Interconverting conformations of slipped‐DNA junctions formed by trinucleotide repeats affect repair outcome
Bibliographic record
Abstract
Slipped‐strand DNAs, formed by out‐of‐register mispairing of repeat units on complementary strands, are transient intermediates in repeat length mutations causing at least 30 neurodegenerative diseases. Expansions of (CTG)•(CAG) repeated DNAs are the mutagenic cause of 14 neurological diseases, likely arising through the formation and processing of slipped‐strand DNAs. The three‐way slipped‐DNA junction, at which the excess repeats slip‐out from the duplex, is a poorly understood feature common to these mutagenic intermediates. Here, we reveal that slipped‐junctions can assume a surprising number of interconverting conformations where the strand opposite the slip‐out is either fully base‐paired, or has one‐ or two‐unpaired nucleotides. These unpaired nucleotides can also arise opposite either of the non‐slipped junction arms. Junction conformation can alter correct nick‐directed repair levels. Junctions that have the potential to contain unpaired nucleotides are repaired with a significantly higher efficiency than constrained fully‐paired junctions. Surprisingly, certain junction conformations are aberrantly repaired to expansion mutations: mis‐direction of repair to the non‐nicked strand opposite the slip‐out leads to integration of the excess slipped‐out repeats rather than their excision. Thus, slipped‐junction structure can determine whether repair attempts lead to correction or expansion mutations. Funding: Canadian Institutes of Health Research (CIHR MOP97896) (C.E.P.); National Institutes of Health ( GM080454 ) (O.S.); the Chemistry section of the Dutch Science Organization (S.S.W.)
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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 | 0.000 | 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 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".