Detection of Neanderthal Adaptively Introgressed Genetic Variants That Modulate Reporter Gene Expression in Human Immune Cells.

Animals Gene Expression Genetic Variation Genome, Human Humans Immunity, Innate / genetics Inflammation Neanderthals / genetics
adaptation immune introgression massively parallel reporter assay neandertal positive selection

Journal

Molecular biology and evolution
ISSN: 1537-1719
Titre abrégé: Mol Biol Evol
Pays: United States
ID NLM: 8501455

Informations de publication

Date de publication:
07 01 2022
Historique:
pubmed: 19 10 2021
medline: 28 1 2022
entrez: 18 10 2021
Statut: ppublish

Résumé

Although some variation introgressed from Neanderthals has undergone selective sweeps, little is known about its functional significance. We used a Massively Parallel Reporter Assay (MPRA) to assay 5,353 high-frequency introgressed variants for their ability to modulate the gene expression within 170 bp of endogenous sequence. We identified 2,548 variants in active putative cis-regulatory elements (CREs) and 292 expression-modulating variants (emVars). These emVars are predicted to alter the binding motifs of important immune transcription factors, are enriched for associations with neutrophil and white blood cell count, and are associated with the expression of genes that function in innate immune pathways including inflammatory response and antiviral defense. We combined the MPRA data with other data sets to identify strong candidates to be driver variants of positive selection including an emVar that may contribute to protection against severe COVID-19 response. We endogenously deleted two CREs containing expression-modulation variants linked to immune function, rs11624425 and rs80317430, identifying their primary genic targets as ELMSAN1, and PAN2 and STAT2, respectively, three genes differentially expressed during influenza infection. Overall, we present the first database of experimentally identified expression-modulating Neanderthal-introgressed alleles contributing to potential immune response in modern humans.

Identifiants

DOI: 10.1093/molbev/msab304 PMID: 34662402 PMC: PMC8760939
pubmed: 34662402
pii: 6400258
doi: 10.1093/molbev/msab304
pmc: PMC8760939
pii:
doi:

Types de publication

Journal Article Research Support, N.I.H., Extramural

Langues

eng

Sous-ensembles de citation

IM

Subventions

Organisme : NHGRI NIH HHS
ID : K99 HG010669
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM125055
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM128946
Pays : United States

