Comparative Population Genetics in the Human Gut Microbiome

Abstract

Genetic variation in the human gut microbiome is responsible for conferring a number of crucial phenotypes like the ability to digest food and metabolize drugs. Yet, our understanding of how this variation arises and is maintained remains relatively poor. Thus, the microbiome remains a largely untapped resource, as the large number of co-existing species in the microbiome presents a unique opportunity to compare and contrast evolutionary processes across species to identify universal trends and deviations. Here we outline features of the human gut microbiome that, while not unique in isolation, as an assemblage make it a system with unparalleled potential for comparative population genomics studies. We consciously take a broad view of comparative population genetics, emphasizing how sampling a large number of species allows researchers to identify universal evolutionary dynamics in addition to new genes, which can then be leveraged to identify exceptional species that deviate from general patterns. To highlight the potential power of comparative population genetics in the microbiome, we re-analyze patterns of purifying selection across ∼40 prevalent species in the human gut microbiome to identify intriguing trends which highlight functional categories in the microbiome that may be under more or less constraint.

A macroecological perspective on genetic diversity in the human gut microbiome

“…Evidence suggests that purifying selection in the human microbiome is widespread [3, 30], though it is unlikely responsible for the allele frequency fluctuations I was able to observe. After accounting for sequencing error using MAPGD, the mean of the lowest inferred allele frequency across all species was ∼ 0.02.…”

“…Such an approach provides the empirical motivation necessary to identify mathematical models that could potentially explain said patterns and aid in the identification of feasible ecological or evolutionary dynamics [9,[25][26][27]. In recent years, substantial progress has been made towards characterizing the typical microbial evolutionary dynamics across species that operate within the human gut [3,4,7,8,[28][29][30]. Using this approach it is possible to leverage the richness of species in the human gut microbiome, where each species can be viewed as a draw from an unknown distribution and, as an ensemble, be used to identify patterns that are statistically invariant [31,32].…”

Pitfalls of genotyping microbial communities with rapidly growing genome collections

“…Sequencing reads from orthologous regions of any one of these species may harbor nucleotide differences due to genetic diversity captured in the sample ( Figure 1A ) as well as sequencing errors. Genetic diversity has multiple sources (Ghazi et al, 2022; Shoemaker et al, 2022; Van Rossum et al, 2020). One common source is the presence of two or more divergent lineages of the same species within a metagenome.…”

“…For human-associated microbes, this enables epidemiological studies of clinically important strains, including transmission and dispersal of different lineages (Mitchell et al, 2020). Finally, genetic variants may be utilized to infer the evolutionary forces acting on microbial species, shedding light on the roles of drift, selection, and recombination across taxonomic groups and environments (Garud and Pollard, 2020; Shoemaker et al, 2022; Van Rossum et al, 2020). Thus, there is great interest in characterizing the genetic diversity of microbiomes beyond the species level.…”

Highlight: Comparative Population Genomics—Answering Old Questions with New Data

“…The Special Section includes two review articles that help to put the emerging field of comparative population genomics into context. A review by Shoemaker et al (2022) at the University of California Los Angeles highlights recent findings from the human gut microbiome, “a system with unparalleled potential for comparative population genomics studies” according to the authors. The article includes a reanalysis of patterns of purifying selection across approximately 40 species prevalent in the human gut microbiome, identifying functional categories that may be under more or less constraint in the microbiome.…”