title: Segregation of Naturally Occurring Mitochondrial DNA Variants in a Mini-Pig Model.
abstract: The maternally inherited mitochondrial genome (mtDNA) is present in multimeric form within cells and harbors sequence variants (heteroplasmy). While a single mtDNA variant at high load can cause disease, naturally occurring variants likely persist at low levels across generations of healthy populations. To determine how naturally occurring variants are segregated and transmitted, we generated a mini-pig model, which originates from the same maternal ancestor. Following next-generation sequencing, we identified a series of low-level mtDNA variants in blood samples from the female founder and her daughters. Four variants, ranging from 3% to 20%, were selected for validation by high-resolution melting analysis in 12 tissues from 31 animals across three generations. All four variants were maintained in the offspring, but variant load fluctuated significantly across the generations in several tissues, with sex-specific differences in heart and liver. Moreover, variant load was persistently reduced in high-respiratory organs (heart, brain, diaphragm, and muscle), which correlated significantly with higher mtDNA copy number. However, oocytes showed increased heterogeneity in variant load, which correlated with increased mtDNA copy number during in vitro maturation. Altogether, these outcomes show that naturally occurring mtDNA variants segregate and are maintained in a tissue-specific manner across generations. This segregation likely involves the maintenance of selective mtDNA variants during organogenesis, which can be differentially regulated in oocytes and preimplantation embryos during maturation.
authors.affiliation: Centre for Genetic Diseases, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia Department of Molecular and Translational Science, Centre for Genetic Diseases, Clayton, Victoria 3168, Australia.
authors.forename: Gael
authors.initials: G
authors.lastname: Cagnone
authors.affiliation: Centre for Genetic Diseases, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia Department of Molecular and Translational Science, Centre for Genetic Diseases, Clayton, Victoria 3168, Australia.
authors.forename: Te-Sha
authors.initials: TS
authors.lastname: Tsai
authors.affiliation: Centre for Genetic Diseases, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia Department of Molecular and Translational Science, Centre for Genetic Diseases, Clayton, Victoria 3168, Australia.
authors.forename: Kanokwan
authors.initials: K
authors.lastname: Srirattana
authors.affiliation: Victorian Bioinformatics Consortium, Monash University, Clayton, Victoria 3168, Australia Life Sciences Computation Centre, Victorian Life Sciences Computation Initiative, Parkville, Victoria, Australia.
authors.forename: Fernando
authors.initials: F
authors.lastname: Rossello
authors.affiliation: Victorian Bioinformatics Consortium, Monash University, Clayton, Victoria 3168, Australia Life Sciences Computation Centre, Victorian Life Sciences Computation Initiative, Parkville, Victoria, Australia.
authors.forename: David R
authors.initials: DR
authors.lastname: Powell
authors.affiliation: US Department of Agriculture, Agricultural Research Service, US Meat Animal Research Center, Clay Center, NE.
authors.forename: Gary
authors.initials: G
authors.lastname: Rohrer
authors.affiliation: Department of Obstetrics and Gynaecology, Faculty of Medical and Health Sciences, University of Auckland, 1023, New Zealand.
authors.forename: Lynsey
authors.initials: L
authors.lastname: Cree
authors.affiliation: Centre for Eye Research Australia, Ophthalmology, University of Melbourne Department of Surgery, Royal Victorian Eye and Ear Hospital, East Melbourne, Victoria 3002, Australia.
authors.forename: Ian A
authors.initials: IA
authors.lastname: Trounce
authors.affiliation: Centre for Genetic Diseases, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia Department of Molecular and Translational Science, Centre for Genetic Diseases, Clayton, Victoria 3168, Australia justin.stjohn@hudson.org.au.
