Systematic identification of functional SNPs interrupting 3’UTR polyadenylation signals
Autoři:
Eldad David Shulman aff001; Ran Elkon aff001
Působiště autorů:
Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
aff001
Vyšlo v časopise:
Systematic identification of functional SNPs interrupting 3’UTR polyadenylation signals. PLoS Genet 16(8): e32767. doi:10.1371/journal.pgen.1008977
Kategorie:
Research Article
doi:
https://doi.org/10.1371/journal.pgen.1008977
Souhrn
Alternative polyadenylation (APA) is emerging as a widespread regulatory layer since the majority of human protein-coding genes contain several polyadenylation (p(A)) sites in their 3’UTRs. By generating isoforms with different 3’UTR length, APA potentially affects mRNA stability, translation efficiency, nuclear export, and cellular localization. Polyadenylation sites are regulated by adjacent RNA cis-regulatory elements, the principals among them are the polyadenylation signal (PAS) AAUAAA and its main variant AUUAAA, typically located ~20-nt upstream of the p(A) site. Mutations in PAS and other auxiliary poly(A) cis-elements in the 3’UTR of several genes have been shown to cause human Mendelian diseases, and to date, only a few common SNPs that regulate APA were associated with complex diseases. Here, we systematically searched for SNPs that affect gene expression and human traits by modulation of 3’UTR APA. First, focusing on the variants most likely to exert the strongest effect, we identified 2,305 SNPs that interrupt the canonical PAS or its main variant. Implementing pA-QTL tests using GTEx RNA-seq data, we identified 330 PAS SNPs (called PAS pA-QTLs) that were significantly associated with the usage of their p(A) site. As expected, PAS-interrupting alleles were mostly linked with decreased cleavage at their p(A) site and the consequential 3’UTR lengthening. However, interestingly, in ~10% of the cases, the PAS-interrupting allele was associated with increased usage of an upstream p(A) site and 3’UTR shortening. As an indication of the functional effects of these PAS pA-QTLs on gene expression and complex human traits, we observed for few dozens of them marked colocalization with eQTL and/or GWAS signals. The PAS-interrupting alleles linked with 3’UTR lengthening were also strongly associated with decreased gene expression, indicating that shorter isoforms generated by APA are generally more stable than longer ones. Last, we carried out an extended, genome-wide analysis of 3’UTR variants and detected thousands of additional pA-QTLs having weaker effects compared to the PAS pA-QTLs.
Klíčová slova:
Alleles – Gene expression – Gene regulation – Genome-wide association studies – Genomic signal processing – Messenger RNA – Polyadenylation – Single nucleotide polymorphisms
Zdroje
1. Tian B, Manley JL: Alternative polyadenylation of mRNA precursors. Nat Rev Mol Cell Biol 2017, 18:18–30. doi: 10.1038/nrm.2016.116 27677860
2. Tian B, Hu J, Zhang H, Lutz CS: A large-scale analysis of mRNA polyadenylation of human and mouse genes. Nucleic Acids Res 2005, 33:201–212. doi: 10.1093/nar/gki158 15647503
3. Cheng Y, Miura RM, Tian B: Prediction of mRNA polyadenylation sites by support vector machine. Bioinformatics 2006, 22:2320–2325. doi: 10.1093/bioinformatics/btl394 16870936
4. Derti A, Garrett-Engele P, Macisaac KD, Stevens RC, Sriram S, Chen R, Rohl CA, Johnson JM, Babak T: A quantitative atlas of polyadenylation in five mammals. Genome Res 2012, 22:1173–1183. doi: 10.1101/gr.132563.111 22454233
