Genome-wide functional screen of 3'UTR variants uncovers causal variants for human disease and evolution.
3' Untranslated Regions
/ genetics
Algorithms
Alleles
Biological Evolution
Disease
/ genetics
Gene Expression Regulation
Genes, Reporter
Genetic Variation
Genome-Wide Association Study
Humans
Phenotype
Polymorphism, Single Nucleotide
/ genetics
Polyribosomes
/ metabolism
Quantitative Trait Loci
/ genetics
RNA
/ genetics
3'UTR
GWAS
MPRA
evolution
functional genomics
genetic variants
regulatory genomics
Journal
Cell
ISSN: 1097-4172
Titre abrégé: Cell
Pays: United States
ID NLM: 0413066
Informations de publication
Date de publication:
30 09 2021
30 09 2021
Historique:
received:
12
12
2020
revised:
25
05
2021
accepted:
19
08
2021
pubmed:
18
9
2021
medline:
8
1
2022
entrez:
17
9
2021
Statut:
ppublish
Résumé
3' untranslated region (3'UTR) variants are strongly associated with human traits and diseases, yet few have been causally identified. We developed the massively parallel reporter assay for 3'UTRs (MPRAu) to sensitively assay 12,173 3'UTR variants. We applied MPRAu to six human cell lines, focusing on genetic variants associated with genome-wide association studies (GWAS) and human evolutionary adaptation. MPRAu expands our understanding of 3'UTR function, suggesting that simple sequences predominately explain 3'UTR regulatory activity. We adapt MPRAu to uncover diverse molecular mechanisms at base pair resolution, including an adenylate-uridylate (AU)-rich element of LEPR linked to potential metabolic evolutionary adaptations in East Asians. We nominate hundreds of 3'UTR causal variants with genetically fine-mapped phenotype associations. Using endogenous allelic replacements, we characterize one variant that disrupts a miRNA site regulating the viral defense gene TRIM14 and one that alters PILRB abundance, nominating a causal variant underlying transcriptional changes in age-related macular degeneration.
Identifiants
pubmed: 34534445
pii: S0092-8674(21)00999-5
doi: 10.1016/j.cell.2021.08.025
pmc: PMC8487971
mid: NIHMS1739899
pii:
doi:
Substances chimiques
3' Untranslated Regions
0
RNA
63231-63-0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
5247-5260.e19Subventions
Organisme : NHGRI NIH HHS
ID : R00 HG008179
Pays : United States
Organisme : Howard Hughes Medical Institute
Pays : United States
Organisme : NIAID NIH HHS
ID : R37 AI147868
Pays : United States
Organisme : NHGRI NIH HHS
ID : R00 HG010669
Pays : United States
Organisme : NHGRI NIH HHS
ID : UM1 HG009435
Pays : United States
Organisme : NHGRI NIH HHS
ID : F32 HG009226
Pays : United States
Organisme : NHGRI NIH HHS
ID : K99 HG010669
Pays : United States
Organisme : NIGMS NIH HHS
ID : F30 GM114940
Pays : United States
Informations de copyright
Copyright © 2021 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests P.C.S. is a co-founder of and consultant to Sherlock Biosciences and Board Member of Danaher Corporation. She is a shareholder in both companies.
Références
PLoS Genet. 2015 Apr 15;11(4):e1005147
pubmed: 25875337
J Immunol. 2020 Jul 1;205(1):153-167
pubmed: 32404352
Cell. 2016 Jun 2;165(6):1530-1545
pubmed: 27259154
Science. 2015 Feb 6;347(6222):664-7
pubmed: 25657249
Cell. 2018 Nov 29;175(6):1701-1715.e16
pubmed: 30449622
Proc Natl Acad Sci U S A. 2013 Oct 29;110(44):17921-6
pubmed: 24127591
Genome Biol. 2017 Oct 23;18(1):194
pubmed: 29061142
Bioinformatics. 2016 May 15;32(10):1493-501
pubmed: 26773131
RNA. 2001 Dec;7(12):1855-66
pubmed: 11780640
Am J Hum Genet. 2013 Jan 10;92(1):5-14
pubmed: 23246289
Nature. 2016 Jun 15;534(7608):500-5
pubmed: 27309819
Genome Res. 2009 Jan;19(1):92-105
pubmed: 18955434
Nature. 2015 Jun 18;522(7556):363-7
pubmed: 25896326
Bioinformatics. 2016 Jun 15;32(12):i351-i359
pubmed: 27307637
Nat Genet. 2016 Feb;48(2):134-43
pubmed: 26691988
