3972ba54c468ace338d4a5578de1d20bf6c1f9ec lrnassar Mon Apr 20 15:39:26 2026 -0700 Adding Rule 4 (long-exon rule, Lindeboom 2016) to NMD Escape tracks and releasing on Apr. 22, 2026. refs #33737 Script: added a fourth rule to genePredNmdEsc. Coding exons longer than 400 bp (excluding the last coding exon, which is already covered by the 50 bp rule) are flagged as NMD-escape regions. Rebuilt the Gencode and NCBI RefSeq bigBed files. trackDb: - nmd.ra: appended "/400nt" to the nmdEsc longLabels, set nmdEscGencode default visibility to dense so the track is visible in cart-reset views, changed all four NMDetective subtracks from "visibility full" to "visibility hide", updated pennantIcon to the Apr. 22, 2026 release date and anchor. - nmd.html: mention long internal exons in the overview description, update the rule count from three to four. - nmdEscTranscripts.html: add the long-exon rule to the rule list and color legend (gold, #FFD700), expand the Background section with mechanisms for the intronless, start-proximal, and long-exon rules, correct the 50 bp rule description to include the entire last coding exon, fix Lindeboom 2016 author initials (RG -> RGH). News: - newsarch.html: add the 2026-04-22 NMD Escape news entry covering all four rules, with acknowledgements to Guido Neidhardt and Andreas Lahner for suggesting the track and the Decipher Genome Browser team for inspiring the visualization. - indexNews.html: add the front-page news link. makedoc: - nmd.txt: dated note for the Rule 4 rebuild. diff --git src/hg/makeDb/trackDb/human/hg38/nmdEscTranscripts.html src/hg/makeDb/trackDb/human/hg38/nmdEscTranscripts.html index 9d5a8195442..8398645cc67 100644 --- src/hg/makeDb/trackDb/human/hg38/nmdEscTranscripts.html +++ src/hg/makeDb/trackDb/human/hg38/nmdEscTranscripts.html @@ -1,133 +1,160 @@

Description

The NMD escape ruleset tracks show predicted regions where a premature termination codon (PTC) or frameshift variant is likely to cause the transcript to escape nonsense-mediated decay (NMD), leading to the production of an aberrant truncated protein rather than degradation of the mRNA.

The following rules were applied to transcript annotations to define predicted NMD escape regions (Nagy et al, Trends Biochem Sci 1998 and Lindeboom et al, Nat Genet 2016):

50 bp rule: The region less than 50 bp upstream of the last - exon-exon junction (after splicing). Non-protein-coding 3' exons are not - considered.
50 bp rule: The entire last coding exon plus the last 50 bp of + the penultimate coding exon. A PTC here has no downstream exon-exon + junction (or is too close to the last one) for NMD to be triggered. + Non-protein-coding 3' exons are not counted when identifying the last + coding junction.
Intronless transcripts: Transcripts with a single exon. Since no EJCs are deposited on single-exon transcripts, all PTCs are predicted to escape NMD.
Start-proximal region: The first 100 bp of coding nucleotides. PTCs in this region do not lead to NMD, a phenomenon known as start-proximal NMD insensitivity. One proposed mechanism, supported by experimental evidence, is re-initiation of translation at a downstream AUG codon.
Long exon rule: Coding exons longer than 400 bp (excluding the last + coding exon, which is already covered by the 50 bp rule). Lindeboom et al. + 2016 showed a marked drop in NMD efficiency (61% vs. 98%) for PTCs in exons + longer than 400 nt, likely because the large distance between the stalled + ribosome and the downstream EJC reduces UPF1-EJC contact.

Non-coding transcripts (where CDS start equals CDS end) are excluded. Overlapping regions from multiple transcripts with identical coordinates and the same rule are collapsed into a single item, with the contributing transcript IDs stored as a comma-separated list.

