Abstract
The role of the nuclear genome in maintaining the stability of the mitochondrial genome (mtDNA) is incompletely known. mtDNA sequence variants can exist in a state of heteroplasmy, which denotes the coexistence of organellar genomes with different sequences. Heteroplasmic variants that impair mitochondrial capacity cause disease, and the state of heteroplasmy itself is deleterious. However, mitochondrial heteroplasmy may provide an intermediate state in the emergence of novel mitochondrial haplogroups. We used genome-wide genotyping data from 982,072 European ancestry individuals to evaluate variation in mitochondrial heteroplasmy and to identify the regions of the nuclear genome that affect it. Age, sex, and mitochondrial haplogroup were associated with the extent of heteroplasmy. GWAS identified 20 loci for heteroplasmy that exceeded genome-wide significance. This included a region overlapping mitochondrial transcription factor A (TFAM), which has multiple roles in mtDNA packaging, replication, and transcription. These results show that mitochondrial heteroplasmy has a heritable nuclear component.
Highlights
Human mitochondrial DNA is the maternally inherited genome that is dedicated to the generation of cellular energy through oxidative phosphorylation [1]. mtDNA is small, expressing only 13 protein-coding genes, along with the ribosomal and transfer RNAs required for their translation
MtDNA is densely genotyped with 3287 single-nucleotide polymorphisms (SNPs) assayed
The use of arrays has previously been validated for MtHz by comparison to allele-specific quantitative polymerase chain reaction but not with the exact array used in this study, and there may be noise present in the estimates of MtHz [33]
Summary
Human mitochondrial DNA (mtDNA) is the maternally inherited genome that is dedicated to the generation of cellular energy through oxidative phosphorylation [1]. mtDNA is small, expressing only 13 protein-coding genes, along with the ribosomal and transfer RNAs required for their translation. Human mitochondrial DNA (mtDNA) is the maternally inherited genome that is dedicated to the generation of cellular energy through oxidative phosphorylation [1]. Sequence changes in mtDNA and their interaction with the nuclear genome may have outsized impact upon health and disease. Control of the mtDNA copy number per cell is variable between different cell types, with some human cells containing no mtDNA and others containing thousands of copies. Mutation of mtDNA leads to a state of mitochondrial heteroplasmy (MtHz) where mtDNA with distinct sequences coexist. It has been recognized that MtHz is widely present in humans [2]. MtHz can be transmitted through the maternal germ line so that mother and offspring are heteroplasmic at the same position(s) [3]. Somatic MtHz occurs in the context of aging and tissue damage [4, 5]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