5. Hoque M, Ji Z, Zheng D, Luo W, Li W, You B, Park JY, Yehia G, Tian B: Analysis of alternative cleavage and polyadenylation by 3’ region extraction and deep sequencing. Nat Methods 2013, 10:133–139. doi: 10.1038/nmeth.2288 23241633
6. Gruber AJ, Zavolan M: Alternative cleavage and polyadenylation in health and disease. Nat Rev Genet 2019, 20:599–614. doi: 10.1038/s41576-019-0145-z 31267064
7. Elkon R, Ugalde AP, Agami R: Alternative cleavage and polyadenylation: extent, regulation and function. Nat Rev Genet 2013, 14:496–506. doi: 10.1038/nrg3482 23774734
8. Fabian MR, Sonenberg N, Filipowicz W: Regulation of mRNA translation and stability by microRNAs. Annu Rev Biochem 2010, 79:351–379. doi: 10.1146/annurev-biochem-060308-103103 20533884
9. Andreassi C, Riccio A: To localize or not to localize: mRNA fate is in 3’UTR ends. Trends Cell Biol 2009, 19:465–474. doi: 10.1016/j.tcb.2009.06.001 19716303
10. Ji Z, Lee JY, Pan Z, Jiang B, Tian B: Progressive lengthening of 3’ untranslated regions of mRNAs by alternative polyadenylation during mouse embryonic development. Proc Natl Acad Sci U S A 2009, 106:7028–7033. doi: 10.1073/pnas.0900028106 19372383
11. Ji Z, Tian B: Reprogramming of 3’ untranslated regions of mRNAs by alternative polyadenylation in generation of pluripotent stem cells from different cell types. PLoS One 2009, 4:e8419. doi: 10.1371/journal.pone.0008419 20037631
12. Liu D, Brockman JM, Dass B, Hutchins LN, Singh P, McCarrey JR, MacDonald CC, Graber JH: Systematic variation in mRNA 3’-processing signals during mouse spermatogenesis. Nucleic Acids Res 2007, 35:234–246. doi: 10.1093/nar/gkl919 17158511
13. Sartini BL, Wang H, Wang W, Millette CF, Kilpatrick DL: Pre-messenger RNA cleavage factor I (CFIm): potential role in alternative polyadenylation during spermatogenesis. Biol Reprod 2008, 78:472–482. doi: 10.1095/biolreprod.107.064774 18032416
14. Li W, Park JY, Zheng D, Hoque M, Yehia G, Tian B: Alternative cleavage and polyadenylation in spermatogenesis connects chromatin regulation with post-transcriptional control. BMC Biol 2016, 14:6. doi: 10.1186/s12915-016-0229-6 26801249
15. Zhang H, Lee JY, Tian B: Biased alternative polyadenylation in human tissues. Genome Biol 2005, 6:R100. doi: 10.1186/gb-2005-6-12-r100 16356263
16. Miura P, Shenker S, Andreu-Agullo C, Westholm JO, Lai EC: Widespread and extensive lengthening of 3’ UTRs in the mammalian brain. Genome Res 2013, 23:812–825. doi: 10.1101/gr.146886.112 23520388
17. Shulman ED, Elkon R: Cell-type-specific analysis of alternative polyadenylation using single-cell transcriptomics data. Nucleic Acids Res 2019.
18. Sandberg R, Neilson JR, Sarma A, Sharp PA, Burge CB: Proliferating cells express mRNAs with shortened 3’ untranslated regions and fewer microRNA target sites. Science 2008, 320:1643–1647. doi: 10.1126/science.1155390 18566288
19. Mayr C, Bartel DP: Widespread shortening of 3’UTRs by alternative cleavage and polyadenylation activates oncogenes in cancer cells. Cell 2009, 138:673–684. doi: 10.1016/j.cell.2009.06.016 19703394
20. Xia Z, Donehower LA, Cooper TA, Neilson JR, Wheeler DA, Wagner EJ, Li W: Dynamic analyses of alternative polyadenylation from RNA-seq reveal a 3’-UTR landscape across seven tumour types. Nat Commun 2014, 5:5274. doi: 10.1038/ncomms6274 25409906
21. Higgs DR, Goodbourn SE, Lamb J, Clegg JB, Weatherall DJ, Proudfoot NJ: Alpha-thalassaemia caused by a polyadenylation signal mutation. Nature 1983, 306:398–400. doi: 10.1038/306398a0 6646217
22. Orkin SH, Cheng TC, Antonarakis SE, Kazazian HH Jr.: Thalassemia due to a mutation in the cleavage-polyadenylation signal of the human beta-globin gene. EMBO J 1985, 4:453–456. 4018033
