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Researchers Examine the Genetic Diversity of the Human Gut Microbiome

NEW YORK (GenomeWeb News) – Hidden in the human gut microbiome is a large amount of genetic diversity, and researchers from the US and Germany reported today in Nature that individuals may have unique profiles of such metagenomic variation.

To characterize the genetic diversity contained in the human gut microbiome, the researchers drew upon stool samples from the MetaHit project, the US National Institutes of Health's Human Microbiome Project, and Washington University in St. Louis.

"We've got all of these metagenomic samples from different people, and so, in principle, each of those samples has independent isolates of all the bacteria in the microbiome," George Weinstock, the associate director of the Genome Institute at WashU, told GenomeWeb Daily News. "In principle, you could do population genetics on hundreds of different species, all in parallel at in same time, if you could just find a way to map their genomes and find their variants in each of those."

By combining samples from those various studies, the researchers generated 1.56 terabases of sequence data from 252 stool samples from 207 individuals from Europe and the US. They then mapped those 7.4 billion metagenomic reads to a bacterial reference genome set they developed that contained the finished genomes from 929 bacterial species. Of those 929 bacterial species, 101 had sufficient coverage in the metagenomic samples for further analysis.

In those 101 bacterial genomes, the researchers identified 10.3 million SNPs, which, they noted, is close to the number of SNPs identified in 179 human genomes by the 1000 Genomes Project. High densities of SNPs were found in regions related to gaining antibiotic resistance genes. In addition, the researchers found 105,991 indels and 1,051 structural variants.

"The idea was to build, for each of those 101 different species, a catalog of all the variants that were in this pooled collection of samples, sort of like the gene pool for each of those 101," Weinstock said.

After characterizing that gut microbiome gene pool the researchers traced the variants back to the samples and individuals from which they were derived. From examining the variant patterns, the researchers noted that individuals appear to have unique genetic variation in their gut microbiome.

Forty-three of the individuals included in the study had their gut microbiomes sampled more than once, and their SNP variation patterns remained fairly stable over time. "Thus, the metagenomic variation patterns observed here support the hypothesis that a healthy individual retains specific strains for extended periods of time," the study authors wrote. "This suggests that each individual has a metagenomic variation profile that could be unique even in very large cohorts."

In the past, microbiome diversity has been assessed by 16S ribosomal sequencing, which determines what taxa were present in a sample and what their abundance is. This approach, Weinstock said, gets to a deeper level of information and is more precise.

"When you look at the taxonomy, you can only look at whatever organisms are abundant enough for you to see, but here … you have 300 million bases that you are looking at, and that gives you tremendous sensitivity in terms of distinguishing people," he added.

While geographic differences have been seen in Helicobacter pylori and some other bacterial pathogens, the researchers were not able to see many genetic differences that distinguished the European and US samples. To find such differences, Weinstock said that researchers would likely need to include more samples or sequence to greater depths to uncover low-frequency alleles.

This, he noted, is "a proof-of principle paper and now we know what the limits are and where we have to push it in order to get down to those kinds of distinctions."