Hypervariable loci in the human gut virome

Minot S, Grunberg S, Wu GD, Lewis JD, Bushman FD. 2012.
Proc Natl Acad Sci USA 109:3962-3926.

The regulation of mutation rates has been intensively studied for specific organisms, but few studies have characterized mutation rates in complex communities such as the human microbiome. Here we quantify and analyze DNA sequence variation in viral communities from the lower gastro-intestinal tract of 12 healthy human volunteers. A total of 48 billion bases of viral sequence was interrogated, an unprecedented depth of coverage, allowing variation to be measured directly for 39,239 partial or complete viral genomes. Viral genomes on average showed only 0.2% divergence of individual nucleotides from the consensus, but 51 short regions, typically ~90 base pairs, showed elevated rates, as high as 22%. The majority of these hotspots of variation were associated with reverse transcriptase genes. Some hotspots resembled the major tropism determinant (MTD) tail fiber diversity-generating system reported previously, while others showed targeted hypermutation of new gene types, including viral genes encoding apparent immunoglobulin folds. Variation was enriched at 5'-AAPy-3' sequences, typically aparagine codons, which allows maximal chemical diversification without creation of stop codons. Analysis of RT sequences in the full data set show that the largest and most diverse class of RTs is functionally associated with targeted hypermutation systems. Thus these data document widespread use of RT-based systems to diversify multiple viral gene types.