Journal Article

Limits and patterns of cytomegalovirus genomic diversity in humans

Jeffrey D. Jensen, William J. Britt, Timothy F. Kowalik, Laura Gibson, Renzette, Nicholas, Bornali Bhattacharjee, Klaus Hamprecht, Aparecida Y. Yamamoto, Marisa M. Mussi-Pinhata, Cornelia Pokalyuk, Mark R. Schleiss

2015

Overview

Human cytomegalovirus (HCMV) is the leading cause of birth defects associated with infections and a leading cause of transplantation failure. This study reveals the patterns and limits of HCMV genomic diversity by performing a large-scale analysis of HCMV sequences sampled from human hosts, identifying the hot and cold spots of variability. We find that the diversity is unevenly distributed across three host compartments and show that HCMV populations of vascular compartments are genetically constrained while enriched for polymorphisms of glycoproteins and regulatory proteins. This work significantly advances our understanding of the genomic diversity of HCMV in humans and has clear implications for the development of therapeutics against HCMV. Human cytomegalovirus (HCMV) exhibits surprisingly high genomic diversity during natural infection although little is known about the limits or patterns of HCMV diversity among humans. To address this deficiency, we analyzed genomic diversity among congenitally infected infants. We show that there is an upper limit to HCMV genomic diversity in these patient samples, with ∼25% of the genome being devoid of polymorphisms. These low diversity regions were distributed across 26 loci that were preferentially located in DNA-processing genes. Furthermore, by developing, to our knowledge, the first genome-wide mutation and recombination rate maps for HCMV, we show that genomic diversity is positively correlated with these two rates. In contrast, median levels of viral genomic diversity did not vary between putatively single or mixed strain infections. We also provide evidence that HCMV populations isolated from vascular compartments of hosts from different continents are genetically similar and that polymorphisms in glycoproteins and regulatory proteins are enriched in these viral populations. This analysis provides the most highly detailed map of HCMV genomic diversity in human hosts to date and informs our understanding of the distribution of HCMV genomic diversity within human hosts.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: Biodiversity / Biological Sciences / Cluster Analysis / cold / congenital abnormalities / congenital CMV / Cytomegalovirus / Cytomegalovirus - genetics / Cytomegalovirus - isolation & purification / Cytomegalovirus Infections - virology / evolution / Evolution, Molecular / Gene Expression Regulation / Genes, Viral / Genetic Variation / Genome, Viral / Genomics / Glycoproteins / Glycoproteins - genetics / HCMV / hosts / Human betaherpesvirus 5 / Human cytomegalovirus / Human herpesvirus 5 / Humans / Infant / Infant, Newborn / Mutation / PNAS Plus / Polymorphism / Polymorphism, Genetic / Recombination, Genetic / regulatory proteins / Sequence Analysis, DNA / therapeutics / virology