Fig. 2

Microbial SNV, structural, and metatranscriptomic variants as features for genetic epidemiology in the human microbiome. Statistical approaches can link subspecies microbial features to human health phenotypes in several ways. a When microbial strains are identified using SNV genotypes (whether from genome bins, marker genes, core genes, etc.), any individual microbial SNV—or overall genotype—is typically of low prevalence and high variability. This means that it is extremely difficult to power significant associations with individual SNVs in reasonably sized human population studies. Instead, significant assortment of a host phenotype with strain phylogeny can be assessed, e.g., by PERMANOVA on per-species genetic distances [8] or by aggregating SNVs to genes or larger loci. b An extreme of this type of association test directly assesses the nonrandom assortment of genes’ presence or absence among microbial strain pangenomes in association with a phenotype of interest [66], since a gene loss (or gain) is essentially the “sum” of variants at every nucleotide within the gene. c Alternatively, even when no differences in genomic SNVs or structural variants are detectable at a study’s level of power, the transcriptional regulatory effects of these variants can be amplified, resulting in strain-specific differences in locus expression in association with a phenotype [156]