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 @@ -1,96 +1,123 @@ <h2>Description</h2> <p> The <b>NMD escape ruleset</b> tracks show predicted regions where a premature termination codon (PTC) or frameshift variant is likely to cause the transcript to <em>escape</em> nonsense-mediated decay (NMD), leading to the production of an aberrant truncated protein rather than degradation of the mRNA. </p> <p> 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): </p> <ol> - <li><b>50 bp rule</b>: The region less than 50 bp upstream of the last - exon-exon junction (after splicing). Non-protein-coding 3' exons are not - considered.</li> + <li><b>50 bp rule</b>: 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.</li> <li><b>Intronless transcripts</b>: Transcripts with a single exon. Since no EJCs are deposited on single-exon transcripts, all PTCs are predicted to escape NMD.</li> <li><b>Start-proximal region</b>: 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.</li> + <li><b>Long exon rule</b>: 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.</li> </ol> <p> 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. </p> <p> Two versions of this track are available, based on different transcript annotation sets: </p> <ul> <li><b><a href="hgTrackUi?g=nmdEscGencode">NMD escape Gencode</a></b>: Derived from GENCODE V49 transcript annotations.</li> <li><b><a href="hgTrackUi?g=nmdEscNcbiRefSeq">NMD escape NCBI RefSeq</a></b>: Derived from NCBI RefSeq transcript annotations.</li> </ul> <h2>Background</h2> <p> 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. </p> <p> -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. </p> +<p> +Additional escape mechanisms, supported by Lindeboom et al. 2016 and other +studies, are captured by three further rules: +</p> +<ul> + <li><b>Intronless transcripts</b> deposit no EJCs during splicing, so any + PTC escapes NMD.</li> + <li><b>Start-proximal PTCs</b> (within the first 100 bp of coding sequence) + escape NMD, likely through translation re-initiation at a downstream AUG + codon.</li> + <li><b>PTCs in long coding exons</b> (>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.</li> +</ul> + <h2>Display Conventions and Configuration</h2> <p> 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. </p> <p> Items are colored by the NMD escape rule that applies: </p> <ul> <li><font color="#FF0000"><b>Red</b></font> – 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.</li> <li><font color="#FF8C00"><b>Orange</b></font> – Rule 2: Intronless (single-exon) transcript. No EJCs are deposited, so all PTCs escape NMD.</li> <li><font color="#8B0000"><b>Dark red</b></font> – 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.</li> + <li><font color="#FFD700"><b>Gold</b></font> – 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.</li> </ul> <h2>Data Access</h2> <p> The data underlying this track can be explored interactively with the <a href="../cgi-bin/hgTables">Table Browser</a> or the <a href="../cgi-bin/hgIntegrator">Data Integrator</a>. For automated analysis, the data may be queried from our <a href="/goldenPath/help/api.html">REST API</a>. Please refer to our <a href="https://groups.google.com/a/soe.ucsc.edu/forum/#!forum/genome">mailing list archives</a> for questions, or our <a href="../FAQ/FAQdownloads.html#download36">Data Access FAQ</a> for more information. </p> @@ -101,31 +128,31 @@ track. </p> <h2>References</h2> <p> Kurosaki T, Popp MW, Maquat LE. <a href="https://doi.org/10.1038/s41580-019-0126-2" target="_blank"> Quality and quantity control of gene expression by nonsense-mediated mRNA decay</a>. <em>Nat Rev Mol Cell Biol</em>. 2019 Jul;20(7):406-420. PMID: <a href="https://www.ncbi.nlm.nih.gov/pubmed/30992545" target="_blank">30992545</a>; PMC: <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6855384/" target="_blank">PMC6855384</a> </p> <p> -Lindeboom RG, Supek F, Lehner B. +Lindeboom RGH, Supek F, Lehner B. <a href="https://doi.org/10.1038/ng.3664" target="_blank"> The rules and impact of nonsense-mediated mRNA decay in human cancers</a>. <em>Nat Genet</em>. 2016 Oct;48(10):1112-8. PMID: <a href="https://www.ncbi.nlm.nih.gov/pubmed/27618451" target="_blank">27618451</a>; PMC: <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5045715/" target="_blank">PMC5045715</a> </p> <p> Nagy E, Maquat LE. <a href="https://linkinghub.elsevier.com/retrieve/pii/S0968-0004(98)01208-0" target="_blank"> A rule for termination-codon position within intron-containing genes: when nonsense affects RNA abundance</a>. <em>Trends Biochem Sci</em>. 1998 Jun;23(6):198-9. PMID: <a href="https://www.ncbi.nlm.nih.gov/pubmed/9644970" target="_blank">9644970</a> </p>