Informations de copyright

© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

Références

Immunity. 2014 Oct 16;41(4):518-28
pubmed: 25367569
Fish Shellfish Immunol. 2019 Jun;89:677-686
pubmed: 30905839
Curr Biol. 2016 Dec 19;26(24):3375-3382
pubmed: 27839976
Biochem Soc Trans. 2014 Feb;42(1):184-7
pubmed: 24450649
Nucleic Acids Res. 1999 Jan 15;27(2):573-80
pubmed: 9862982
Nature. 2016 May 02;534(7606):200-5
pubmed: 27135931
Nature. 2016 Oct 13;538(7624):238-242
pubmed: 27654910
Diagnostics (Basel). 2020 Mar 22;10(3):
pubmed: 32235747
Front Immunol. 2013 Oct 08;4:289
pubmed: 24115947
Proc Natl Acad Sci U S A. 1998 Mar 17;95(6):2850-5
pubmed: 9501179
PLoS One. 2015 Mar 04;10(3):e0118551
pubmed: 25738304
Nature. 2014 Aug 14;512(7513):194-7
pubmed: 25043035
Stroke. 2004 Mar;35(3):622-6
pubmed: 14976328
Cell. 2016 Jun 2;165(6):1530-1545
pubmed: 27259154
Hum Mol Genet. 2007 Dec 15;16(24):3008-16
pubmed: 17881657
Science. 2016 Feb 12;351(6274):737-41
pubmed: 26912863
Proc Natl Acad Sci U S A. 2021 Jun 1;118(22):
pubmed: 34050022
Bioinformatics. 2011 Apr 1;27(7):1017-8
pubmed: 21330290
Genes Dev. 1997 Nov 15;11(22):2952-7
pubmed: 9367978
J Biol Chem. 2004 Apr 9;279(15):14477-80
pubmed: 14722108
Nat Protoc. 2009;4(1):44-57
pubmed: 19131956
Cell. 2017 Feb 23;168(5):916-927.e12
pubmed: 28235201
Nature. 2020 Jun;582(7810):78-83
pubmed: 32494067
Proc Natl Acad Sci U S A. 2013 Feb 26;110(9):3519-24
pubmed: 23401514
Cell. 2016 Oct 20;167(3):643-656.e17
pubmed: 27768888
Nature. 2014 Mar 20;507(7492):354-7
pubmed: 24476815
Am J Hum Genet. 2012 Aug 10;91(2):265-74
pubmed: 22883142
J Biol Chem. 2014 Oct 10;289(41):28213-24
pubmed: 25170077
Proc Natl Acad Sci U S A. 2019 Jan 29;116(5):1639-1644
pubmed: 30647110
Cell. 2016 Oct 20;167(3):657-669.e21
pubmed: 27768889
Genome Biol. 2014;15(12):550
pubmed: 25516281
Nucleic Acids Res. 2012 Jan;40(Database issue):D930-4
pubmed: 22064851
Elife. 2021 Apr 22;10:
pubmed: 33885362
Cancer Res. 1983 Oct;43(10):4569-74
pubmed: 6349795
Nature. 2014 Jan 2;505(7481):43-9
pubmed: 24352235
Mol Biol Evol. 2017 Feb 1;34(2):296-317
pubmed: 27756828
Arthritis Rheum. 2006 Dec;54(12):3815-9
pubmed: 17133578
Am J Hum Genet. 2017 Oct 5;101(4):578-589
pubmed: 28985494
Proc Natl Acad Sci U S A. 2013 Nov 12;110(46):18620-5
pubmed: 24167252
Nature. 2020 Nov;587(7835):610-612
pubmed: 32998156
Autophagy. 2016 Aug 2;12(8):1240-58
pubmed: 27171064
Cell. 2016 Nov 17;167(5):1415-1429.e19
pubmed: 27863252
Nature. 2016 Oct 13;538(7624):201-206
pubmed: 27654912
Cell. 2009 Dec 24;139(7):1255-67
pubmed: 20064372
Immunity. 2014 Jun 19;40(6):896-909
pubmed: 24882217
Nucleic Acids Res. 2020 Jan 8;48(D1):D498-D503
pubmed: 31691815
Genome Biol. 2016 Nov 29;17(1):246
pubmed: 27899133
Nature. 2012 Sep 6;489(7414):57-74
pubmed: 22955616
Genome Res. 2017 Jan;27(1):38-52
pubmed: 27831498
Am J Hum Genet. 2016 Jan 7;98(1):22-33
pubmed: 26748514
Cell. 1991 Jan 25;64(2):439-46
pubmed: 1988156
Science. 2016 Apr 8;352(6282):235-9
pubmed: 26989198
Nucleic Acids Res. 2018 Jan 4;46(D1):D252-D259
pubmed: 29140464
Am J Hum Genet. 2016 Jan 7;98(1):5-21
pubmed: 26748513
Cell. 2016 Jun 2;165(6):1519-1529
pubmed: 27259153
Cell. 2018 Oct 4;175(2):360-371.e13
pubmed: 30290142
Genetics. 2016 Jun;203(2):881-91
pubmed: 27038113
Eur J Hum Genet. 2020 Jun;28(6):715-718
pubmed: 32404885
Nucleic Acids Res. 2009 Jan;37(1):1-13
pubmed: 19033363
Science. 2017 Nov 3;358(6363):655-658
pubmed: 28982794
Nat Commun. 2020 Nov 17;11(1):5838
pubmed: 33203860
PLoS Genet. 2016 Nov 8;12(11):e1006340
pubmed: 27824859
Nature. 2015 Oct 1;526(7571):68-74
pubmed: 26432245
Database (Oxford). 2018 Jan 1;2018:
pubmed: 30576484
Oncogene. 2016 Jul 14;35(28):3636-46
pubmed: 26549026
Eur J Hum Genet. 2019 Nov;27(11):1745-1756
pubmed: 31296926
Aging (Albany NY). 2020 Aug 21;12(17):17167-17208
pubmed: 32833672
Bioinformatics. 2015 Feb 1;31(3):418-20
pubmed: 25316677
Biochem J. 2013 Apr 15;451(2):185-94
pubmed: 23398456
Proc Natl Acad Sci U S A. 2021 Jan 12;118(2):
pubmed: 33372131
Science. 2011 Jun 17;332(6036):1429-33
pubmed: 21617040
PLoS Med. 2015 Mar 31;12(3):e1001779
pubmed: 25826379
Genome Biol. 2017 Apr 3;18(1):61
pubmed: 28366169
Genome Biol Evol. 2021 Jan 7;13(1):
pubmed: 33247712
Nat Protoc. 2013 Nov;8(11):2281-2308
pubmed: 24157548
Immunol Rev. 2014 Jan;257(1):191-209
pubmed: 24329798
Science. 2015 May 8;348(6235):648-60
pubmed: 25954001
Nat Genet. 2019 Oct;51(10):1442-1449
pubmed: 31501517
Nucleic Acids Res. 2016 Jan 4;44(D1):D726-32
pubmed: 26527727
Mol Biol Evol. 2018 Mar 1;35(3):623-630
pubmed: 29220488
Nat Protoc. 2017 Dec;12(12):2478-2492
pubmed: 29120462
J Cell Sci. 2010 Aug 1;123(Pt 15):2565-75
pubmed: 20587593
Nat Rev Genet. 2007 Nov;8(11):857-68
pubmed: 17943193
Curr Biol. 2016 May 9;26(9):1241-7
pubmed: 27032491
Genetics. 2021 May 17;218(1):
pubmed: 33787889

