Modeling of mitochondrial genetic polymorphisms reveals induction of heteroplasmy by pleiotropic disease locus 10398A>G.

Heteroplasmy Mitochondria / genetics Polymorphism, Single Nucleotide Phenotype Base Sequence DNA, Mitochondrial / genetics

Journal

Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288

Informations de publication

Date de publication:
27 06 2023
Historique:
received: 23 02 2023
accepted: 23 06 2023
medline: 29 6 2023
pubmed: 28 6 2023
entrez: 27 6 2023
Statut: epublish

Résumé

Mitochondrial (MT) dysfunction has been associated with several neurodegenerative diseases including Alzheimer's disease (AD). While MT-copy number differences have been implicated in AD, the effect of MT heteroplasmy on AD has not been well characterized. Here, we analyzed over 1800 whole genome sequencing data from four AD cohorts in seven different tissue types to determine the extent of MT heteroplasmy present. While MT heteroplasmy was present throughout the entire MT genome for blood samples, we detected MT heteroplasmy only within the MT control region for brain samples. We observed that an MT variant 10398A>G (rs2853826) was significantly associated with overall MT heteroplasmy in brain tissue while also being linked with the largest number of distinct disease phenotypes of all annotated MT variants in MitoMap. Using gene-expression data from our brain samples, our modeling discovered several gene networks involved in mitochondrial respiratory chain and Complex I function associated with 10398A>G. The variant was also found to be an expression quantitative trait loci (eQTL) for the gene MT-ND3. We further characterized the effect of 10398A>G by phenotyping a population of lymphoblastoid cell-lines (LCLs) with and without the variant allele. Examination of RNA sequence data from these LCLs reveal that 10398A>G was an eQTL for MT-ND4. We also observed in LCLs that 10398A>G was significantly associated with overall MT heteroplasmy within the MT control region, confirming the initial findings observed in post-mortem brain tissue. These results provide novel evidence linking MT SNPs with MT heteroplasmy and open novel avenues for the investigation of pathomechanisms that are driven by this pleiotropic disease associated loci.

Identifiants

DOI: 10.1038/s41598-023-37541-y PMID: 37369829 PMC: PMC10300032
pubmed: 37369829
doi: 10.1038/s41598-023-37541-y
pii: 10.1038/s41598-023-37541-y
pmc: PMC10300032
doi:

Substances chimiques

DNA, Mitochondrial 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

10405

Subventions

Organisme : NIA NIH HHS
ID : U01 AG046152
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG030146
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG017917
Pays : United States
Organisme : NIA NIH HHS
ID : R21 AG063068
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS080820
Pays : United States
Organisme : NIA NIH HHS
ID : RC2 AG036547
Pays : United States
Organisme : NIA NIH HHS
ID : P01 AG017216
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG018023
Pays : United States
Organisme : NIA NIH HHS
ID : P50 AG016574
Pays : United States
Organisme : NIA NIH HHS
ID : U01 AG061835
Pays : United States
Organisme : NIA NIH HHS
ID : U01 AG061356
Pays : United States
Organisme : NIA NIH HHS
ID : U01 AG032984
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG036042
Pays : United States
Organisme : NIA NIH HHS
ID : P30 AG010161
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG032990
Pays : United States
Organisme : NIA NIH HHS
ID : U01AG061835
Pays : United States
Organisme : NIA NIH HHS
ID : RF1 AG057473
Pays : United States
Organisme : NIA NIH HHS
ID : U01 AG046139
Pays : United States
Organisme : NIA NIH HHS
ID : P01 AG003949
Pays : United States
Organisme : NINDS NIH HHS
ID : U24 NS072026
Pays : United States
Organisme : NIA NIH HHS
ID : U01 AG046161
Pays : United States
Organisme : NIA NIH HHS
ID : P30 AG019610
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG048015
Pays : United States
Organisme : NIA NIH HHS
ID : P50 AG025711
Pays : United States
Organisme : NIA NIH HHS
ID : U01 AG006786
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG036836
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG015819
Pays : United States

Informations de copyright

© 2023. The Author(s).

