Abstract
Heteroplasmy—the presence of more than one mitochondrial DNA (mtDNA) sequence type in a cell, tissue, or individual—impacts human mitochondrial disease and numerous aging-related syndromes. Understanding the trans-generational dynamics of mtDNA is critical to understanding the underlying mechanisms of mitochondrial disease and evolution. We investigated mtDNA mutation and heteroplasmy using a set of wild-type (N2 strain) and mitochondrial electron transport chain (ETC) mutant (gas-1) mutant Caenorhabditis elegans mutation-accumulation (MA) lines. The N2 MA lines, derived from a previous experiment, were bottlenecked for 250 generations. The gas-1 MA lines were created for this study, and bottlenecked in the laboratory for up to 50 generations. We applied Illumina-MiSeq DNA sequencing to L1 larvae from five gas-1 MA lines and five N2 MA lines to detect and characterize mtDNA mutation and heteroplasmic inheritance patterns evolving under extreme drift. mtDNA copy number increased in both sets of MA lines: three-fold on average among the gas-1 MA lines and five-fold on average among N2 MA lines. Eight heteroplasmic single base substitution polymorphisms were detected in the gas-1 MA lines; only one was observed in the N2 MA lines. Heteroplasmy frequencies ranged broadly in the gas-1 MA lines, from as low as 2.3% to complete fixation (homoplasmy). An initially low-frequency (<5%) heteroplasmy discovered in the gas-1 progenitor was observed to fix in one gas-1 MA line, achieve higher frequency (37.4%) in another, and be lost in the other three lines. A similar low-frequency heteroplasmy was detected in the N2 progenitor, but was lost in all five N2 MA lines. We identified three insertion-deletion (indel) heteroplasmies in gas-1 MA lines and six indel variants in the N2 MA lines, most occurring at homopolymeric nucleotide runs. The observed bias toward accumulation of single nucleotide polymorphisms in gas-1 MA lines is consistent with the idea that impaired mitochondrial activity renders mtDNA more vulnerable to this type of mutation. The consistent increases in mtDNA copy number implies that extreme genetic drift provides a permissive environment for elevated organelle genome copy number in C. elegans reference and gas-1 strains. This study broadens our understanding of the heteroplasmic mitochondrial mutation process in a multicellular model organism.
Highlights
Most lifeforms observable with the naked eye are composed of eukaryotic cells, most all of which harbor multiple mitochondria (Lane, 2011)
Coverage patterns across sites were consistent among lines, indicating that mitochondrial DNA (mtDNA) copy number had increased at all sites rather than at isolated sections of the mitochondrial genome
This study provides new insights into the heteroplasmic paths of mutation in an animal mitochondrial genome
Summary
Most lifeforms observable with the naked eye are composed of eukaryotic cells, most all of which harbor multiple mitochondria (Lane, 2011). These organelles are fundamental to eukaryotic life. Each mitochondrion contains multiple genome copies (Wallace, 2005), the regulation of which is essential for maintaining proper mitochondrial activity (Lynch et al, 2011). Changes in mtDNA copy number and associated organelle dysfunction may induce mitochondrial retrograde signaling (mitochondria-to-nucleus) as a cellular adaptive response (Guha and Avadhani, 2013). As fluctuations in mtDNA copy number may signify alterations in cellular activity, recent studies in humans and model organisms support the use of mtDNA copy number as a biomarker for aging-related diseases and metabolic syndromes (Lynch et al, 2011; Podlesniy et al, 2013)
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