Document Detail


Persistent heteroplasmy of a mutation in the human mtDNA control region: hypermutation as an apparent consequence of simple-repeat expansion/contraction.
MedLine Citation:
PMID:  10762545     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
In the genealogical and phylogenetic analyses that are reported here, we obtained evidence for an unusual pattern of mutation/reversion in the human mitochondrial genome. The cumulative results indicate that, when there is a T-->C polymorphism at nt 16189 and a C-->T substitution at nt 16192, there is an extremely high rate of reversion (hypermutation) at the latter site. The apparent reversion rate is sufficiently high that there is persistent heteroplasmy at nt 16192 in maternal lineages and at the phylogenetic level, a situation that is similar to that observed for the rapid expansion/contraction of simple repeats within the control region. This is the first specific instance in which the mutation frequency at one site in the D-loop is markedly influenced by the local sequence "context." The 16189 T-->C polymorphism lengthens a (C:G)n simple repeat, which then undergoes expansion and contraction, probably through replication slippage. This proclivity toward expansion/contraction is more pronounced when there is a C residue, rather than a T, at nt 16192. The high T-->C reversion frequency at nt 16192 apparently is the result of polymerase misincorporation or slippage during replication, the same mechanism that also causes the expansion/contraction of this simple-repeat sequence. In addition to the first analysis of this mitochondrial hypermutation process, these results also yield mechanistic insights into the expansion/contraction of simple-repeat sequences in mtDNA.
Authors:
N Howell; C B Smejkal
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2000-04-10
Journal Detail:
Title:  American journal of human genetics     Volume:  66     ISSN:  0002-9297     ISO Abbreviation:  Am. J. Hum. Genet.     Publication Date:  2000 May 
Date Detail:
Created Date:  2000-06-28     Completed Date:  2000-06-28     Revised Date:  2009-11-18    
Medline Journal Info:
Nlm Unique ID:  0370475     Medline TA:  Am J Hum Genet     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  1589-98     Citation Subset:  IM    
Affiliation:
Biology Division 0656, Department of Radiation Oncology, The University of Texas Medical Branch, Galveston, TX 77555, USA. nhowell@utmb.edu.
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MeSH Terms
Descriptor/Qualifier:
Base Sequence
Cells, Cultured
Cloning, Molecular
Cytoplasm / genetics*
DNA Replication / genetics
DNA, Mitochondrial / genetics*
Female
Gene Frequency / genetics
Haplotypes / genetics
Humans
Kinetics
Male
Models, Genetic
Mutagenesis / genetics
Mutation / genetics*
Optic Atrophies, Hereditary / blood,  genetics,  pathology
Pedigree
Phylogeny
Polymorphism, Genetic / genetics
Regulatory Sequences, Nucleic Acid / genetics*
Trinucleotide Repeat Expansion / genetics*
Chemical
Reg. No./Substance:
0/DNA, Mitochondrial
Comments/Corrections

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