Clonally expanded mtDNA point mutations are abundant in individual cells of human tissues

被引:156
作者
Nekhaeva, E
Bodyak, ND
Kraytsberg, Y
McGrath, SB
Van Orsouw, NJ
Pluzhnikov, A
Wei, JY
Vijg, J
Khrapko, K
机构
[1] Harvard Univ, Sch Med, Boston, MA 02115 USA
[2] Beth Israel Deaconess Med Ctr, Boston, MA 02115 USA
[3] Univ Texas, Hlth Sci Ctr, Sam & Ann Bishop Ctr, San Antonio, TX 78245 USA
[4] S Texas Vet Hlth Care Syst, Ctr Geriatr Res Educ & Clin, San Antonio, TX 78245 USA
[5] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA
关键词
somatic mutation; clonal expansion; single cell; aging; cancer;
D O I
10.1073/pnas.072670199
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Using single-cell sequence analysis, we discovered that a high proportion of cells in tissues as diverse as buccal epithelium and heart muscle contain high proportions of clonal mutant mtDNA expanded from single initial mutant mtDNA molecules. We demonstrate that intracellular clonal expansion of somatic point mutations is a common event in normal human tissues. This finding implies efficient homogenization of mitochondrial genomes within individual cells. Significant qualitative differences observed between the spectra of clonally expanded mutations in proliferating epithelial cells and postmitotic cardiomyocytes suggest, however, that either the processes generating these mutations or mechanisms driving them to homoplasmy are likely to be fundamentally different between the two tissues. Furthermore, the ability of somatic mtDNA mutations to expand (required for their phenotypic expression), as well as their apparently high incidence, reinforces the possibility that these mutations may be involved actively in various physiological processes such as aging and degenerative disease. The abundance of clonally expanded point mutations in individual cells of normal tissues also suggests that the recently discovered accumulation of mtDNA mutations in tumors may be explained by processes that are similar or identical to those operating in the normal tissue.
引用
收藏
页码:5521 / 5526
页数:6
相关论文
共 48 条
[1]  
Agresti A., 1992, STAT SCI, V7, P131, DOI DOI 10.1214/SS/1177011454
[2]   Detection of somatic mutations in the mitochondrial DNA control region of colorectal and gastric tumors by heteroduplex and single-strand conformation analysis [J].
Alonso, A ;
Martin, P ;
Albarran, C ;
Aguilera, B ;
Garcia, O ;
Guzman, A ;
Oliva, H ;
Sancho, M .
ELECTROPHORESIS, 1997, 18 (05) :682-685
[3]   SEQUENCE AND ORGANIZATION OF THE HUMAN MITOCHONDRIAL GENOME [J].
ANDERSON, S ;
BANKIER, AT ;
BARRELL, BG ;
DEBRUIJN, MHL ;
COULSON, AR ;
DROUIN, J ;
EPERON, IC ;
NIERLICH, DP ;
ROE, BA ;
SANGER, F ;
SCHREIER, PH ;
SMITH, AJH ;
STADEN, R ;
YOUNG, IG .
NATURE, 1981, 290 (5806) :457-465
[4]   COMPLEMENTATION AND SEGREGATION BEHAVIOR OF DISEASE-CAUSING MITOCHONDRIAL-DNA MUTATIONS IN CELLULAR-MODEL SYSTEMS [J].
ATTARDI, G ;
YONEDA, M ;
CHOMYN, A .
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE, 1995, 1271 (01) :241-248
[5]   Role of mitochondrial DNA mutations in human aging: Implications for the central nervous system and muscle [J].
Brierley, EJ ;
Johnson, MA ;
Lightowlers, RN ;
James, OFW ;
Turnbull, DM .
ANNALS OF NEUROLOGY, 1998, 43 (02) :217-223
[6]   High frequency of homoplasmic mitochondrial DNA mutations in human tumors can be explained without selection [J].
Coller, HA ;
Khrapko, K ;
Bodyak, ND ;
Nekhaeva, E ;
Herrero-Jimenez, P ;
Thilly, WG .
NATURE GENETICS, 2001, 28 (02) :147-150
[7]   A proposed refinement of the mitochondrial free radical theory of aging [J].
deGrey, ADNJ .
BIOESSAYS, 1997, 19 (02) :161-166
[8]   Distinct spectra of somatic mutations accumulated with age in mouse heart and small intestine [J].
Dollé, MET ;
Snyder, WK ;
Gossen, JA ;
Lohman, PHM ;
Vijg, J .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2000, 97 (15) :8403-8408
[9]   Mutational fingerprints of aging [J].
Dollé, MET ;
Snyder, WK ;
Dunson, DB ;
Vijg, J .
NUCLEIC ACIDS RESEARCH, 2002, 30 (02) :545-549
[10]   DIFFERENT CELLULAR BACKGROUNDS CONFER A MARKED ADVANTAGE TO EITHER MUTANT OR WILD-TYPE MITOCHONDRIAL GENOMES [J].
DUNBAR, DR ;
MOONIE, PA ;
JACOBS, HT ;
HOLT, IJ .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1995, 92 (14) :6562-6566