Pervasive CpG suppression in animal mitochondrial genomes.

Abstract

AU available complete mitochondrial genomes (21 species) are evaluated for dinucleotide over-and under-representation. The CpG dinucleotide is pervasively under-represented in all animal mitochondria, but it is of variable relative abundance in fungal, protist, and plant mitochondrial genomes. Interpretations and hypotheses are considered relative to mitochondrial genome organization, methylation, structural specificities, directed mutation, and evolutionary events. In particular, our results support Mycoplasma capricolum or a dose relative as the most likely bacterial ancestor of the mitochondria.Over the past two decades and continuing, mitochondrial molecular biology has been under intensive study, yielding data and insights on genome structure, organization, expression, and evolution (for recent reviews see ref. 1). The complete mitochondrial genomes of 15 animals, 3 fungi, 2 protists, and 1 plant have been sequenced. The animal mitochondrial genomes range in size from 13.8 to 17.5 kb (Table 1). Fungal and protist mitochondrial genome sizes are larger and their compositions are more variable. Plant mtDNA can be as large as bacterial genomes (2) METHODSLet fx denote the frequency of mononucleotide X in the sequence at hand, fxy the frequency of dinucleotide XY, and so on. A usual assessment of dinucleotide bias is through the odds-ratio measure, pxy = fxy/fxfy. From data experience and statistical theory, for pxy more (less) than 1.23 (0.78), the XY pair is considered to be of high (low) relative abundance compared with a random association of mononucleotides. There are statistical tests indicating the degree of statistical significance for high and low relative abundance (e.g., seerefs. 7 and 8). The measure pxy is suitable for a single sequence. To accommodate the complementary antiparallel structure of double-stranded DNA, we form the symmetrized frequency of mononucleotides asf =f*T = (fA + fT)/2 and fC= ft = (fc + fG)/2, and f*GT = (fGT + fAc)/2 is the symmetrized double-stranded frequency of GTAC, etc. The symmetrized dinucleotide odds ratio measure is taken to be P*GT = ftT/fThr = 2CJGT + fAC)/f + fc)(fT + fA) and similarly for all dinucleotides (see ref. 9 for rationale and justifications). A third-order measure of similar type is Vy*Xyz = Vzyf t/>fyzfxNz where N is any nucleotide.

Compositional differences within and between eukaryotic genomes

“…Animal (vertebrate and invertebrate) mt sequences show significant underrepresentations of CG dinucleotides, * CG Ϸ 0.40 to 0.60 (13), almost to the same extent as occurs in vertebrate genomic sequences. The adjusted D. melanogaster and (unadjusted) D. yakuba mt genomes entail * CG ϭ 0.73 and 0.68, respectively (13).…”

“…The adjusted D. melanogaster and (unadjusted) D. yakuba mt genomes entail * CG ϭ 0.73 and 0.68, respectively (13). The fungal S. pombe has * CG ϭ 0.54 typical of animal mitochondria.…”

CpG motifs present in bacteria DNA rapidly induce lymphocytes to secrete interleukin 6, interleukin 12, and interferon gamma.

“…Recent work from our laboratory suggested that this B-cell stimulation was mediated by a 6-base nt motif consisting of an unmethylated CpG dinucleotide flanked by two 5' purines and two 3' pyrimidines (12). This motif is expressed nearly 20 times more frequently in bacterial than vertebrate DNA (12)(13)(14).…”

“…Recent work from our laboratory suggested that this B-cell stimulation was mediated by a 6-base nt motif consisting of an unmethylated CpG dinucleotide flanked by two 5' purines and two 3' pyrimidines (12). This motif is expressed nearly 20 times more frequently in bacterial than vertebrate DNA (12)(13)(14).In addition to B-cell activation, the innate immune response to bacterial infection is characterized by the production of immunomodulatory cytokines (15,16). These include interleukin (IL) 6, which contributes to T-and B-cell activation (17-20), IFN-y, which (25)(26)(27).…”

Methylated CpG‐Containing Plasmid Activates the Immune System

“…The bioactive molecular entities were identified as being palindromic nucleotide sequences containing a cytosine-phosphate-guanosine (CpG) core [3]. These sequences are highly frequent in non-vertebrate DNA but are rare in vertebrate DNA [4,5]. Synthetic oligodeoxynucleotides (ODNs) that contain such CpG motifs (CpG ODNs) induce B-cell proliferation, interleukin-6 (IL-6) production and antibody [immunoglobulin (Ig)] secretion in vitro [4,6].…”