By tracking how adaptive genes sweep through gut bacteria across continents, researchers uncover a hidden evolutionary response to modern diets and lifestyles, and a powerful new way to study microbiome evolution.
Study: Gene-specific selective sweeps are pervasive across human gut microbiomes. Image credit: Danijela Maksimovic/Shutterstock.com
A recent study in Nature developed an integrated linkage disequilibrium score (iLDS), a novel selection scan statistic, to identify adaptive alleles spreading across host microbiomes through recombination-mediated processes, including migration and horizontal gene transfer (HGT). This highlights common selective pressures and their role in shaping microbiome diversity and function.
Genetic adaptations within gut microbiome
The different species in the human gut microbiome change and evolve throughout a person's life and even across multiple generations. Studies show that gut bacteria often evolve rapidly, with new mutations becoming common in healthy adults within days or months, even without antibiotic treatment. Further research is needed to understand how these changes spread among individuals over time.
When a new adaptation arises in a person's gut microbiome, it can spread to others through horizontal gene transfer (HGT). The human gut is a known hotspot for HGT, facilitating the incorporation of useful genes into new bacterial strains. HGT is important for spreading certain genes, like those for antibiotic resistance, especially between different species. To date, it remains unclear how much HGT facilitates the movement of adaptive genes between strains of the same species, particularly through homologous recombination.
When an adaptive gene spreads through a population via a process called a ‘gene-specific’ selective sweep, nearby genetic variants, which can be harmless or possibly harmful, can get carried along with it. This means the same stretch of DNA, including both the adaptive gene and these ‘hitchhikers,’ can appear in unrelated bacterial strains living in different people's gut microbiomes. This sharing of DNA creates a noticeable pattern called elevated linkage disequilibrium (LD), which means certain gene combinations appear together more often than expected near the adaptive gene.
LD-based scans for selection in bacteria have been limited, possibly because of the pervasiveness and dynamics of recombination in many bacterial species, particularly gut commensals. Furthermore, LD-based statistics can be confounded by other non-selective evolutionary forces, including demographic contractions, which can elevate LD20.
Uncovering Selection Forces in Gut Bacterial Populations through Linkage Disequilibrium Patterns
Researchers used simulations to test if positive selection and hitchhiking raise LD between non-synonymous variants compared to synonymous ones, and whether this pattern is unique to selection or can occur by chance. They found that this genetic pattern does not arise without positive selection, even under various evolutionary scenarios. The signature appeared only when purifying selection was stronger than drift, and positive selection was stronger than purifying selection. In such cases, weakly deleterious variants could hitchhike during a sweep, resulting in increased LD among common non-synonymous variants.
After simulations showed that selective sweeps can increase LD among common variants, researchers measured LD in human gut bacteria to determine whether this pattern occurs in natural populations. They analyzed metagenomic data from 693 people across three continents. By aligning sequencing reads and identifying samples with a dominant strain, they reliably determined haplotypes. This allowed the calculation of LD between pairs of alleles. A total of 3,316 haplotypes from 32 species were analyzed. Additional evidence was gathered using metagenome assembled genomes (MAGs) and isolates from 24 global populations. Since LD can be affected by population structure, only haplotypes from the largest clade of each species were considered.
In most species analyzed, LD was significantly higher among common non-synonymous variants, suggesting positive selection. For rare variants, LD was lower, indicating purifying selection. These patterns point to widespread purifying and positive selection on non-synonymous sites in gut bacteria.
Application of iLDS to examine gut microbial gene adaptations
The iLDS statistic was designed to identify candidate genomic regions under recent positive selection by measuring overall and non-synonymous LD. It was calculated in sliding windows across the genome and highlighted outliers after standardization. The current study tested iLDS on simulated and real Clostridioides difficile data, demonstrating sensitivity to recent and ongoing sweeps while maintaining a low false-positive rate. In 135 C. difficile isolates, iLDS pinpointed known sweep regions, such as tcdB and the S-layer cassette, with most regions showing no signal, while a few indicated selection.
Six sweeps were identified, including tcdB and S-layer. iLDS outperformed other statistics, often matching known virulence genes and revealing sweeps consistent with recombination-mediated spread of adaptive alleles. Its effectiveness was confirmed in Helicobacter pylori and Drosophila melanogaster as well.
iLDS applied to 32 gut microbiome species identified 155 sweeps affecting 447 genes, with some gene classes, such as the starch utilization genes susC/susD and glycoside hydrolases, repeatedly under selection. This indicated that carbohydrate metabolism and transport genes were frequently targeted by selection.
The mdxE and mdxF genes, involved in maltodextrin transport, were under selection in starch-metabolizing gut bacteria and showed signs of recent recombination and horizontal transfer. Previous studies have shown that industrialization is associated with reduced microbiome diversity and elevated rates of gene transfer. iLDS scans revealed 309 sweeps in 24 populations and 16 species, with most unique to one population, suggesting local adaptation.
Thirty-five percent of sweeps were shared between populations, with some globally widespread. Industrialized groups shared sweeps more often among themselves than with non-industrialized groups, indicating shared ecology and dietary selection pressures.
Only three sweeps were shared between the two groups, while 32 were unique to either the industrialized or the non-industrialized populations. The R. bromii mdxEF locus was under selection in all industrialized but not non-industrialized groups, suggesting adaptation to modern lifestyles. Sweep numbers per population were similar between groups, indicating comparable rates of adaptation.
Conclusions
The development and application of iLDS revealed how selective pressures shape the gut microbiome and how gut bacteria adapt. Although hundreds of selective sweeps were detected, the conservative calibration of iLDS likely missed some true positives, suggesting that positive selection in gut commensals may be more widespread than observed. Further studies of loci identified by iLDS are required to clarify how microbiome genetics impact host phenotypes, aid in disease diagnosis and treatment, and inform the design of targeted probiotics.
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