Mitochondrial DNA Sequence Variation in Human Evolution and Disease

Germ-line and somatic mtDNA mutations are hypothesized to act together to shape our history and our health. Germ-line mtDNA mutations, both ancient and recent, have been associated with a variety of degenerative diseases. Mildly to moderately deleterious germ-line mutations, like neutral polymorphis...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 1994-09, Vol.91 (19), p.8739-8746
Main Author: Wallace, Douglas C.
Format: Article
Language:English
Subjects:
Alzheimers disease
Amino Acid Sequence
Animals
Biological Evolution
Chromosome Mapping
Consensus Sequence
Deoxyribonucleic acid
Disease
DNA
DNA, Mitochondrial - genetics
Dystonia
Enzymes
Evolution
Genes
Genetic diseases
Genetic mutation
Haplotypes
Humans
man
mitochondria
Mitochondria - physiology
Mitochondrial DNA
Mitochondrial Myopathies - genetics
Molecular Sequence Data
Nervous system diseases
Parkinson disease
Review
reviews
Sequence Alignment
Sequence Homology, Amino Acid
Symptoms
Citations: Items that cite this one
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Summary:Germ-line and somatic mtDNA mutations are hypothesized to act together to shape our history and our health. Germ-line mtDNA mutations, both ancient and recent, have been associated with a variety of degenerative diseases. Mildly to moderately deleterious germ-line mutations, like neutral polymorphisms, have become established in the distant past through genetic drift but now may predispose certain individuals to late-onset degenerative diseases. As an example, a homoplasmic, Caucasian, tRNAGlnmutation at nucleotide pair (np) 4336 has been observed in 5% of Alzheimer disease and Parkinson disease patients and may contribute to the multifactorial etiology of these diseases. Moderately to severely deleterious germ-line mutations, on the other hand, appear repeatedly but are eliminated by selection. Hence, all extant mutations of this class are recent and associated with more devastating diseases of young adults and children. Representative of these mutations is a heteroplasmic mutation in MTND6 at np 14459 whose clinical presentations range from adult-onset blindness to pediatric dystonia and basal ganglial degeneration. To the inherited mutations are added somatic mtDNA mutations which accumulate in random arrays within stable tissues. These mutations provide a molecular clock that measures our age and may cause a progressive decline in tissue energy output that could precipitate the onset of degenerative diseases in individuals harboring inherited deleterious mutations.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.91.19.8739