Auteurs

Evelyn Jagoda (E)

Department of Human Evolutionary Biology, Harvard University, Cambridge, MA, USA.

James R Xue (JR)

Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA, USA.
Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Steven K Reilly (SK)

Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA, USA.
Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Michael Dannemann (M)

Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany.
Estonian Biocentre, Institute of Genomics, University of Tartu, Tartu, Estonia.

Fernando Racimo (F)

Lundbeck GeoGenetics Centre, The Globe Institute, University of Copenhagen, Copenhagen, Denmark.

Emilia Huerta-Sanchez (E)

Department of Ecology and Evolutionary Biology, Brown University, Providence, RI, USA.
Center for Computational Molecular Biology, Brown University, Providence, RI, USA.

Sriram Sankararaman (S)

Department of Computer Science, UCLA, Los Angeles, CA, USA.
Department of Human Genetics, UCLA, Los Angeles, CA, USA.

Janet Kelso (J)

Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany.

Luca Pagani (L)

Estonian Biocentre, Institute of Genomics, University of Tartu, Tartu, Estonia.
Department of Biology, University of Padova, Padova, Italy.

Pardis C Sabeti (PC)

Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA, USA.
Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
Howard Hughes Medical Institute, Chevy Chase, MD, USA.

Terence D Capellini (TD)

Department of Human Evolutionary Biology, Harvard University, Cambridge, MA, USA.
Broad Institute of MIT and Harvard, Cambridge, MA, USA.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Detection of Neanderthal Adaptively...
questionsmedicales.fr › Phénomènes génétiques › Expression des gènes › Detection of Neanderthal Adaptively...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Detection of Neanderthal Adaptively...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Génome › Génome humain › Detection of Neanderthal Adaptively...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Detection of Neanderthal Adaptively...
questionsmedicales.fr › Phénomènes du système immunitaire › Immunité › Immunité innée › Detection of Neanderthal Adaptively...
questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Inflammation › Detection of Neanderthal Adaptively...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Néandertaliens › Detection of Neanderthal Adaptively...