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Dissecting the effects of mtDNA variations on complex traits using mouse conplastic strains
Abstract
Previous reports have demonstrated that the mtDNA of mouse common inbred strains (CIS) originated from a single female ancestor and that mtDNA mutations occurred during CIS establishment. This situation provides a unique opportunity to investigate the impact of individual mtDNA variations on complex traits in mammals. In this study, we compiled the complete mtDNA sequences of 52 mouse CIS. Phylogenetic analysis demonstrated that 50 of the 52 CIS descended from a single female Mus musculus domesticus mouse, and mtDNA mutations have accumulated in 26 of the CIS. We then generated conplastic strains on the C57BL/6J background for 12 mtDNA variants with one to three functional mtDNA mutations. We also generated conplastic strains for mtDNA variants of the four M. musculus subspecies, each of which contains hundreds of mtDNA variations. In total, a panel of conplastic strains was generated for 16 mtDNA variants. Phenotypic analysis of the conplastic strains demonstrated that mtDNA variations affect susceptibility to experimental autoimmune encephalomyelitis and anxiety-related behavior, which confirms that mtDNA variations affect complex traits. Thus, we have developed a unique genetic resource that will facilitate exploration of the biochemical and physiological roles of mitochondria in complex traits.
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The C57/BL6(mtFVB) mouse model was created by backcrossing the FVB model onto the C57/BL6 background.
“the model has been backcrossed onto the C57/BL6 background [88,89], resulting in the C57/BL6(mtFVB) mouse model.”
From Codon optimization is an essential parameter for the efficient allotopic expression of mtDNA genes (2020) · cites this paper as [88]
The conplastic C57BL/6J(mtFVB) model was developed by crossing male C57BL/6J(mtC57BL/6J) mice onto female FVB/NJmtFVB/NJ mice to produce a mouse with a C57BL/6J nuclear genome and an FVB/NJ mitochondrial genome.
“As mitochondria are maternally inherited, the conplastic model was developed by crossing male C57BL/6J(mtC57BL/6J) mice onto female FVB/NJmtFVB/NJ mice to produce the C57BL/6J(mtFVB) mouse that contains a C57BL/6J nuclear genome and an FVB/NJ mitochondrial genome.31”
From Exogenous expression of ATP8, a mitochondrial encoded protein, from the nucleus in vivo (2024) · cites this paper as [31]
The conplastic C57BL/6J(mtFVB) strain contains the mitochondrial FVB/NJ polymorphism with a C57BL/6J nuclear genome, free from potential modifiers.
“We utilized a conplastic C57BL/6JmtFVB/NJ/IbraJ (JAX strain no. 010810; from here on C57BL/6J(mtFVB)) strain which contains the mitochondrial FVB/NJ polymorphism with a C57BL/6J nuclear genome, free from potential modifiers that allows for the assessment of the impact of the mitochondrial mutation in the absence of any confounding variation of the FVB/NJmtFVB/NJ nuclear genome.31”
From Exogenous expression of ATP8, a mitochondrial encoded protein, from the nucleus in vivo (2024) · cites this paper as [31]
Previously, behavior studies indicated an elevated anxiety phenotype in C57BL/6J(mtFVB) mice.
“Previously, behavior studies comparing the conplastic C57BL/6J(mtFVB) mice with the wild-type mitochondrial variant indicated an elevated anxiety phenotype in the C57BL/6J(mtFVB) mice.31”
From Exogenous expression of ATP8, a mitochondrial encoded protein, from the nucleus in vivo (2024) · cites this paper as [31]
We utilized the conplastic C57BL/6J(mtFVB) mouse strain with a naturally occurring ATP8 missense mutation that exhibits mild phenotypes not significantly different from C57BL/6J(mtC57BL/6J) animals.
“In our study, we utilized the conplastic C57BL/6J(mtFVB) mouse strain with a naturally occurring ATP8 missense mutation that exhibits mild phenotypes not significantly different from C57BL/6J(mtC57BL/6J) animals.31”
From Exogenous expression of ATP8, a mitochondrial encoded protein, from the nucleus in vivo (2024) · cites this paper as [31]
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Codon optimization is an essential parameter for the efficient allotopic expression of mtDNA genes
Lewis, C. J., Dixit, B., Batiuk, E., Hall, C. J., O'Connor, M. S., & Boominathan, A. (2020) · Redox Biology · doi:10.1016/j.redox.2020.101429 · Cited by 20
Exogenous expression of ATP8, a mitochondrial encoded protein, from the nucleus in vivo
Begelman, D. V., Dixit, B., Truong, C., King, C. D., Watson, M. A., Schilling, B., Brand, M. D., & Boominathan, A. (2024) · Molecular Therapy - Methods & Clinical Development · doi:10.1016/j.omtm.2024.101372 · Cited by 5
Metadata
- Authors
- Yu, X., Gimsa, U., Wester-Rosenlöf, L., Kanitz, E., Otten, W., Kunz, M., & Ibrahim, S. M.
- Venue
- Genome Research
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2008-11-26
- Volume
- 19
- Issue
- 1
- Pages
- 159-165
- ISSN
- 1088-9051
- Cited by
- 120
- References
- 1
- Language
- en
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