Two versions of this track are available, based on different transcript annotation sets:

NMD escape Gencode: Derived from GENCODE V49 transcript annotations.
NMD escape NCBI RefSeq: Derived from NCBI RefSeq transcript annotations.

Background

NMD escape regions were predicted based on the Exon Junction Complex (EJC)-dependent model of NMD. During normal translation, EJCs are deposited at exon-exon junctions after splicing. As the ribosome translates the mRNA, it displaces each EJC it encounters. When a PTC causes the ribosome to stall prematurely, any remaining downstream EJCs recruit surveillance factors (notably UPF1) that trigger mRNA degradation via NMD.

-However, if the PTC is located within approximately 50 bp upstream of the last -exon-exon junction, the ribosome is close enough to the final EJC that the -interaction does not trigger NMD—the transcript escapes degradation. -Conversely, PTCs located more than 50–55 bp upstream of the last -exon-exon junction are predicted to elicit NMD. +However, PTCs located in the last coding exon or within approximately 50 bp +upstream of the last exon-exon junction are too close to the final EJC (or +have no downstream EJC at all) for NMD to be triggered—the transcript +escapes degradation. Conversely, PTCs located more than 50–55 bp +upstream of the last exon-exon junction are predicted to elicit NMD.

+Additional escape mechanisms, supported by Lindeboom et al. 2016 and other +studies, are captured by three further rules: +

Intronless transcripts deposit no EJCs during splicing, so any + PTC escapes NMD.
Start-proximal PTCs (within the first 100 bp of coding sequence) + escape NMD, likely through translation re-initiation at a downstream AUG + codon.
PTCs in long coding exons (>400 bp) show reduced NMD + efficiency (61% vs. 98% for shorter exons in Lindeboom et al. 2016), + likely because the large distance between the stalled ribosome and the + downstream EJC reduces UPF1-EJC contact.

Display Conventions and Configuration

Regions from overlapping transcripts with the same coordinates are collapsed into a single item. The gene symbol is shown as the item name. Mouseover displays the NMD escape rule and the number of transcripts. The details page lists all contributing transcript IDs.

Items are colored by the NMD escape rule that applies:

Red – Rule 1: Last 50 bp of the last coding exon-exon junction. A PTC here is too close to the last exon junction complex (EJC) for NMD to be triggered.
Orange – Rule 2: Intronless (single-exon) transcript. No EJCs are deposited, so all PTCs escape NMD.
Dark red – Rule 3: First 100 bp of coding nucleotides. PTCs in this start-proximal region are insensitive to NMD, possibly due to translation re-initiation at a downstream AUG codon.
Gold – Rule 4: Coding exons + longer than 400 bp (excluding the last coding exon). NMD efficiency is + reduced in these long exons because the PTC is far from the downstream + exon-exon junction.

Data Access

The data underlying this track can be explored interactively with the Table Browser or the Data Integrator. For automated analysis, the data may be queried from our REST API. Please refer to our mailing list archives for questions, or our Data Access FAQ for more information.

Credits

Thanks to Guido Neidhardt for suggesting this track at HUGO VEPTC 2025 and Andreas Lahner for feedback. Thanks to the Decipher Genome Browser team for introducing the idea of a track.

References

Kurosaki T, Popp MW, Maquat LE. Quality and quantity control of gene expression by nonsense-mediated mRNA decay. Nat Rev Mol Cell Biol. 2019 Jul;20(7):406-420. PMID: 30992545; PMC: PMC6855384

-Lindeboom RG, Supek F, Lehner B. +Lindeboom RGH, Supek F, Lehner B. The rules and impact of nonsense-mediated mRNA decay in human cancers. Nat Genet. 2016 Oct;48(10):1112-8. PMID: 27618451; PMC: PMC5045715

Nagy E, Maquat LE. A rule for termination-codon position within intron-containing genes: when nonsense affects RNA abundance. Trends Biochem Sci. 1998 Jun;23(6):198-9. PMID: 9644970