Global analysis of suppressor mutations that rescue human genetic defects.
Journal
Genome medicine
ISSN: 1756-994X
Titre abrégé: Genome Med
Pays: England
ID NLM: 101475844
Informations de publication
Date de publication:
12 10 2023
12 10 2023
Historique:
received:
07
04
2023
accepted:
12
09
2023
medline:
2
11
2023
pubmed:
12
10
2023
entrez:
11
10
2023
Statut:
epublish
Résumé
Genetic suppression occurs when the deleterious effects of a primary "query" mutation, such as a disease-causing mutation, are rescued by a suppressor mutation elsewhere in the genome. To capture existing knowledge on suppression relationships between human genes, we examined 2,400 published papers for potential interactions identified through either genetic modification of cultured human cells or through association studies in patients. The resulting network encompassed 476 unique suppression interactions covering a wide spectrum of diseases and biological functions. The interactions frequently linked genes that operate in the same biological process. Suppressors were strongly enriched for genes with a role in stress response or signaling, suggesting that deleterious mutations can often be buffered by modulating signaling cascades or immune responses. Suppressor mutations tended to be deleterious when they occurred in absence of the query mutation, in apparent contrast with their protective role in the presence of the query. We formulated and quantified mechanisms of genetic suppression that could explain 71% of interactions and provided mechanistic insight into disease pathology. Finally, we used these observations to predict suppressor genes in the human genome. The global suppression network allowed us to define principles of genetic suppression that were conserved across diseases, model systems, and species. The emerging frequency of suppression interactions among human genes and range of underlying mechanisms, together with the prevalence of suppression in model organisms, suggest that compensatory mutations may exist for most genetic diseases.
Sections du résumé
BACKGROUND
Genetic suppression occurs when the deleterious effects of a primary "query" mutation, such as a disease-causing mutation, are rescued by a suppressor mutation elsewhere in the genome.
METHODS
To capture existing knowledge on suppression relationships between human genes, we examined 2,400 published papers for potential interactions identified through either genetic modification of cultured human cells or through association studies in patients.
RESULTS
The resulting network encompassed 476 unique suppression interactions covering a wide spectrum of diseases and biological functions. The interactions frequently linked genes that operate in the same biological process. Suppressors were strongly enriched for genes with a role in stress response or signaling, suggesting that deleterious mutations can often be buffered by modulating signaling cascades or immune responses. Suppressor mutations tended to be deleterious when they occurred in absence of the query mutation, in apparent contrast with their protective role in the presence of the query. We formulated and quantified mechanisms of genetic suppression that could explain 71% of interactions and provided mechanistic insight into disease pathology. Finally, we used these observations to predict suppressor genes in the human genome.
CONCLUSIONS
The global suppression network allowed us to define principles of genetic suppression that were conserved across diseases, model systems, and species. The emerging frequency of suppression interactions among human genes and range of underlying mechanisms, together with the prevalence of suppression in model organisms, suggest that compensatory mutations may exist for most genetic diseases.
Identifiants
pubmed: 37821946
doi: 10.1186/s13073-023-01232-0
pii: 10.1186/s13073-023-01232-0
pmc: PMC10568808
doi:
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
78Informations de copyright
© 2023. BioMed Central Ltd., part of Springer Nature.
