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Gut Microbe Structural Variants Implicated in Health-Related Host Traits

NEW YORK (GenomeWeb) – An international team led by investigators in Israel and the US has garnered new evidence suggesting structural variants in the genomes of gut microbial community members may correspond to some health-related traits in human hosts.

"[W]e show that [structural variants] represent a nascent layer of information in the microbiome that we suggest is of high relevance to human health," senior and co-corresponding author Eran Segal, a computer science, applied mathematics, and molecular cell biology researcher at the Weizmann Institute of Science, and his colleagues wrote in their study, published online today in Nature.

Starting with metagenomic sequence data generated for samples from 887 healthy individuals from Israel, Segal and his colleagues used "iterative coverage-based read assignment" (ICRA) and "SGV-Finder" algorithms to find 7,479 structural variants in 56 of the gut microbial species detected. These structural variants, which included 5,056 deletions and 2,423 variable structural variants, were particularly prevalent in genes contributing to CRISPR function and antibiotic production, while housekeeping genes showed a relative shortage of structural variants.

"We found that [structural variants] harbor genes of distinct functions and are associated with bacterial growth rates," the researchers reported, "indicating a potential utility in bacterial adaptation."

When the researchers considered the functional consequences of the microbial structural variants and set them beside human host traits such as blood pressure, body mass index, and cholesterol levels, they saw 124 significant associations between microbial structural variants and disease-related host traits. Of those, 81 associations involved variable structural variants, while the remaining 43 associations stemmed from deletion structural variants.

More than three-quarters of the same deletion structural variants — and 47 of the bacterial species — turned up when the team did ICRA and SGV-Finder analyses on more than 1,000 gut microbe samples from Dutch Lifelines DEEP project participants. The investigators also replicated 40 of the 124 structural variant-host trait associations in the Dutch cohort and went on to dig into the function of genes found in structural variant-affected region that stood out in the association analyses.

"Although further research is needed to fully understand the interactions between the host, its microbiome, and disease," the authors wrote, "we demonstrate the wealth of mechanistic hypotheses obtained through examining genes with variable copy number along with neighboring variable genes."

When the team focused in on a 31,000-base pair deletion structural variant that appeared to be over-represented in Anaerostipes hadrus microbes from the guts of individuals with lower-than-usual metabolic risk, for example, it found a set of inositol catabolism-butyrate production genes involved in sugar alcohol transport and metabolism.

The authors noted that these results appeared to line up with prior studies in mice pointing to a role for butyrate, and other short-chain fatty acids formed from sugar alcohol fermentation, in enhanced insulin sensitivity and energy expenditure. They hypothesized that "by possessing this [structural variant], bacteria demonstrate increased symbiosis with the host, as fermenting sugar alcohols to butyrate benefits the microbe by producing additional energy and benefits the host with the advantageous effects of butyrate."