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Human Cytomegalovirus Harbors Hot, Cold Spots of Genetic Diversity, Report Finds

NEW YORK (GenomeWeb) – A team led by University of Massachusetts Medical School researchers has characterized the genomic diversity of human cytomegalovirus, finding that it harbors hot and cold spots of variability.

As they reported in the Proceedings of the National Academy of Sciences today, Timothy Kowalik from UMMS and his colleagues analyzed the genomic diversity of the viruses infecting 17 infants and one adult to note that about a quarter of the HCMV genome is conserved and lacked any polymorphisms.

These regions of low diversity included core herpesvirus — the viral family to which HCMV belongs — genes and genes encoding proteins involved in DNA replication and processing as well as genes encoding capsid, tegument, and regulatory proteins. Regions of high genomic diversity, meanwhile, included genes encoding glycoproteins, envelope protein genes, and genes linked to immune evasion.

Understanding conserved sites in the viral genome could inform the selection of therapeutic targets, the researchers said. Currently, they noted, resistance has developed to all FDA-approved small molecule treatments for HCMV infection.

"HCMV is an important human pathogen and one for which prevention strategies and therapeutic interventions are needed," Kowalik and his colleagues wrote in their paper. "With the current study, we have begun to understand the patterns and limits of HCMV genomic diversity and have laid the groundwork for translating these results into future clinical interventions."

The researchers examined 48 HCMV samples collected from 18 patients, 47 of whom were infants with congenital infections and one of whom was an adult with glioblastoma multiforme, included for comparison. Some of the patients contributed longitudinal samples and samples from various tissues.

Through sequencing the samples, the researchers uncovered more than 859,000 SNPs and nearly 154,000 unique sites in the viral genome that were polymorphic.

SNP density varied across the HCMV genome, the researchers reported. They noted some 26 regions had statistically significant low levels of SNP density. These low-density regions include genes conserved across herpesviruses, genes encoding DNA replication and processing proteins, and those encoding capsid, tegument, and regulatory proteins.

At the same time, the researchers reported that high SNP-density regions included genes that encode envelope proteins and glycoproteins, and genes linked to immune evasion.

Kowalik and his colleagues also calculated mutation and recombination rates for HCMV, estimating a genome-wide average mutation rate of 2x10-7mutations per base pair per generation and a recombination rate of about 0.23 crossover events per genome per generation.

They noted weak but positive correlations between both the mutation and recombination rates and SNP density, and further estimated that about 10 percent of the variance in SNP density could be due to variations in the mutation and recombination rates. This suggests that variation in genome-wide diversity is linked not only to protein function, but also to mutation and recombination rates, they said.

As earlier work had indicated that HCMV diversity differs between various host sites, the researchers compared samples obtained from urine, plasma, and cord blood, among other tissues, using a discriminant analysis of principal components approach. This method, the researchers said, enabled them to examine group membership and identify uncorrelated variables.

From this, they found that five clusters best characterized their HCMV populations, and one cluster was most closely related to all the other clusters. This cluster, the researchers reported, included all the plasma samples, though also samples from other compartments.

Urine samples were represented in all five clusters, and the saliva samples in three.

The researchers noted that the pattern of clustering suggests that plasma HCMV populations may be more alike than those found in saliva or urine, a supposition they confirmed.

In addition, they found some 655 polymorphisms that were associated with plasma populations, including polymorphisms in the open-reading frames of the genes encoding the glycoproteins gB, gO, gN, and gH.

Analysis of the longitudinal samples from the patients further showed evidence of both single strain and mixed infections.

The small, highly conserved, and likely highly constrained sites in the HCMV genome that Kowalik and his colleagues uncovered could be potential therapeutic targets or inform the design of such treatments, according to the paper.