23. Bennett CL, Brunkow ME, Ramsdell F, O’Briant KC, Zhu Q, Fuleihan RL, Shigeoka AO, Ochs HD, Chance PF: A rare polyadenylation signal mutation of the FOXP3 gene (AAUAAA—>AAUGAA) leads to the IPEX syndrome. Immunogenetics 2001, 53:435–439. doi: 10.1007/s002510100358 11685453
24. Danckwardt S, Hentze MW, Kulozik AE: 3’ end mRNA processing: molecular mechanisms and implications for health and disease. EMBO J 2008, 27:482–498. doi: 10.1038/sj.emboj.7601932 18256699
25. Graham RR, Kyogoku C, Sigurdsson S, Vlasova IA, Davies LR, Baechler EC, Plenge RM, Koeuth T, Ortmann WA, Hom G, et al: Three functional variants of IFN regulatory factor 5 (IRF5) define risk and protective haplotypes for human lupus. Proc Natl Acad Sci U S A 2007, 104:6758–6763. doi: 10.1073/pnas.0701266104 17412832
26. Prasad MK, Bhalla K, Pan ZH, O’Connell JR, Weder AB, Chakravarti A, Tian B, Chang YP: A polymorphic 3’UTR element in ATP1B1 regulates alternative polyadenylation and is associated with blood pressure. PLoS One 2013, 8:e76290. doi: 10.1371/journal.pone.0076290 24098465
27. Wang R, Zheng D, Yehia G, Tian B: A compendium of conserved cleavage and polyadenylation events in mammalian genes. Genome Res 2018, 28:1427–1441. doi: 10.1101/gr.237826.118 30143597
28. Consortium GT, Laboratory DA, Coordinating Center -Analysis Working G, Statistical Methods groups-Analysis Working G, Enhancing Gg, Fund NIHC, Nih/Nci, Nih/Nhgri, Nih/Nimh, Nih/Nida, et al: Genetic effects on gene expression across human tissues. Nature 2017, 550:204–213. doi: 10.1038/nature24277 29022597
29. Ongen H, Buil A, Brown AA, Dermitzakis ET, Delaneau O: Fast and efficient QTL mapper for thousands of molecular phenotypes. Bioinformatics 2016, 32:1479–1485. doi: 10.1093/bioinformatics/btv722 26708335
30. Hormozdiari F, Kostem E, Kang EY, Pasaniuc B, Eskin E: Identifying causal variants at loci with multiple signals of association. Genetics 2014, 198:497–508. doi: 10.1534/genetics.114.167908 25104515
31. Liu B, Gloudemans MJ, Rao AS, Ingelsson E, Montgomery SB: Abundant associations with gene expression complicate GWAS follow-up. Nat Genet 2019, 51:768–769. doi: 10.1038/s41588-019-0404-0 31043754
32. Hormozdiari F, van de Bunt M, Segre AV, Li X, Joo JWJ, Bilow M, Sul JH, Sankararaman S, Pasaniuc B, Eskin E: Colocalization of GWAS and eQTL Signals Detects Target Genes. Am J Hum Genet 2016, 99:1245–1260. doi: 10.1016/j.ajhg.2016.10.003 27866706
33. Kuramoto K, He C: The BECN1-BCL2 complex regulates insulin secretion and storage in mice. Autophagy 2018, 14:2026–2028. doi: 10.1080/15548627.2018.1502566 30081744
34. Hong W, Ruan H, Zhang Z, Ye Y, Liu Y, Li S, Jing Y, Zhang H, Diao L, Liang H, Han L: APAatlas: decoding alternative polyadenylation across human tissues. Nucleic Acids Res 2020, 48:D34–D39. doi: 10.1093/nar/gkz876 31586392
35. Urbut SM, Wang G, Carbonetto P, Stephens M: Flexible statistical methods for estimating and testing effects in genomic studies with multiple conditions. Nat Genet 2019, 51:187–195. doi: 10.1038/s41588-018-0268-8 30478440
36. Spies N, Burge CB, Bartel DP: 3’ UTR-isoform choice has limited influence on the stability and translational efficiency of most mRNAs in mouse fibroblasts. Genome Res 2013, 23:2078–2090. doi: 10.1101/gr.156919.113 24072873
37. Gruber AR, Martin G, Muller P, Schmidt A, Gruber AJ, Gumienny R, Mittal N, Jayachandran R, Pieters J, Keller W, et al: Global 3’ UTR shortening has a limited effect on protein abundance in proliferating T cells. Nat Commun 2014, 5:5465. doi: 10.1038/ncomms6465 25413384
38. Guhaniyogi J, Brewer G: Regulation of mRNA stability in mammalian cells. Gene 2001, 265:11–23. doi: 10.1016/s0378-1119(01)00350-x 11255003
