Signatures of Co-evolution and Co-regulation in the CYP3A and CYP4F Genes in Humans
Bibliographic record
Abstract
Cytochromes P450 (CYP450) are hemoproteins generally involved in the detoxification of the body of xenobiotic molecules. They participate in the metabolism of many drugs and genetic polymorphisms in humans have been found to impact drug responses and metabolic functions. In this study, we investigate the genetic diversity of CYP450 genes. We found that two clusters, CYP3A and CYP4F, are notably differentiated across human populations with evidence for selective pressures acting on both clusters: we found signals of recent positive selection in CYP3A and CYP4F genes and signals of balancing selection in CYP4F genes. Furthermore, an extensive amount of unusual linkage disequilibrium is detected in this latter cluster, indicating co-evolution signatures among CYP4F genes. Several of the selective signals uncovered co-localize with expression quantitative trait loci (eQTL), which could suggest epistasis acting on co-regulation in these gene families. In particular, we detected a potential co-regulation event between CYP3A5 and CYP3A43, a gene whose function remains poorly characterized. We further identified a causal relationship between CYP3A5 expression and reticulocyte count through Mendelian randomization analyses, potentially involving a regulatory region displaying a selective signal specific to African populations. Our findings linking natural selection and gene expression in CYP3A and CYP4F subfamilies are of importance in understanding population differences in metabolism of nutrients and drugs.
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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 | 0.001 | 0.000 |
| 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".