PMID- 22529999
OWN - NLM
STAT- MEDLINE
DCOM- 20121119
LR  - 20211021
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 7
IP  - 4
DP  - 2012
TI  - Role of direct repeat and stem-loop motifs in mtDNA deletions: cause or 
      coincidence?
PG  - e35271
LID - 10.1371/journal.pone.0035271 [doi]
LID - e35271
AB  - Deletion mutations within mitochondrial DNA (mtDNA) have been implicated in 
      degenerative and aging related conditions, such as sarcopenia and 
      neuro-degeneration. While the precise molecular mechanism of deletion formation 
      in mtDNA is still not completely understood, genome motifs such as direct repeat 
      (DR) and stem-loop (SL) have been observed in the neighborhood of deletion 
      breakpoints and thus have been postulated to take part in mutagenesis. In this 
      study, we have analyzed the mitochondrial genomes from four different mammals: 
      human, rhesus monkey, mouse and rat, and compared them to randomly generated 
      sequences to further elucidate the role of direct repeat and stem-loop motifs in 
      aging associated mtDNA deletions. Our analysis revealed that in the four species, 
      DR and SL structures are abundant and that their distributions in mtDNA are not 
      statistically different from randomized sequences. However, the average distance 
      between the reported age associated mtDNA breakpoints and their respective 
      nearest DR motifs is significantly shorter than what is expected of random chance 
      in human (p<10(-4)) and rhesus monkey (p = 0.0034), but not in mouse (p = 0.0719) 
      and rat (p = 0.0437), indicating the existence of species specific difference in 
      the relationship between DR motifs and deletion breakpoints. In addition, the 
      frequencies of large DRs (>10 bp) tend to decrease with increasing lifespan among 
      the four mammals studied here, further suggesting an evolutionary selection 
      against stable mtDNA misalignments associated with long DRs in long-living 
      animals. In contrast to the results on DR, the probability of finding SL motifs 
      near a deletion breakpoint does not differ from random in any of the four mtDNA 
      sequences considered. Taken together, the findings in this study give support for 
      the importance of stable mtDNA misalignments, aided by long DRs, as a major 
      mechanism of deletion formation in long-living, but not in short-living mammals.
FAU - Lakshmanan, Lakshmi Narayanan
AU  - Lakshmanan LN
AD  - Institute for Chemical and Bioengineering, ETH Zurich, Zurich, Switzerland.
FAU - Gruber, Jan
AU  - Gruber J
FAU - Halliwell, Barry
AU  - Halliwell B
FAU - Gunawan, Rudiyanto
AU  - Gunawan R
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120418
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (DNA, Mitochondrial)
SB  - IM
MH  - Age Factors
MH  - Animals
MH  - Cellular Senescence/genetics
MH  - DNA, Mitochondrial/*chemistry
MH  - Databases, Nucleic Acid
MH  - Gene Order
MH  - Genome, Mitochondrial
MH  - Genomic Instability
MH  - Humans
MH  - Inverted Repeat Sequences
MH  - Macaca mulatta/genetics
MH  - Mice
MH  - Nucleotide Motifs
MH  - Rats
MH  - *Repetitive Sequences, Nucleic Acid
MH  - *Sequence Deletion
PMC - PMC3329436
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2012/04/25 06:00
MHDA- 2012/12/10 06:00
PMCR- 2012/04/18
CRDT- 2012/04/25 06:00
PHST- 2011/09/07 00:00 [received]
PHST- 2012/03/14 00:00 [accepted]
PHST- 2012/04/25 06:00 [entrez]
PHST- 2012/04/25 06:00 [pubmed]
PHST- 2012/12/10 06:00 [medline]
PHST- 2012/04/18 00:00 [pmc-release]
AID - PONE-D-11-17427 [pii]
AID - 10.1371/journal.pone.0035271 [doi]
PST - ppublish
SO  - PLoS One. 2012;7(4):e35271. doi: 10.1371/journal.pone.0035271. Epub 2012 Apr 18.