39. Nam JW, Rissland OS, Koppstein D, Abreu-Goodger C, Jan CH, Agarwal V, Yildirim MA, Rodriguez A, DP: Global analyses of the effect of different cellular contexts on microRNA targeting. Mol Cell 2014, 53:1031–1043. doi: 10.1016/j.molcel.2014.02.013 24631284
40. Hoffman Y, Bublik DR, Ugalde AP, Elkon R, Biniashvili T, Agami R, Oren M, Pilpel Y: 3’UTR Shortening Potentiates MicroRNA-Based Repression of Pro-differentiation Genes in Proliferating Human Cells. PLoS Genet 2016, 12:e1005879. doi: 10.1371/journal.pgen.1005879 26908102
41. MacArthur J, Bowler E, Cerezo M, Gil L, Hall P, Hastings E, Junkins H, McMahon A, Milano A, Morales J, et al: The new NHGRI-EBI Catalog of published genome-wide association studies (GWAS Catalog). Nucleic Acids Res 2017, 45:D896–D901. doi: 10.1093/nar/gkw1133 27899670
42. Elkon R, Agami R: Characterization of noncoding regulatory DNA in the human genome. Nat Biotechnol 2017, 35:732–746. doi: 10.1038/nbt.3863 28787426
43. Finucane HK, Bulik-Sullivan B, Gusev A, Trynka G, Reshef Y, Loh PR, Anttila V, Xu H, Zang C, Farh K, et al: Partitioning heritability by functional annotation using genome-wide association summary statistics. Nat Genet 2015, 47:1228–1235. doi: 10.1038/ng.3404 26414678
44. Yang Y, Zhang Q, Miao YR, Yang J, Yang W, Yu F, Wang D, Guo AY, Gong J: SNP2APA: a database for evaluating effects of genetic variants on alternative polyadenylation in human cancers. Nucleic Acids Res 2019.
45. Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N, Marth G, Abecasis G, Durbin R, Genome Project Data Processing S: The Sequence Alignment/Map format and SAMtools. Bioinformatics 2009, 25:2078–2079. doi: 10.1093/bioinformatics/btp352 19505943
46. Frankish A, Diekhans M, Ferreira AM, Johnson R, Jungreis I, Loveland J, Mudge JM, Sisu C, Wright J, Armstrong J, et al: GENCODE reference annotation for the human and mouse genomes. Nucleic Acids Res 2019, 47:D766–D773. doi: 10.1093/nar/gky955 30357393
47. Quinlan AR, Hall IM: BEDTools: a flexible suite of utilities for comparing genomic features. Bioinformatics 2010, 26:841–842. doi: 10.1093/bioinformatics/btq033 20110278
48. Liao Y, Smyth GK, Shi W: featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics 2014, 30:923–930. doi: 10.1093/bioinformatics/btt656 24227677
49. Storey JD, Tibshirani R: Statistical significance for genomewide studies. Proc Natl Acad Sci U S A 2003, 100:9440–9445. doi: 10.1073/pnas.1530509100 12883005
50. Li H. A statistical framework for SNP calling, mutation discovery, association mapping and population genetical parameter estimation from sequencing data. Bioinformatics 2011, 27:2987–2993. doi: 10.1093/bioinformatics/btr509 21903627
Článek vyšel v časopise
PLOS Genetics
2020 Číslo 8
- Může hubnutí souviset s vyšším rizikem nádorových onemocnění?
- Polibek, který mi „vzal nohy“ aneb vzácný výskyt EBV u 70leté ženy – kazuistika
- AI může chirurgům poskytnout cenná data i zpětnou vazbu v reálném čase
- Antibiotika na nachlazení nezabírají! Jak můžeme zpomalit šíření rezistence?
- Metamizol jako analgetikum první volby: kdy, pro koho, jak a proč?
Nejčtenější v tomto čísle
- Genomic imprinting: An epigenetic regulatory system
- Uptake of exogenous serine is important to maintain sphingolipid homeostasis in Saccharomyces cerevisiae
- A human-specific VNTR in the TRIB3 promoter causes gene expression variation between individuals
- Immediate activation of chemosensory neuron gene expression by bacterial metabolites is selectively induced by distinct cyclic GMP-dependent pathways in Caenorhabditis elegans