Nat Methods. 2016 Jun;13(6):508-14
pubmed: 27018577
Nucleic Acids Res. 2016 Jan 4;44(D1):D877-81
pubmed: 26657631
Nat Commun. 2020 Jun 1;11(1):2718
pubmed: 32483191
Cell. 2013 Feb 14;152(4):703-13
pubmed: 23415221
Nucleic Acids Res. 2008 Jul 1;36(Web Server issue):W70-4
pubmed: 18424795
Proc Natl Acad Sci U S A. 2014 Jan 14;111(2):E245-54
pubmed: 24379373
Trends Cell Biol. 2009 Sep;19(9):465-74
pubmed: 19716303
Genome Biol. 2016 Jun 06;17(1):122
pubmed: 27268795
Genome Biol. 2014;15(12):550
pubmed: 25516281
Nucleic Acids Res. 2012 Jan;40(1):37-52
pubmed: 21911355
Mol Cell. 2016 Oct 6;64(1):105-119
pubmed: 27666593
Nat Genet. 2021 Sep;53(9):1290-1299
pubmed: 34493866
Nat Genet. 2021 Jul;53(7):994-1005
pubmed: 33986536
Science. 2020 Sep 11;369(6509):1318-1330
pubmed: 32913098
Nat Commun. 2019 Jun 4;10(1):2434
pubmed: 31164647
Nat Rev Rheumatol. 2017 Feb;13(2):100-109
pubmed: 28053336
Neuron. 2018 May 2;98(3):495-511.e6
pubmed: 29656876
Front Microbiol. 2019 Feb 26;10:344
pubmed: 30873142
Heredity (Edinb). 2014 Sep;113(3):259-67
pubmed: 24667833
Science. 2010 Feb 12;327(5967):883-6
pubmed: 20056855
Nat Genet. 2011 Oct 30;43(12):1224-7
pubmed: 22037555
Bioinformatics. 2011 Nov 1;27(21):2957-63
pubmed: 21903629
Am J Hum Genet. 2014 Nov 6;95(5):535-52
pubmed: 25439723
Nature. 2017 Oct 11;550(7675):204-213
pubmed: 29022597
Cell Rep. 2014 Apr 10;7(1):281-92
pubmed: 24656821
Cell Rep. 2020 Jan 28;30(4):1246-1259.e6
pubmed: 31995762
Nat Biotechnol. 2014 Apr;32(4):387-91
pubmed: 24633241
Nat Genet. 2013 Jun;45(6):580-5
pubmed: 23715323
Nature. 2017 Oct 11;550(7675):239-243
pubmed: 29022581
Nucleic Acids Res. 2001 Jan 1;29(1):246-54
pubmed: 11125104
Nucleic Acids Res. 2019 Jan 8;47(D1):D1005-D1012
pubmed: 30445434
Proc Natl Acad Sci U S A. 1997 Mar 18;94(6):2410-4
pubmed: 9122208
Nat Commun. 2018 Feb 6;9(1):529
pubmed: 29410437
Genome Res. 2019 Oct;29(10):1635-1647
pubmed: 31530582
Proc Natl Acad Sci U S A. 2006 Feb 21;103(8):2746-51
pubmed: 16477010
Nat Genet. 2015 Nov;47(11):1228-35
pubmed: 26414678
Nature. 2013 Sep 26;501(7468):506-11
pubmed: 24037378
Cell. 2016 Jun 2;165(6):1519-1529
pubmed: 27259153
Cell. 2010 Apr 2;141(1):129-41
pubmed: 20371350
Circ Cardiovasc Genet. 2010 Apr;3(2):179-86
pubmed: 20150529
N Engl J Med. 2017 Apr 27;376(17):1615-1626
pubmed: 28445677
Nat Biotechnol. 2019 Mar;37(3):224-226
pubmed: 30809026
Nat Genet. 2019 Jan;51(1):187-195
pubmed: 30478440
Mol Cell Biol. 2008 Jun;28(12):4093-103
pubmed: 18411299
Nature. 2015 Oct 1;526(7571):68-74
pubmed: 26432245
PLoS Genet. 2014 Mar 27;10(3):e1004263
pubmed: 24676100
Nat Genet. 2019 Jul;51(7):1160-1169
pubmed: 31253979
Metabolism. 2015 Jan;64(1):13-23
pubmed: 25305050
Mol Cell. 2017 Oct 19;68(2):293-307.e5
pubmed: 29053956
Science. 2012 Sep 7;337(6099):1190-5
pubmed: 22955828
Am J Hum Genet. 2007 Sep;81(3):559-75
pubmed: 17701901
Genome Res. 2019 Jun;29(6):896-906
pubmed: 31152051
Nat Methods. 2016 Apr;13(4):366-70
pubmed: 26950747
Nat Biotechnol. 2019 Jul;37(7):803-809
pubmed: 31267113
Cell. 2020 May 28;181(5):1036-1045.e9
pubmed: 32416070
BMC Bioinformatics. 2018 Dec 10;19(1):473
pubmed: 30526486
PLoS Genet. 2014 Jun 19;10(6):e1004423
pubmed: 24945404
Nat Commun. 2021 Jun 7;12(1):3394
pubmed: 34099641
Cell. 2019 Jun 27;178(1):91-106.e23
pubmed: 31178116
Nucleic Acids Res. 2019 Jan 25;47(2):570-581
pubmed: 30517751
Mol Cell. 2018 Jun 7;70(5):854-867.e9
pubmed: 29883606
PLoS One. 2008 Sep 08;3(9):e3164
pubmed: 18776931
Nucleic Acids Res. 2014 Jan;42(Database issue):D1001-6
pubmed: 24316577
Mol Ecol Resour. 2013 Sep;13(5):946-52
pubmed: 23738873
Mol Cell. 2008 Feb 1;29(2):263-70
pubmed: 18243120
Neuromuscul Disord. 2013 Aug;23(8):670-4
pubmed: 23770102
BMC Genet. 2010 Apr 23;11:26
pubmed: 20416077
Nat Commun. 2019 Aug 8;10(1):3583
pubmed: 31395865
Gastroenterology. 2014 Jul;147(1):65-68.e10
pubmed: 24726755