Interpreting Sequence-Levenshtein distance for determining error type and frequency between two embedded sequences of equal length

Levenshtein distance is a commonly used edit distance metric, typically applied in language processing, and to a lesser extent, in molecular biology analysis. Biological nucleic acid sequences are often embedded in longer sequences and are subject to insertion and deletion errors that introduce frameshift during sequencing. These frameshift errors are due to string context and should not be counted as true biological errors. Sequence-Levenshtein distance is a modification to Levenshtein distance that is permissive of frameshift error without additional penalty. However, in a biological context Levenshtein distance needs to accommodate both frameshift and weighted errors, which Sequence-Levenshtein distance cannot do. Errors are weighted when they are associated with a numerical cost that corresponds to their frequency of appearance. Here, we describe a modification that allows the use of Levenshtein distance and Sequence-Levenshtein distance to appropriately accommodate penalty-free frameshift between embedded sequences and correctly weight specific error types.Comment: 10 pages, 8 figure

Distinct patterns of mitochondrial genome diversity in bonobos (Pan paniscus) and humans

<p>Abstract</p> <p>Background</p> <p>We have analyzed the complete mitochondrial genomes of 22 <it>Pan paniscus </it>(bonobo, pygmy chimpanzee) individuals to assess the detailed mitochondrial DNA (mtDNA) phylogeny of this close relative of <it>Homo sapiens</it>.</p> <p>Results</p> <p>We identified three major clades among bonobos that separated approximately 540,000 years ago, as suggested by Bayesian analysis. Incidentally, we discovered that the current reference sequence for bonobo likely is a hybrid of the mitochondrial genomes of two distant individuals. When comparing spectra of polymorphic mtDNA sites in bonobos and humans, we observed two major differences: (i) Of all 31 bonobo mtDNA homoplasies, i.e. nucleotide changes that occurred independently on separate branches of the phylogenetic tree, 13 were not homoplasic in humans. This indicates that at least a part of the unstable sites of the mitochondrial genome is species-specific and difficult to be explained on the basis of a mutational hotspot concept. (ii) A comparison of the ratios of non-synonymous to synonymous changes (<it>d</it>_<it>N</it><it>/d</it>_<it>S</it>) among polymorphic positions in bonobos and in 4902 <it>Homo sapiens </it>mitochondrial genomes revealed a remarkable difference in the strength of purifying selection in the mitochondrial genes of the F₀F₁-ATPase complex. While in bonobos this complex showed a similar low value as complexes I and IV, human haplogroups displayed 2.2 to 7.6 times increased <it>d</it>_<it>N</it><it>/d</it>_{<it>S </it>}ratios when compared to bonobos.</p> <p>Conclusions</p> <p>Some variants of mitochondrially encoded subunits of the ATPase complex in humans very likely decrease the efficiency of energy conversion leading to production of extra heat. Thus, we hypothesize that the species-specific release of evolutionary constraints for the mitochondrial genes of the proton-translocating ATPase is a consequence of altered heat homeostasis in modern humans.</p

Clonally expanded mitochondrial DNA deletions within the choroid plexus in multiple sclerosis

OBJECTIVE: Mitochondrial DNA deletions (Δ-mtDNA) are implicated in the pathogenesis of multiple sclerosis (MS), Parkinson’s disease (PD), Alzheimer’s disease (AD) and ageing. Given the diffuse nature of inflammation in MS, aim of this study was to determine whether Δ-mtDNA caused respiratory deficient cells in excess of age within choroid plexus (CP) and ongoing mutagenesis or clonal expansion accounted for the respiratory deficiency in MS. METHODS: Respiratory chain complex IV and complex II activity was determined sequentially using histochemistry. Δ-mtDNA were characterized using real time PCR, long range PCR, sequencing and single molecule PCR. Sources of reactive oxygen and nitrogen species (RONS) were explored using immunohistochemistry. RESULTS: Respiratory deficient cells (lacking complex IV and with intact complex II activity) within CP epithelium were in excess of age in MS, PD and AD. Subunit-I of complex IV was lacking to a greater extent in MS than controls. Percentage of respiratory deficient cells harboring >50% heteroplasmy level of Δ-mtDNA was significantly greater in MS than PD, AD and controls. Long range PCR and sequencing confirmed Δ-mtDNA. Single molecule PCR identified clonally expanded Δ-mtDNA in MS, despite an increase in sources of RONS. INTERPRETATION: Our findings establish clonal expansion of Δ-mtDNA causing respiratory deficiency in MS and the extraparenchymal intracranial location indicated the potential to involve multiple cell types. Understanding factors that influence clonal expansion of Δ-mtDNA, a molecular link between inflammation and delayed cellular energy failure, may identify potential therapeutic targets for progressive forms of MS as well as other neurodegenerative disorders

Influence of Maternal Aging on Mitochondrial Heterogeneity, Inheritance, and Function in Oocytes and Preimplantation Embryos

Contrasting the equal contribution of nuclear genetic material from maternal and paternal sources to offspring, passage of mitochondria, and thus mitochondrial DNA (mtDNA), is uniparental through the egg. Since mitochondria in eggs are ancestral to all somatic mitochondria of the next generation and to all cells of future generations, oocytes must prepare for the high energetic demands of maturation, fertilization and embryogenesis while simultaneously ensuring that their mitochondrial genomes are inherited in an undamaged state. Although significant effort has been made to understand how the mtDNA bottleneck and purifying selection act coordinately to prevent silent and unchecked spreading of invisible mtDNA mutations through the female germ line across successive generations, it is unknown if and how somatic cells of the immediate next generation are spared from inheritance of detrimental mtDNA molecules. Here, we review unique aspects of mitochondrial activity and segregation in eggs and early embryos, and how these events play into embryonic developmental competency in the face of advancing maternal age