Aenmd: Annotating Escape from Nonsense-mediated Decay for Transcripts with Protein-truncating Variants

Overview

Journal bioRxiv

Date 2023 Mar 30

PMID 36993377

Authors

Jonathan Klonowski

Qianqian Liang

Zeynep Coban-Akdemir

Cecilia Lo

Dennis Kostka

Affiliations

Soon will be listed here.

Abstract

DNA changes that cause premature termination codons (PTCs) represent a large fraction of clinically relevant pathogenic genomic variation. Typically, PTCs induce a transcript's degradation by nonsense-mediated mRNA decay (NMD) and render such changes loss-of-function alleles. However, certain PTC-containing transcripts escape NMD and can exert dominant-negative or gain-of-function (DN/GOF) effects. Therefore, systematic identification of human PTC-causing variants and their susceptibility to NMD contributes to the investigation of the role of DN/GOF alleles in human disease. Here we present aenmd, a software for annotating PTC-containing transcript-variant pairs for predicted escape from NMD. aenmd is user-friendly and self-contained. It offers functionality not currently available in other methods and is based on established and experimentally validated rules for NMD escape; the software is designed to work at scale, and to integrate seamlessly with existing analysis workflows. We applied aenmd to variants in the gnomAD, Clinvar, and GWAS catalog databases and report the prevalence of human PTC-causing variants in these databases, and the subset of these that could exert DN/GOF effects via NMD escape. Availability and implementation: aenmd is implemented in the R programming language. Code is available on GitHub as an R package (github.com/kostkalab/aenmd.git), and as a containerized command-line interface (github.com/kostkalab/aenmd_cli.git).

References

Gehring N, Neu-Yilik G, Schell T, Hentze M, Kulozik A . Y14 and hUpf3b form an NMD-activating complex. Mol Cell. 2003; 11(4):939-49. DOI: 10.1016/s1097-2765(03)00142-4. View

Inoue K, Ohyama T, Sakuragi Y, Yamamoto R, Inoue N, Yu L . Translation of SOX10 3' untranslated region causes a complex severe neurocristopathy by generation of a deleterious functional domain. Hum Mol Genet. 2007; 16(24):3037-46. DOI: 10.1093/hmg/ddm262. View

Hunt S, Moore B, Amode R, Armean I, Lemos D, Mushtaq A . Annotating and prioritizing genomic variants using the Ensembl Variant Effect Predictor-A tutorial. Hum Mutat. 2021; 43(8):986-997. PMC: 7613081. DOI: 10.1002/humu.24298. View

Frischmeyer P, Dietz H . Nonsense-mediated mRNA decay in health and disease. Hum Mol Genet. 1999; 8(10):1893-900. DOI: 10.1093/hmg/8.10.1893. View

Lykke-Andersen S, Jensen T . Nonsense-mediated mRNA decay: an intricate machinery that shapes transcriptomes. Nat Rev Mol Cell Biol. 2015; 16(11):665-77. DOI: 10.1038/nrm4063. View

Nogueira G, Fernandes R, Garcia-Moreno J, Romao L . Nonsense-mediated RNA decay and its bipolar function in cancer. Mol Cancer. 2021; 20(1):72. PMC: 8082775. DOI: 10.1186/s12943-021-01364-0. View

Bayram Y, White J, Elcioglu N, Cho M, Zadeh N, Gedikbasi A . REST Final-Exon-Truncating Mutations Cause Hereditary Gingival Fibromatosis. Am J Hum Genet. 2017; 101(1):149-156. PMC: 5501868. DOI: 10.1016/j.ajhg.2017.06.006. View

Inacio A, Silva A, Morgado A, Pereira F, Lavinha J, Romao L . Comment on 'Nonsense-mediated mRNA decay modulates clinical outcome of genetic disease'. Eur J Hum Genet. 2007; 15(5):533-4. DOI: 10.1038/sj.ejhg.5201808. View

Silva A, Pereira F, Morgado A, Kong J, Martins R, Faustino P . The canonical UPF1-dependent nonsense-mediated mRNA decay is inhibited in transcripts carrying a short open reading frame independent of sequence context. RNA. 2006; 12(12):2160-70. PMC: 1664719. DOI: 10.1261/rna.201406. View

10.

Lawrence M, Huber W, Pages H, Aboyoun P, Carlson M, Gentleman R . Software for computing and annotating genomic ranges. PLoS Comput Biol. 2013; 9(8):e1003118. PMC: 3738458. DOI: 10.1371/journal.pcbi.1003118. View

11.

Lindeboom R, Supek F, Lehner B . The rules and impact of nonsense-mediated mRNA decay in human cancers. Nat Genet. 2016; 48(10):1112-8. PMC: 5045715. DOI: 10.1038/ng.3664. View

12.

Nagy E, Maquat L . A rule for termination-codon position within intron-containing genes: when nonsense affects RNA abundance. Trends Biochem Sci. 1998; 23(6):198-9. DOI: 10.1016/s0968-0004(98)01208-0. View

13.

Khajavi M, Inoue K, Lupski J . Nonsense-mediated mRNA decay modulates clinical outcome of genetic disease. Eur J Hum Genet. 2006; 14(10):1074-81. DOI: 10.1038/sj.ejhg.5201649. View

14.

Lindeboom R, Vermeulen M, Lehner B, Supek F . The impact of nonsense-mediated mRNA decay on genetic disease, gene editing and cancer immunotherapy. Nat Genet. 2019; 51(11):1645-1651. PMC: 6858879. DOI: 10.1038/s41588-019-0517-5. View

15.

Schweingruber C, Rufener S, Zund D, Yamashita A, Muhlemann O . Nonsense-mediated mRNA decay - mechanisms of substrate mRNA recognition and degradation in mammalian cells. Biochim Biophys Acta. 2013; 1829(6-7):612-23. DOI: 10.1016/j.bbagrm.2013.02.005. View

16.

Karczewski K, Francioli L, Tiao G, Cummings B, Alfoldi J, Wang Q . The mutational constraint spectrum quantified from variation in 141,456 humans. Nature. 2020; 581(7809):434-443. PMC: 7334197. DOI: 10.1038/s41586-020-2308-7. View

17.

Mort M, Ivanov D, Cooper D, Chuzhanova N . A meta-analysis of nonsense mutations causing human genetic disease. Hum Mutat. 2008; 29(8):1037-47. DOI: 10.1002/humu.20763. View

18.

Miyake N, Takahashi H, Nakamura K, Isidor B, Hiraki Y, Koshimizu E . Gain-of-Function MN1 Truncation Variants Cause a Recognizable Syndrome with Craniofacial and Brain Abnormalities. Am J Hum Genet. 2019; 106(1):13-25. PMC: 7042485. DOI: 10.1016/j.ajhg.2019.11.011. View

19.

Miller J, Pearce D . Nonsense-mediated decay in genetic disease: friend or foe?. Mutat Res Rev Mutat Res. 2014; 762:52-64. PMC: 4260155. DOI: 10.1016/j.mrrev.2014.05.001. View

20.

Inoue K, Khajavi M, Ohyama T, Hirabayashi S, Wilson J, Reggin J . Molecular mechanism for distinct neurological phenotypes conveyed by allelic truncating mutations. Nat Genet. 2004; 36(4):361-9. DOI: 10.1038/ng1322. View