Robustness of Ancestral Sequence Reconstruction to Among-site and Among-lineage Evolutionary Heterogeneity.

ABSTRACT: Ancestral sequence reconstruction is typically performed using homogeneous evolutionary models, which assume that the same substitution propensities affect all sites and lineages. These assumptions are routinely violated: heterogeneous structural and functional constraints favor different amino acids at different sites, and these constraints often change among lineages as epistatic substitutions accrue at other sites. To evaluate how violations of the homogeneity assumption affect ancestral sequence reconstruction under realistic conditions, we developed site-specific substitution models and parameterized them using data from deep mutational scanning experiments on three protein families; we then used these models to perform ancestral sequence reconstruction on the empirical alignments and

SUBMITTER: Muniz-Trejo R 

PROVIDER: S-EPMC12046983 | biostudies-literature | 2025 Apr

REPOSITORIES: biostudies-literature