authors.forename: Justin C
authors.initials: JC
authors.lastname: St John
mesh_terms: D000818:Animals; D056915:DNA Copy Number Variations; D004272:DNA, Mitochondrial / Q000235:genetics*; D005260:Female; D018703:Founder Effect; D014644:Genetic Variation; D054629:Genome, Mitochondrial; D059014:High-Throughput Nucleotide Sequencing; D040582:Inheritance Patterns; D008297:Male; D009865:Oocytes / Q000166:cytology; D009928:Organ Specificity / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA; D012737:Sex Factors; D013552:Swine; D013556:Swine, Miniature / Q000235:genetics
chemical_list: D004272:DNA, Mitochondrial
keywords: embryo; generations; mitochondrial DNA; segregation; variants
references.citation: Nat Genet. 2005 Aug;37(8):873-7
references.pmid: 16025113
references.citation: Acta Neuropathol Commun. 2014;2:1
references.pmid: 24383468
references.citation: Hum Mol Genet. 2013 Jan 15;22(2):384-90
references.pmid: 23077218
references.citation: Genetics. 2000 Jun;155(2):777-83
references.pmid: 10835398
references.citation: Cold Spring Harb Perspect Biol. 2013 Nov;5(11):a021220
references.pmid: 24186072
references.citation: Hum Reprod Update. 2010 Sep-Oct;16(5):488-509
references.pmid: 20231166
references.citation: Nature. 2010 Mar 25;464(7288):610-4
references.pmid: 20200521
references.citation: Genetics. 2001 Sep;159(1):173-87
references.pmid: 11560895
references.citation: Nat Genet. 2006 Aug;38(8):904-9
references.pmid: 16862161
references.citation: N Engl J Med. 2006 Apr 6;354(14):1507-14
references.pmid: 16598047
references.citation: J Pharmacol Toxicol Methods. 2010 Nov-Dec;62(3):196-220
references.pmid: 20685310
references.citation: Science. 2004 Jan 9;303(5655):223-6
references.pmid: 14716012
references.citation: Nucleic Acids Res. 2008 Oct;36(18):5872-81
references.pmid: 18796524
references.citation: PLoS Genet. 2013 Nov;9(11):e1003929
references.pmid: 24244193
references.citation: Nat Genet. 2008 Dec;40(12):1484-8
references.pmid: 19029901
references.citation: Cell. 2010 Apr 16;141(2):280-9
references.pmid: 20403324
references.citation: Proc Natl Acad Sci U S A. 2013 Feb 5;110(6):E458-67
references.pmid: 23341591
references.citation: Hum Mol Genet. 2013 May 1;22(9):1867-72
references.pmid: 23390135
references.citation: PLoS One. 2013;8(10):e74636
references.pmid: 24098342
references.citation: Am J Hum Genet. 2010 Aug 13;87(2):237-49
references.pmid: 20696290
references.citation: Mol Reprod Dev. 2012 May;79(5):311-20
references.pmid: 22431437
references.citation: Biochim Biophys Acta. 2013 Aug;1833(8):1979-84
references.pmid: 23524114
references.citation: Nature. 2013 Sep 19;501(7467):412-5
references.pmid: 23965628
references.citation: Nat Genet. 1997 May;16(1):93-5
references.pmid: 9140402
references.citation: Hum Reprod Update. 2006 Jul-Aug;12(4):401-15
references.pmid: 16581809
references.citation: Science. 2008 Feb 15;319(5865):958-62
references.pmid: 18276892
references.citation: Proc Natl Acad Sci U S A. 1988 Nov;85(21):8107-10
references.pmid: 2460862
references.citation: Nature. 1983 Nov 24-30;306(5941):400-2
references.pmid: 6646218
references.citation: Trends Cell Biol. 2007 Dec;17(12):586-92
references.pmid: 17981466
references.citation: Hum Reprod Update. 2012 Jul;18(4):341-9
references.pmid: 22456975
references.citation: Bioessays. 2002 Sep;24(9):845-9
references.pmid: 12210521
references.citation: Cell Rep. 2014 Jun 26;7(6):2031-41
references.pmid: 24910436
references.citation: Front Neuroenergetics. 2013 Aug 12;5:7
references.pmid: 23964235
references.citation: Gene Ther. 2010 Feb;17(2):147-9
references.pmid: 20054354
references.citation: Trends Genet. 2000 Nov;16(11):500-5
references.pmid: 11074292
references.citation: Mol Hum Reprod. 2014 Dec;20(12):1238-46
references.pmid: 25232043
references.citation: Diabet Med. 2005 Dec;22(12):1683-9
references.pmid: 16401312
references.citation: PLoS Biol. 2008 Jan;6(1):e10
