Mitochondrial Genetics: Impact on Health
Extensive pathogenicity of mitochondrial heteroplasmy in healthy human individuals
Kaixiong Ye et al. PNAS, July 7, 2014
Kaixiong Ye et al. PNAS, July 7, 2014
Almost all of us have genetic defects hidden in our cellular furnaces,
Internet Medicine blog post, Jul 17
What is mitochondrial DNA?
From the NIH Genetics Home Reference
mtDNA and mitochondrial diseases- Did you know that you have a second genome?
By: Heidi Chial, et al. Nature Education (2008)
Ten years on: Genetic screening for mitochondrial disease in Ireland
O'Brien M, et al. Clin Neuropathol 2014 Jul-2014 Aug;33(4):279-83
O'Brien M, et al. Clin Neuropathol 2014 Jul-2014 Aug;33(4):279-83
Extensive pathogenicity of mitochondrial heteroplasmy in healthy human individuals
- Kaixiong Yea,1,
- Jian Lua,b,
- Fei Mac,
- Alon Keinand, and
- Zhenglong Gua,1
- Edited* by Wen-Hsiung Li, University of Chicago, Chicago, IL, and approved June 10, 2014 (received for review February 25, 2014)
- Abstract
- Authors & Info
- SI
- Metrics
- Related Content
- PDF + SI
Significance
There are hundreds to thousands of copies of mitochondrial DNA (mtDNA) in each human cell in contrast to only two copies of nuclear DNA. High-frequency pathogenic mtDNA mutations have been found in patients with classic mitochondrial diseases, premature aging, cancers, and neurodegenerative diseases. In this study we investigated the distribution of heteroplasmic mutations, their pathogenic potential, and their underlying evolutionary forces using genome sequence data from the 1000 Genomes Project. Our results demonstrated the prevalence of low-frequency high-pathogenic-potential mtDNA mutations in healthy human individuals. These deleterious mtDNA mutations, when reaching high frequency, could provide a likely source of mitochondrial dysfunction. Managing the expansion of deleterious mtDNA mutations could be a promising means of preventing disease progression.
Abstract
A majority of mitochondrial DNA (mtDNA) mutations reported to be implicated in diseases are heteroplasmic, a status with coexisting mtDNA variants in a single cell. Quantifying the prevalence of mitochondrial heteroplasmy and its pathogenic effect in healthy individuals could further our understanding of its possible roles in various diseases. A total of 1,085 human individuals from 14 global populations have been sequenced by the 1000 Genomes Project to a mean coverage of ∼2,000× on mtDNA. Using a combination of stringent thresholds and a maximum-likelihood method to define heteroplasmy, we demonstrated that ∼90% of the individuals carry at least one heteroplasmy. At least 20% of individuals harbor heteroplasmies reported to be implicated in disease. Mitochondrial heteroplasmy tend to show high pathogenicity, and is significantly overrepresented in disease-associated loci. Consistent with their deleterious effect, heteroplasmies with derived allele frequency larger than 60% within an individual show a significant reduction in pathogenicity, indicating the action of purifying selection. Purifying selection on heteroplasmies can also be inferred from nonsynonymous and synonymous heteroplasmy comparison and the unfolded site frequency spectra for different functional sites in mtDNA. Nevertheless, in comparison with population polymorphic mtDNA mutations, the purifying selection is much less efficient in removing heteroplasmic mutations. The prevalence of mitochondrial heteroplasmy with high pathogenic potential in healthy individuals, along with the possibility of these mutations drifting to high frequency inside a subpopulation of cells across lifespan, emphasizes the importance of managing mitochondrial heteroplasmy to prevent disease progression.
Footnotes
- 1To whom correspondence may be addressed. Email: zg27@cornell.edu or ky279@cornell.edu.
- Author contributions: K.Y., A.K., and Z.G. designed research; K.Y., J.L., and Z.G. performed research; K.Y. contributed new reagents/analytic tools; K.Y. and F.M. analyzed data; and K.Y., J.L., F.M., A.K., and Z.G. wrote the paper.
- The authors declare no conflict of interest.
- *This Direct Submission article had a prearranged editor.
- This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1403521111/-/DCSupplemental.
No hay comentarios:
Publicar un comentario