Periodicity in nucleotide sequences arises from regular repeating patterns which may reflect important structure and function. Although a three-base periodicity in coding regions has been known for some time and has provided the basis for powerful gene prediction algorithms, its origins are still not fully understood. Here, we show that, contrary to common belief, amino acid (AA) bias and codon usage bias are insufficient to create base-3 periodicity. This article applies the rigorous method of spectral envelope to systematically characterize the contributions of codon bias, AA bias and protein structural motifs to the three-base periodicity of coding sequences. The method is also used to classify CpG islands in the human genome. In addition, we show how spectral envelope can be used to trace the evolution of viral genomes and monitor global sequence changes without having to align to previously known genomes. This approach also detects reassortment events, such as those that led to the 2009 pandemic H1N1 virus.
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