references.pmid: 18232733
references.citation: Nat Commun. 2014;5:4093
references.pmid: 24912735
references.citation: Genome Biol. 2011;12(6):R59
references.pmid: 21699709
references.citation: Nat Genet. 2003 Feb;33(2):183-6
references.pmid: 12539044
references.citation: Proc Natl Acad Sci U S A. 2014 Oct 28;111(43):15474-9
references.pmid: 25313049
references.citation: PLoS One. 2012;7(4):e35160
references.pmid: 22523573
references.citation: Mol Hum Reprod. 2013 Jul;19(7):444-50
references.pmid: 23468533
references.citation: Science. 2011 May 13;332(6031):845-8
references.pmid: 21566193
references.citation: J Med Genet. 2006 Aug;43(8):671-7
references.pmid: 16490799
references.citation: Biol Reprod. 2012 Feb;86(2):50
references.pmid: 22075474
references.citation: J Endocrinol. 2008 Sep;198(3):635-43
references.pmid: 18603607
references.citation: Genetics. 2006 Apr;172(4):2515-27
references.pmid: 16452133
references.citation: Hum Mutat. 2006 Nov;27(11):1072-81
references.pmid: 16947981
references.citation: Proc Natl Acad Sci U S A. 1995 Jul 3;92(14):6562-6
references.pmid: 7604033
references.citation: Curr Top Dev Biol. 2007;77:113-55
references.pmid: 17222702
references.citation: PLoS Genet. 2014 Oct;10(10):e1004670
references.pmid: 25299061
references.citation: Genetics. 2007 Jul;176(3):1511-26
references.pmid: 17507682
references.citation: Hum Reprod. 2014 Dec;29(12):2719-35
references.pmid: 25269568
references.citation: Cancer Res. 2005 Sep 1;65(17):8028-33
references.pmid: 16140977
references.citation: Nat Genet. 2014 Apr;46(4):389-92
references.pmid: 24614072
references.citation: Proc Natl Acad Sci U S A. 2014 Jul 22;111(29):10654-9
references.pmid: 25002485
references.citation: Curr Opin Cell Biol. 2000 Dec;12(6):725-30
references.pmid: 11063939
references.citation: Brain. 1998 Oct;121 ( Pt 10):1889-94
references.pmid: 9798744
references.citation: Nucleic Acids Res. 2012 Nov 1;40(20):10124-38
references.pmid: 22941637
references.citation: Cell. 2012 Oct 12;151(2):333-43
references.pmid: 23063123
references.citation: Nat Genet. 2008 Feb;40(2):249-54
references.pmid: 18223651
references.citation: Reproduction. 2006 Feb;131(2):233-45
references.pmid: 16452717
references.citation: Nat Genet. 2012 Nov;44(11):1282-5
references.pmid: 23042113
references.citation: Mol Reprod Dev. 2001 Jan;58(1):39-44
references.pmid: 11144218
references.citation: Nat Rev Genet. 2001 May;2(5):342-52
references.pmid: 11331900
references.citation: Biochim Biophys Acta. 2014 Apr;1840(4):1345-54
references.pmid: 24183916
references.citation: Stem Cell Res. 2013 May;10(3):361-70
references.pmid: 23455392
references.citation: Curr Top Dev Biol. 2007;77:87-111
references.pmid: 17222701
references.citation: Genomics. 1993 Jul;17(1):171-84
references.pmid: 8104867
references.citation: Mitochondrion. 2006 Aug;6(4):194-210
references.pmid: 16920408
references.citation: Am J Hum Genet. 1998 Sep;63(3):769-75
references.pmid: 9718339
references.citation: J Mol Evol. 1998 Sep;47(3):302-6
references.pmid: 9732457
references.citation: Proc Natl Acad Sci U S A. 2005 Nov 15;102(46):16765-70
references.pmid: 16275929
references.citation: Hum Reprod. 2007 Dec;22(12):3047-50
references.pmid: 17956925
references.citation: ILAR J. 2004;45(3):303-13
references.pmid: 15229377
references.citation: Hum Mutat. 2008 Feb;29(2):248-57
references.pmid: 17999439
references.citation: Theriogenology. 2005 Nov;64(8):1852-66
references.pmid: 15923030
references.citation: Biol Reprod. 2007 Feb;76(2):327-35
references.pmid: 17035641
references.citation: J Med Genet. 2001 May;38(5):312-7
references.pmid: 11333867
references.citation: PLoS Genet. 2013;9(3):e1003356
references.pmid: 23516375
references.citation: Hum Mol Genet. 2001 Oct 15;10(22):2469-79
references.pmid: 11709534
references.citation: Fertil Steril. 2006 Mar;85(3):584-91
references.pmid: 16500323