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.

Association of UCP2 −866 G/A polymorphism with chronic inflammatory diseases

“…The ROS production in macrophages from UCP2-deficient mice is B80% higher than in wild-type mice, and the deficiency of the UCP2 gene increases the susceptibility to EAE, a mouse model for MS. 9,11 In addition, mouse mtDNA variations affecting mitochondrial ROS production are associated with susceptibility to autoimmune diabetes and EAE. 14,15 This indicates that mitochondrial ROS production could be a regulator of susceptibility to chronic inflammatory diseases. Hence, a possible mechanism underlying the association of the mitochondrial gene with chronic inflammatory diseases could be that gene variations reduce/increase the production of mitochondrial ROS and consequently decrease/increase the susceptibility to chronic inflammatory diseases.…”

Polymorphism in Murine mtATP8 Gene Correlates with Decreased Reactive Oxygen Species in Aging Hematopoietic Cells

“…Conplastic mouse strains were implemented as described before (24). In brief, due to the maternal inheritance of mtDNA, female animals of the mitochondrial donor strain AKR/J and FVB/NJ, respectively, were crossed with males with the corresponding genomic background (C57BL/6NTac Isolation of BMC.…”

“…It would, thus, impact the whole respiratory chain, influencing ROS and ATP production. Recently, the impact of the nt7778 G/T polymorphism on cell function has been studied in different tissues (19)(20)(21)(22), as well as its effects on anxiety and stress reactivity (23,24).…”

Understanding Mitochondrial Polymorphisms in Cancer

“…1B and legend for details), thus essentially establishing new inbred strains similar to MNX mice, although the time to establish conplastic strains can take 4 to 5 years (36). Yu and colleagues demonstrated how a panel of conplastic strains carrying different mtDNA mutations can be generated and used to study disease (36). They sequenced the mtDNA of 27 inbred strains and compared their results with published mtDNA sequences of 29 inbred mouse strains.…”

“…Conplastic strains are mice that have been bred via a series of backcrosses to have their nuclear genome from one inbred strain and their mtDNA from a different inbred strain (see Fig. 1B and legend for details), thus essentially establishing new inbred strains similar to MNX mice, although the time to establish conplastic strains can take 4 to 5 years (36). Yu and colleagues demonstrated how a panel of conplastic strains carrying different mtDNA mutations can be generated and used to study disease (36).…”