which undergo mutation, with individuals replaced according to their fitnesses. This model provides a reasonably complete framework for simulations but is numerically and analytically intractable. We also introduce a second model which includes several simplifying assumptions but for which some theoretical results can be derived. We analyze the simplified model to determine conditions where linkage is likely to have meaningful effects on sitewise substitution probabilities, as well as conditions under which the effects are likely to be negligible. These findings are an important step in the generation of tractable phylogenetic models that parameterize selective coefficients for amino acid substitution while accounting for linkage of sites leading to both hitchhiking and background selection.