Introduction
The populations of bacteria that reside within the gastrointestinal
tracts of humans experience a diversity of oscillating environmental
variables. Within and among hosts, gut bacterial populations face
fluctuating selection pressures imposed by variation in host diet (David
et al., 2014), drug use (e.g., antibiotics) (Modi et al., 2014), and
immunity (Schluter et al., 2020) as well as by variation in biotic
interactions with other constituents of the microbiota (Coyte and
Rakoff-Nahoum, 2019). These cyclic changes in the adaptive landscapes on
which gut bacterial populations evolve may promote the maintenance of
genetic diversity within gut bacterial species. However, the degree to
which balancing/diversifying selection operates on gut bacterial genomes
has not been widely investigated, and the genomic loci that represent
the targets of such selective forces have not been identified.
Theory predicts that genes under balancing selection will display a
greater number of pairwise sequence differences between copies in a
population than expected under neutral evolution based on the number of
polymorphic sites in the population. The difference between these
values—the observed average number of pairwise differences
(πo) and the expected number of pairwise differences
based on the number of segregating sites under neutrality
(πe)—provides a test statistic for balancing selection
termed Tajima’s D (Tajima, 1989). Recent advances in assembling
bacterial genomes directly from metagenomic sequence data have generated
unprecedented opportunities for interrogating the strength and genomic
targets of balancing selection in the human gut microbiota (Pasolli,
2019). Metagenome assembled genomes are now available for nearly all of
the bacterial species detected at appreciable abundances in the human
gut microbiota and, for many species, multiple genomes from a diversity
of strains have been assembled from metagenomes of numerous host
populations and individuals.
Here, we analyzed 118,617 metagenome assembled genomes (MAGs) to
identify the targets of balancing selection in 288 species of human gut
bacteria. We find that gut bacterial genomes evolve primarily under
purifying selection. However, a subset of loci displayed significant
population genetic evidence of balancing selection. In multiple
prominent gut bacterial species, these loci included coding regions for
components of multidrug efflux pumps, which were overrepresented among
the gene functions displaying the most significant evidence of balancing
selection. Integrating comparative genomic analyses with metagenomic
measurements of microbiota composition revealed that bacterial species
whose genomes contain targets of balancing selection tend to be more
abundant in the human gut than do other bacterial species, implying a
relationship between the loci under selection and fitness. Cumulatively,
these findings reveal adaptive genomic diversity maintained by balancing
selection within gut bacterial species.