Références
Genome Biol. 2014;15(12):554
pubmed: 25476604
Cell. 2020 Mar 5;180(5):915-927.e16
pubmed: 32084333
N Engl J Med. 2005 May 12;352(19):1992-2001
pubmed: 15888700
Nat Cell Biol. 2013 Jan;15(1):103-12
pubmed: 23242217
Nat Metab. 2020 Jun;2(6):499-513
pubmed: 32694731
Nucleic Acids Res. 2021 Jan 8;49(D1):D939-D946
pubmed: 33152070
Carcinogenesis. 2005 Oct;26(10):1731-40
pubmed: 15905196
Science. 2021 Nov 12;374(6569):eabj1541
pubmed: 34648354
Nature. 2019 May;569(7757):503-508
pubmed: 31068700
Trends Genet. 1999 Jul;15(7):261-6
pubmed: 10390624
Science. 2016 Nov 4;354(6312):
pubmed: 27811238
Nucleic Acids Res. 2019 Jan 8;47(D1):D559-D563
pubmed: 30357367
Mol Syst Biol. 2020 Sep;16(9):e9828
pubmed: 32939983
Trends Genet. 2011 Aug;27(8):323-31
pubmed: 21684621
Nucleic Acids Res. 2014 Dec 16;42(22):e168
pubmed: 25300484
Cell. 2021 May 27;184(11):3022-3040.e28
pubmed: 33961781
Proc Natl Acad Sci U S A. 2008 Feb 5;105(5):1620-5
pubmed: 18245381
G3 (Bethesda). 2017 Aug 7;7(8):2719-2727
pubmed: 28655737
Nat Genet. 2010 Dec;42(12):1049-51
pubmed: 21057501
Blood. 2006 Aug 1;108(3):1077-83
pubmed: 16861354
Nucleic Acids Res. 2015 Jan;43(Database issue):D789-98
pubmed: 25428349
Clin Hemorheol Microcirc. 2018;68(2-3):263-299
pubmed: 29614637
Nature. 2006 Oct 5;443(7111):574-7
pubmed: 17006452
N Engl J Med. 2021 Jan 21;384(3):252-260
pubmed: 33283989
PLoS Genet. 2019 Feb 15;15(2):e1007958
pubmed: 30768593
Nature. 2020 May;581(7809):434-443
pubmed: 32461654
EMBO J. 2014 Aug 1;33(15):1698-712
pubmed: 24966277
Bioessays. 2017 Jul;39(7):
pubmed: 28582599
Nat Genet. 1996 Nov;14(3):324-8
pubmed: 8896564
Nat Rev Mol Cell Biol. 2019 Apr;20(4):199-210
pubmed: 30824861
Lancet. 2017 Dec 17;388(10063):3017-3026
pubmed: 27939059
Nucleic Acids Res. 2022 Jan 7;50(D1):D687-D692
pubmed: 34788843
Nat Rev Genet. 2015 Dec;16(12):689-701
pubmed: 26503796
Genome Res. 2014 Aug;24(8):1363-70
pubmed: 24823668
Nucleic Acids Res. 2019 Jul 2;47(W1):W191-W198
pubmed: 31066453
Genome Biol. 2017 May 16;18(1):86
pubmed: 28506277
Nature. 2021 Nov;599(7886):628-634
pubmed: 34662886
Sci Rep. 2021 Feb 3;11(1):2879
pubmed: 33536571
Nat Commun. 2018 Jun 11;9(1):2280
pubmed: 29891926
Science. 2017 May 26;356(6340):
pubmed: 28495876
Hum Genet. 2008 Nov;124(4):357-68
pubmed: 18784943
Nature. 2019 Apr;568(7753):511-516
pubmed: 30971826
Pediatr Pulmonol. 2018 Nov;53(S3):S30-S50
pubmed: 29999593
Lancet Neurol. 2021 Apr;20(4):284-293
pubmed: 33743238
Nucleic Acids Res. 2018 Sep 28;46(17):8898-8907
pubmed: 30032296
N Engl J Med. 2021 Jan 21;384(3):205-215
pubmed: 33283990
Cell. 2019 Mar 21;177(1):85-100
pubmed: 30901552
Front Pharmacol. 2021 Feb 08;11:629266
pubmed: 33628188
BMC Evol Biol. 2009 May 16;9:106
pubmed: 19445716
Nat Commun. 2021 Feb 26;12(1):1334
pubmed: 33637765
PLoS Biol. 2014 Aug 26;12(8):e1001935
pubmed: 25157590
Cancer Discov. 2012 May;2(5):401-4
pubmed: 22588877
Nature. 2020 Apr;580(7803):402-408
pubmed: 32296183
Methods. 2000 Jan;20(1):18-34
pubmed: 10610801
Nucleic Acids Res. 2020 Jan 8;48(D1):D845-D855
pubmed: 31680165
Nat Rev Genet. 2002 May;3(5):356-69
pubmed: 11988761
Nucleic Acids Res. 2019 Jan 8;47(D1):D419-D426
pubmed: 30407594
Cell. 2017 Jul 27;170(3):564-576.e16
pubmed: 28753430
Nat Commun. 2021 Nov 11;12(1):6506
pubmed: 34764293
BMC Bioinformatics. 2011 Dec 30;12:495
pubmed: 22208852
Protein Sci. 2021 Jan;30(1):187-200
pubmed: 33070389
Nature. 2021 May;593(7858):238-243
pubmed: 33828297
Nat Biotechnol. 2017 May;35(5):463-474
pubmed: 28319085
Nat Methods. 2015 Mar;12(3):211-4, 3 p following 214
pubmed: 25581801
Am J Hematol. 2012 Aug;87(8):795-803
pubmed: 22641398
Cell. 1995 Oct 6;83(1):121-7
pubmed: 7553863
WormBook. 2005 Dec 27;:1-13
pubmed: 18023120