Long-Distance Phasing of a Tentative “Enhancer” Single-Nucleotide Polymorphism With CYP2D6 Star Allele Definitions
Bibliographic record
Abstract
Background: The CYP2D6 gene locus has been extensively studied over decades, yet a portion of variability in CYP2D6 activity cannot be explained by known sequence variations within the gene, copy number variation or structural rearrangements. It was proposed that rs5758550 located 116 kb downstream of the CYP2D6 gene locus increases gene expression and thus contributes to variability in CYP2D6 activity. This finding has, however, not been validated. The purpose of the study was to address a major technological barrier, i.e. experimentally linking rs5758550, also referred to as the ‘enhancer’ SNP, to CYP2D6 haplotypes >100 kb away. To overcome this challenge is essential to ultimately determine the contribution of the ‘enhancer’ SNP to interindividual variability in CYP2D6 activity. Methods: A large ethnically mixed population sample (n=3162) was computationally phased to determine linkage between the ‘enhancer’ SNP and CYP2D6 haplotypes (or star alleles). To experimentally validate predicted linkages, DropPhase2D6, a digital droplet PCR (ddPCR)-based method was developed. 10X Genomics Linked-Reads were utilized as a proof of concept. Results: Phasing predicted that the ‘enhancer’ SNP can occur on numerous CYP2D6 haplotypes including CYP2D6 *1, *2, *5 and *41 and suggested that linkage is incomplete, i.e. a portion of these alleles do not have the ‘enhancer’ SNP. Phasing also revealed differences amongst the European and African ancestry data sets regarding the proportion of alleles with and without the ‘enhancer’ SNP. DropPhase2D6 was utilized to confirm or refute the predicted ‘enhancer’ SNP location for individual samples, e.g. of n=3 samples genotyped as *1/*41, rs5758550 was on the *41 allele of two samples and on *1 allele of one sample. Our findings highlights that the location of the ‘enhancer’ SNP must not be assigned by ‘default’. Furthermore, linkage between the ‘enhancer’ SNP and CYP2D6 star allele haplotypes was confirmed with 10X Genomics technology. We were unable, however, to verify selected haplotypes predicted by Ray et al (PMID 30520769). Conclusions: Since the ‘enhancer’ SNP can be present on a portion of normal, decreased, or no function alleles, the phase of the ‘enhancer’ SNP must be considered when investigating the impact of the ‘enhancer’ SNP on CYP2D6 activity.
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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 | 0.003 | 0.007 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.002 |
| Bibliometrics | 0.001 | 0.002 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.007 | 0.002 |
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".