Evolution of the genome and the genetic code: selection at the dinucleotide level by methylation and polyribonucleotide cleavage.

Abstract

Noting the scarcity of CpG dinucleotide in total genomic DNA derived from higher organisms and the scarcity of TpA dinucleotide in total genomic DNA derived from most life forms, we examined the distribution of these dinucleotides in sequences derived from functionally distinct types of human DNA, including mitochondrial DNA, intergenic DNA, intron DNA, and DNA destined to be represented in the cytoplasm as mRNA, tRNA, or rRNA. While CpG frequency has fallen to its lowest levels in DNA that is transcriptionally silent, TpA is most stringently excluded in DNA destined to be expressed as mRNA in the cytosol. This observation suggests that the selective pressures leading to the removal of CpG and TpA operate at different levels. With respect to TpA, dinucleotide scarcity may reflect a requirement for mRNA stability and may indicate the action of UpA-selective ribonucleases. We propose that, by reason of its instability, UpA must have been very rare in primordial RNA. Therefore, tRNA with the anticodon for this dinucleotide may have failed to evolve, making UpA the primordial doublet "stop" codon. The modern triplet code has faithfully conserved this arrangement in the two universal stop codons, UAA and UAG.In 1961, at a time when the determination of DNA sequences was but a dream, Kornberg and his associates (1, 2) developed the ingenious technique of nearest-neighbor analysis and found that representation of some dinucleotides in DNA deviated significantly from that expected were the mononucleotides associated randomly with each other. Specifically, there seemed to be a marked deficiency in the number of CpG dinucleotides and a slight but significant underrepresentation of TpA dinucleotides in animal and plant cells. With the development of techniques for sequencing large stretches of DNA and with the establishment of computer-accessible data bases, sequence analyses also revealed a scarcity of CpG and TpA dinucleotides (3-5).Underrepresentation of these dinucleotides could have evolved because of constraints operating at the level of DNA, primary messenger, processed messenger, or protein. Although a number of studies comparing the frequency of dinucleotides in different species have been performed (5-7), the distribution of dinucleotides in functionally different types of DNA has received scant attention.We have now studied the occurrence of CpG and TpA dinucleotides in different functional domains of DNA. While CpG frequency is lowest in transcriptionally silent DNA, TpA is most stringently excluded from DNA destined to be expressed as cytosolic mRNA. We show that UpA dinucleotides in RNA are unstable to nucleosidic cleavage and suggest that instability of this dinucleotide may account for the fact that the conserved stop codons start with UpA. MATERIALS AND METHODSData were from the GenBank and the EMBL data libraries supplemented by sequences determined in our own laboratory and made available through the generosity of E. W. Davie (University of Washington, Seattle). Only human genes were examined and...

Dinucleotide and stop codon frequencies in single-stranded RNA viruses.

“…when R UA was 0n70. A potential reason for UpA suppression is the suggested susceptibility of the dinucleotide to RNase activity (Beutler et al, 1989). These authors argued that the suppression of TpA in DNA was caused by the instability of UpA in RNA as the suppresssion was greater in exons than in introns and nontranscribed regions.…”

Compositional differences within and between eukaryotic genomes

“…Interestingly, TA occurrences are in the random (normal) range in animal mitochondrial (mt) and chloroplast genomes (5). Possible reasons for TA underrepresentation may be its low thermodynamic stacking energy, which is the lowest among all dinucleotides (6), the high degree of degradation of UA dinucleotides by ribonucleases in mRNA tracts (7), and the presence of TA as part of many regulatory signals (e.g., TATA box, transcription terminators, and polyadenylation signal AATAAA). In this last context, TA suppression may help to avoid inappropriate binding of regulatory factors.…”

Genome-Scale Compositional Comparisons in Eukaryotes

“…Avoidance of spurious signal sequences and considerations of DNA stability could both act to suppress overall levels of TA. In coding regions, TA may be low because UA is disfavored in mRNAs, where it is relatively susceptible to cleavage by ribonucleases (Beutler et al 1989). * GC is high in Drosophila (1.27), whereas C.elegans has high * TT/AA = 1.28.…”