Shifts in amino acid preferences as proteins evolve: A synthesis of experimental and theoretical work
Bibliographic record
Abstract
Amino acid preferences vary across sites and time. While variation across sites is widely accepted, the extent and frequency of temporal shifts are contentious. Our understanding of the drivers of amino acid preference change is incomplete: To what extent are temporal shifts driven by adaptive versus nonadaptive evolutionary processes? We review phenomena that cause preferences to vary (e.g., evolutionary Stokes shift, contingency, and entrenchment) and clarify how they differ. To determine the extent and prevalence of shifted preferences, we review experimental and theoretical studies. Analyses of natural sequence alignments often detect decreases in homoplasy (convergence and reversions) rates, and variation in replacement rates with time-signals that are consistent with temporally changing preferences. While approaches inferring shifts in preferences from patterns in natural alignments are valuable, they are indirect since multiple mechanisms (both adaptive and nonadaptive) could lead to the observed signal. Alternatively, site-directed mutagenesis experiments allow for a more direct assessment of shifted preferences. They corroborate evidence from multiple sequence alignments, revealing that the preference for an amino acid at a site varies depending on the background sequence. However, shifts in preferences are usually minor in magnitude and sites with significantly shifted preferences are low in frequency. The small yet consistent perturbations in preferences could, nevertheless, jeopardize the accuracy of inference procedures, which assume constant preferences. We conclude by discussing if and how such shifts in preferences might influence widely used time-homogenous inference procedures and potential ways to mitigate such effects.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.007 | 0.018 |
| Meta-epidemiology (narrow) | 0.002 | 0.001 |
| Meta-epidemiology (broad) | 0.003 | 0.002 |
| Bibliometrics | 0.005 | 0.005 |
| Science and technology studies | 0.001 | 0.005 |
| Scholarly communication | 0.004 | 0.008 |
| Open science | 0.002 | 0.002 |
| Research integrity | 0.002 | 0.004 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".