Widespread Historical Contingency in Influenza Viruses
Bibliographic record
Abstract
In systems biology and genomics, epistasis characterizes the impact that a substitution at a particular location in a genome can have on a substitution at another location. This phenomenon is often implicated in the evolution of drug resistance or to explain why particular "disease-causing" mutations do not have the same outcome in all individuals. Hence, uncovering these mutations and their locations in a genome is a central question in biology. However, epistasis is notoriously difficult to uncover, especially in fast-evolving organisms. Here, we present a novel statistical approach that replies on a model developed in ecology and that we adapt to analyze genetic data in fast-evolving systems such as the influenza A virus. We validate the approach using a two-pronged strategy: extensive simulations demonstrate a low-to-moderate sensitivity with excellent specificity and precision, while analyses of experimentally validated data recover known interactions, including in a eukaryotic system. We further evaluate the ability of our approach to detect correlated evolution during antigenic shifts or at the emergence of drug resistance. We show that in all cases, correlated evolution is prevalent in influenza A viruses, involving many pairs of sites linked together in chains; a hallmark of historical contingency. Strikingly, interacting sites are separated by large physical distances, which entails either long-range conformational changes or functional tradeoffs, for which we find support with the emergence of drug resistance. Our work paves a new way for the unbiased detection of epistasis in a wide range of organisms by performing whole-genome scans.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
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 teacher head, 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".