Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
PLoS Genet. 2013;9(9):e1003735. doi: 10.1371/journal.pgen.1003735. Epub 2013 Sep 26.
Populations of human cytomegalovirus (HCMV), a large DNA virus, are highly polymorphic in patient samples, which may allow for rapid evolution within human hosts. To understand HCMV evolution, longitudinally sampled genomic populations from the urine and plasma of 5 infants with symptomatic congenital HCMV infection were analyzed. Temporal and compartmental variability of viral populations were quantified using high throughput sequencing and population genetics approaches. HCMV populations were generally stable over time, with 88% of SNPs displaying similar frequencies. However, samples collected from plasma and urine of the same patient at the same time were highly differentiated with approximately 1700 consensus sequence SNPs (1.2% of the genome) identified between compartments. This inter-compartment differentiation was comparable to the differentiation observed in unrelated hosts. Models of demography (i.e., changes in population size and structure) and positive selection were evaluated to explain the observed patterns of variation. Evidence for strong bottlenecks (>90% reduction in viral population size) was consistent among all patients. From the timing of the bottlenecks, we conclude that fetal infection occurred between 13-18 weeks gestational age in patients analyzed, while colonization of the urine compartment followed roughly 2 months later. The timing of these bottlenecks is consistent with the clinical histories of congenital HCMV infections. We next inferred that positive selection plays a small but measurable role in viral evolution within a single compartment. However, positive selection appears to be a strong and pervasive driver of evolution associated with compartmentalization, affecting ≥ 34 of the 167 open reading frames (20%) of the genome. This work offers the most detailed map of HCMV in vivo evolution to date and provides evidence that viral populations can be stable or rapidly differentiate, depending on host environment. The application of population genetic methods to these data provides clinically useful information, such as the timing of infection and compartment colonization.
人巨细胞病毒（HCMV）是一种大型 DNA 病毒，其在患者样本中的种群高度多态，这可能使其在人类宿主中能够快速进化。为了了解 HCMV 的进化，对 5 例有症状先天性 HCMV 感染的婴儿的尿液和血浆中纵向采集的基因组种群进行了分析。利用高通量测序和群体遗传学方法定量分析了病毒种群的时间和区室变异性。HCMV 种群随时间通常较为稳定，约 88%的 SNP 显示出相似的频率。然而，同一患者同一时间采集的血浆和尿液样本之间存在高度分化，在区室之间鉴定出约 1700 个共识序列 SNP（占基因组的 1.2%）。这种区室间分化与在无关宿主中观察到的分化相当。评估了人口统计学模型（即种群大小和结构的变化）和正选择，以解释所观察到的变异模式。所有患者的证据都表明存在强烈的瓶颈（病毒种群大小减少>90%）。从瓶颈的时间推断，我们得出结论，分析的患者的胎儿感染发生在妊娠 13-18 周之间，而尿液区室的定植发生在大约 2 个月后。这些瓶颈的时间与先天性 HCMV 感染的临床病史一致。我们进一步推断，正选择在单个区室的病毒进化中起着微小但可衡量的作用。然而，正选择似乎是区室化相关进化的一个强大且普遍的驱动因素，影响基因组中 167 个开放阅读框中的≥34 个（约 20%）。这项工作提供了迄今为止最详细的 HCMV 体内进化图谱，并提供了证据表明病毒种群可以保持稳定或快速分化，这取决于宿主环境。将群体遗传学方法应用于这些数据提供了有用的临床信息，例如感染和区室定植的时间。
