Genome sequence divergences and functional variations in human cytomegalovirus strains

Genome sequences of numerous and wide-ranging species have been completed, but genome-wide sequence variation patterns linked to biological functions are just starting to be investigated. Here, by comparatively analyzing the genome variation patterns of human cytomegalovirus (HCMV) genomes, we revealed large sequence divergences and functional variations existing in HCMV genomes. They are divergent in genome-size, inversion, orientation and coding potential, even within conserved genes, including nucleotide polymorphism, DNA strand composition asymmetry, and evolutionary rate variation in conserved genes. These divergences in conserved genes are linked to HCMV biology. Codon usage variation of conserved genes located in the negative DNA strand is significantly different between HCMV strains, and this variation associates with virion production and virulence factor, suggesting that the negative DNA strand primarily contributes to virion production and virulence factor in HCMV. In addition, we also revealed that genes functioning for entry and egress are the most adaptable, and that those for transcription and replication are the most conserved in HCMV genomes. The conserved-transcription system is generally controlled by a genome-wide motif GCGC revealed in this study by Chaos map analysis. Our findings demonstrated that genome sequences of HCMV are generally divergent and these divergences directly reflect viral biology.