The genetic diversity and populational specificity of the human gut virome at single-nucleotide resolution.

Background: Large-scale characterization of gut viral genomes provides strain-resolved insights into host-microbe interactions. However, existing viral genomes are mainly derived from Western populations, limiting our understanding of global gut viral diversity and functional variations necessary for personalized medicine and addressing regional health disparities.

Results: Here, we introduce the Chinese Gut Viral Reference (CGVR) set, consisting of 120,568 viral genomes from 3234 deeply sequenced fecal samples collected nationwide, covering 72,751 viral operational taxonomic units (vOTUs), nearly 90% of which are likely absent from current databases. Analysis of single-nucleotide variations (SNVs) in 233 globally prevalent vOTUs revealed that 18.9% showed significant genetic stratification between Chinese and non-Chinese populations, potentially linked to bacterial infection susceptibility. The predicted bacterial hosts of population-stratified viruses exhibit distinct genetic components associated with health-related functions, including multidrug resistance. Additionally, viral strain diversity at the SNV level correlated with human phenotypic traits, such as age and gastrointestinal issues like constipation. Our analysis also indicates that the human gut bacteriome is specifically shaped by the virome, which mediates associations with human phenotypic traits. Video Abstract CONCLUSIONS: Our analysis underscores the unique genetic makeup of the gut virome across populations and emphasizes the importance of recognizing gut viral genetic heterogeneity for deeper insights into regional health implications.