role of direct repeat and stem-loop motifs in mtdna deletions cause or coincidence的角色直接重复和茎环结构图案mtdna删除原因或巧合.pdfVIP

Role of Direct Repeat and Stem-Loop Motifs in mtDNA Deletions: Cause or Coincidence? 1,2 3 3 1 Lakshmi Narayanan Lakshmanan , Jan Gruber , Barry Halliwell , Rudiyanto Gunawan * 1 Institute for Chemical and Bioengineering, ETH Zurich, Zurich, Switzerland, 2 Department of Chemical and Biomolecular Engineering, National University of Singapore, Singapore, Singapore, 3 Department of Biochemistry, Neurobiology and Ageing Program, Centre for Life Sciences (CeLS), National University of Singapore, Singapore, Singapore Abstract 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,1024) and rhesus monkey (p = 0.0034), but not in mouse (p = 0.0719) and rat (p = 0.0437), indica