Références

Nat Rev Genet. 2015 Sep;16(9):530-42
pubmed: 26281784
Nature. 1981 Apr 9;290(5806):457-65
pubmed: 7219534
BMC Genet. 2009 May 27;10:23
pubmed: 19473544
Cancer Lett. 2007 May 8;249(2):249-55
pubmed: 17081685
Oncol Rep. 2010 Feb;23(2):531-5
pubmed: 20043118
Front Aging Neurosci. 2019 Nov 20;11:311
pubmed: 31824296
Ann Neurol. 2016 Aug;80(2):301-6
pubmed: 27315116
Alzheimers Dement. 2020 Jan;16(1):200-208
pubmed: 31914220
J Neurol. 2014 Mar;261(3):504-10
pubmed: 24375076
J Hum Genet. 2008;53(10):924-928
pubmed: 18709563
Bioinformatics. 2009 Jul 15;25(14):1754-60
pubmed: 19451168
Am J Hum Genet. 2003 Apr;72(4):804-11
pubmed: 12618962
Cancer Genet Cytogenet. 2008 Feb;181(1):16-9
pubmed: 18262047
Nat Commun. 2022 Jul 1;13(1):3790
pubmed: 35778412
J Neurol Sci. 2005 Sep 15;236(1-2):49-54
pubmed: 15975594
Neuron. 2018 Jul 11;99(1):64-82.e7
pubmed: 29937276
EMBO J. 2013 Jan 9;32(1):9-29
pubmed: 23149385
BMC Bioinformatics. 2013 Apr 15;14:128
pubmed: 23586463
Mol Neurodegener. 2020 May 29;15(1):30
pubmed: 32471464
CNS Neurosci Ther. 2016 Jan;22(1):38-42
pubmed: 26336829
Proc Natl Acad Sci U S A. 2004 Jul 20;101(29):10726-31
pubmed: 15247418
Nature. 2020 May;581(7809):434-443
pubmed: 32461654
Mitochondrial DNA A DNA Mapp Seq Anal. 2020 Jan;31(1):11-16
pubmed: 31797714
Neurosci Lett. 2004 Jul 15;365(1):28-32
pubmed: 15234467
Gigascience. 2015 Feb 25;4:7
pubmed: 25722852
Neurosci Lett. 2007 Feb 21;413(3):202-5
pubmed: 17174475
Front Cell Dev Biol. 2021 Feb 22;9:625020
pubmed: 33692999
Cell Prolif. 2022 Jul;55(7):e13274
pubmed: 35698260
Science. 2020 Sep 11;369(6509):1318-1330
pubmed: 32913098
Mol Neurodegener. 2021 Nov 6;16(1):75
pubmed: 34742335
Sci Rep. 2017 Apr 07;7:46148
pubmed: 28387241
Hum Genet. 2007 Feb;120(6):821-6
pubmed: 17066297
Hum Genet. 2007 Dec;122(5):535-40
pubmed: 17701054
Neurosci Lett. 2004 Nov 11;370(2-3):171-4
pubmed: 15488317
J Hum Genet. 2008;53(4):349-356
pubmed: 18286226
Curr Protoc. 2021 Mar;1(3):e90
pubmed: 33780170
Front Aging Neurosci. 2021 Feb 18;13:617588
pubmed: 33679375
Mitochondrion. 2010 Jan;10(1):32-7
pubmed: 19703591
BMC Cancer. 2014 Sep 09;14:659
pubmed: 25199876
Biochim Biophys Acta. 2013 Dec;1836(2):336-44
pubmed: 24140413
Br J Pharmacol. 2019 Sep;176(18):3489-3507
pubmed: 30675901
J Appl Genet. 2014 May;55(2):173-81
pubmed: 24414975
Science. 2015 Sep 25;349(6255):1494-9
pubmed: 26404827
PLoS Genet. 2006 Aug;2(8):e128
pubmed: 16895436
Neuron. 2018 Jul 11;99(1):56-63.e3
pubmed: 30001512
Genome Med. 2014 Feb 28;6(2):10
pubmed: 24713084
Alzheimers Dement. 2017 Sep;13(9):965-984
pubmed: 28341160
PLoS Genet. 2016 Oct 28;12(10):e1006391
pubmed: 27792786
Neurology. 2020 Jun 9;94(23):e2404-e2411
pubmed: 32457210
Cancer Res. 2007 May 15;67(10):4687-94
pubmed: 17510395
Tohoku J Exp Med. 2008 Aug;215(4):377-84
pubmed: 18679013
Neurol Sci. 2007 Jun;28(3):142-7
pubmed: 17603766
Am J Hum Genet. 1991 Feb;48(2):370-82
pubmed: 1990843
Eur J Hum Genet. 2005 Jun;13(6):748-52
pubmed: 15827561
Cancer Res. 2005 Sep 1;65(17):8028-33
pubmed: 16140977
Gigascience. 2016 Oct 11;5(1):42
pubmed: 27724973
Nucleic Acids Res. 2016 Jul 8;44(W1):W90-7
pubmed: 27141961
Neurobiol Aging. 2019 Jan;73:161-170
pubmed: 30359878
Ann Neurol. 2005 Apr;57(4):564-7
pubmed: 15786469
Bioinformatics. 2009 Aug 15;25(16):2078-9
pubmed: 19505943
Nat Commun. 2020 Mar 20;11(1):1487
pubmed: 32198407
Int J Med Sci. 2018 Aug 10;15(12):1329-1333
pubmed: 30275759
Proc Natl Acad Sci U S A. 2012 Jul 24;109(30):11920-7
pubmed: 22797899
Mol Biol Rep. 2022 Mar;49(3):1687-1700
pubmed: 34854014
Curr Protoc Bioinformatics. 2013 Dec;44:1.23.1-26
pubmed: 25489354
PLoS One. 2009;4(4):e5356
pubmed: 19390621
Vaccines (Basel). 2021 Jun 21;9(6):
pubmed: 34205498
Nat Commun. 2020 Feb 3;11(1):667
pubmed: 32015339
Tumour Biol. 2016 Apr;37(4):5599-607
pubmed: 26577855

