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Genetics. 2016 Mar;202(3):931-44. doi: 10.1534/genetics.115.181321. Epub 2016 Jan 27.

Segregation of Naturally Occurring Mitochondrial DNA Variants in a Mini-Pig Model.

Author information

1
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.
2
Victorian Bioinformatics Consortium, Monash University, Clayton, Victoria 3168, Australia Life Sciences Computation Centre, Victorian Life Sciences Computation Initiative, Parkville, Victoria, Australia.
3
US Department of Agriculture, Agricultural Research Service, US Meat Animal Research Center, Clay Center, NE.
4
Department of Obstetrics and Gynaecology, Faculty of Medical and Health Sciences, University of Auckland, 1023, New Zealand.
5
Centre for Eye Research Australia, Ophthalmology, University of Melbourne Department of Surgery, Royal Victorian Eye and Ear Hospital, East Melbourne, Victoria 3002, Australia.
6
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.

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.

KEYWORDS:

embryo; generations; mitochondrial DNA; segregation; variants

PMID:
26819245
PMCID:
PMC4788130
[Available on 2017-03-01]
DOI:
10.1534/genetics.115.181321
[Indexed for MEDLINE]
Free PMC Article

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