Bibliographic record
Abstract
Genetic differences between species and within populations are two sides of the same coin under the neutral theory of molecular evolution. This theory posits that a vast majority of evolutionary substitutions, which appear as differences between species, are (nearly) neutral, that is, these substitutions are permitted without a significantly adverse impact on a species' survival. We refer to them as evolutionarily permissible (ePerm) variation. Evolutionary permissibility of any possible variant can be inferred from multispecies sequence alignments by applying sophisticated statistical methods to the evolutionary tree of species. Here, we explore the evolutionary permissibility of amino acid variants associated with genetic diseases and those observed in personal exomes. Consistent with the predictions of the neutral theory, disease associated amino acid variants are rarely ePerm, much more biochemically radical, and found predominantly at more conserved positions than their non-disease counterparts. Only 10% of amino acid mutations are ePerm, but these variants rise to become two-thirds of all substitutions in the human lineage (a 6-fold enrichment). In contrast, only a minority of the variants in a personal exome are ePerm, a seemingly counterintuitive pattern that results from a combination of mutational and evolutionary processes that are, in fact, broadly consistent with the neutral theory. Evolutionarily forbidden variants outnumber detrimental variants in individual exomes and may play an underappreciated role in protecting against disease. We discuss these observations and conclude that the long-term evolutionary history of species can illuminate functional biomedical properties of variation present in personal exomes.
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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 | 0.002 | 0.007 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.002 | 0.001 |
| Science and technology studies | 0.001 | 0.004 |
| Scholarly communication | 0.002 | 0.004 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.002 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 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 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".