title: GC content increased at CpG flanking positions of fish genes compared with sea squirt orthologs as a mechanism for reducing impact of DNA methylation.
abstract: BACKGROUND
  Fractional DNA methylation in sea squirts evolved to global DNA methylation in fish. The impact of global DNA methylation is reflected by more CpG depletions and/or more A/T to G/C changes at CpG flanking positions due to context-dependent mutations of methylated CpG sites.
  
  
  RESULTS
  In this report, we demonstrate that the sea squirt genes have undergone more CpG to TpG/CpA substitutions than the fish orthologs using homologous fragments from orthologous genes among Ciona intestinalis, Ciona savignyi, fugufish and zebrafish. To avoid premature transcription, the TGA sites derived from CGA were largely converted to TGG in sea squirt genes. By contrast, a significant increment of GC content at CpG flanking positions was shown in fish genes. The positively selected A/T to G/C substitutions, in combination with the CpG to TpG/CpA substitutions, are the sources of the extremely low CpG observed/expected ratios in vertebrates. The nonsynonymous substitutions caused by the GC content increase have resulted in frequent amino acid replacements in the directions that were not noticed previously.
  
  
  CONCLUSIONS
  The increased GC content at CpG flanking positions can reduce CpG loss in fish genes and attenuate the impact of DNA methylation on CpG-containing codons, probably accounting for evolution towards vertebrates.
authors.affiliation: Department of Zoology and Genome Research Centre, The University of Hong Kong, Pokfulam, Hong Kong.
authors.forename: Yong
authors.initials: Y
authors.lastname: Wang
authors.forename: Frederick C C
authors.initials: FC
authors.lastname: Leung
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001482:Base Composition; D003062:Codon; D017124:Conserved Sequence; D018899:CpG Islands; D019175:DNA Methylation; D015226:Dinucleoside Phosphates; D019143:Evolution, Molecular; D017354:Point Mutation; D017422:Sequence Analysis, DNA; D023741:Takifugu / Q000235:genetics*; D014561:Urochordata / Q000235:genetics*; D015027:Zebrafish / Q000235:genetics*
chemical_list: D003062:Codon; D015226:Dinucleoside Phosphates; C015772:CpG dinucleotide