Auteurs

Molly Smullen (M)

Department of Neurology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
Program in Bioinformatics and Integrative Biology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
NeuroNexus Institute, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.

Meagan N Olson (MN)

Department of Neurology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
Program in Bioinformatics and Integrative Biology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
NeuroNexus Institute, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.

Liam F Murray (LF)

Department of Neurology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
Program in Bioinformatics and Integrative Biology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
NeuroNexus Institute, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.

Madhusoodhanan Suresh (M)

Department of Neurology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
Program in Bioinformatics and Integrative Biology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
NeuroNexus Institute, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.

Guang Yan (G)

Department of Neurology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
Program in Bioinformatics and Integrative Biology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
NeuroNexus Institute, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.

Pepper Dawes (P)

Department of Neurology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
Program in Bioinformatics and Integrative Biology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
NeuroNexus Institute, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.

Nathaniel J Barton (NJ)

Department of Neurology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
Program in Bioinformatics and Integrative Biology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
NeuroNexus Institute, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.

Jivanna N Mason (JN)

Department of Neurology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
Program in Bioinformatics and Integrative Biology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
NeuroNexus Institute, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.

Yucheng Zhang (Y)

Department of Neurology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
Program in Bioinformatics and Integrative Biology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
NeuroNexus Institute, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.

Aria A Fernandez-Fontaine (AA)

Department of Neurology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
Program in Bioinformatics and Integrative Biology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
NeuroNexus Institute, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.

George M Church (GM)

Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, 02115, USA.
Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, 02115, USA.

Diego Mastroeni (D)

ASU-Banner Neurodegenerative Disease Research Center, Arizona State University, Tempe, AZ, 85281, USA.

Qi Wang (Q)

ASU-Banner Neurodegenerative Disease Research Center, Arizona State University, Tempe, AZ, 85281, USA.

Elaine T Lim (ET)

Department of Neurology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
Program in Bioinformatics and Integrative Biology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
NeuroNexus Institute, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.

Yingleong Chan (Y)

Department of Neurology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA. Rigel.Chan@umassmed.edu.
Program in Bioinformatics and Integrative Biology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA. Rigel.Chan@umassmed.edu.
NeuroNexus Institute, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA. Rigel.Chan@umassmed.edu.

Benjamin Readhead (B)

ASU-Banner Neurodegenerative Disease Research Center, Arizona State University, Tempe, AZ, 85281, USA. Ben.Readhead@asu.edu.

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Classifications MeSH

questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Hétéroplasmie › Modeling of mitochondrial genetic...
questionsmedicales.fr › Cellules › Structures cellulaires › Fractions subcellulaires › Mitochondries › Modeling of mitochondrial genetic...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Polymorphisme génétique › Polymorphisme de nucléotide simple › Modeling of mitochondrial genetic...
questionsmedicales.fr › Phénomènes génétiques › Phénotype › Modeling of mitochondrial genetic...
questionsmedicales.fr › Sciences de l'information › Sources d'information › Services d'information › Documentation › Données de séquences moléculaires › Séquence nucléotidique › Modeling of mitochondrial genetic...
questionsmedicales.fr › Acides nucléiques, nucléotides et nucléosides › Acides nucléiques › ADN › ADN mitochondrial › Modeling of mitochondrial genetic...