An analysis of microbial genes in the human gut and oral microbiomes has yielded results suggesting that the collective microbiome may contain more genes than there are stars in the observable universe. Scientists in the United States and Canada have generated a catalog and searchable web resource detailing tens of millions of microbial genes identified through their first-sweep analysis of thousands of human samples. Their findings, reported in Cell Host & Microbe, suggest that the mouth and gut microbiomes comprise “staggering” microbial genetic diversity, and found that at least half of all the genes identified were unique to an individual.

The Harvard Medical School-led study represents only the start of efforts to analyze the genes contained in the entire human microbiome. Their results suggest that at least half of the genes are unique to each individual, and the apparent diversity is exceeding the researchers’ expectations. “Ours is a gateway study, the first step on a what will likely be a long journey toward understanding how differences in gene content drive microbial behavior and modify disease risk,” said Braden Tierney, a graduate student at Harvard Medical School. Tierney is first author of the researchers’ published paper, which is titled, “The Landscape of Genetic Content in the Gut and Oral Human Microbiome.”

Research indicates that the human gut microbiome may contain upwards of 150,000 different microbial strains, and that even minute variations in microbiome composition can impact on human health and disease. But as the authors pointed out, “The field still does not have a grasp on the scope of the microbiome’s genetic content—in the gut and otherwise—a question crucial for understanding microbial function in the context of disease.”

Even microbes of the same strain will carry different genes, suggested Chirag Patel, PhD, assistant professor of biomedical informatics at Harvard Medical School’s Blavatnik Institute. “Just like no two siblings are genetically identical, no two bacterial strains are genetically identical, either. Two members of the same bacterial strain could have markedly different genetic makeup, so information about bacterial species alone could mask critical differences that arise from genetic variation.”

Building a catalog of the complete landscape of microbial genes could help to direct the design and development of precision treatments, added study senior co-author Alex Kostic, PhD, assistant professor of microbiology at Harvard Medical School and an investigator at the Joslin Diabetes Center. “Such narrowly targeted therapies would be based on the unique microbial genetic make-up of a person rather than on bacterial type alone.”

Scientists can only estimate the total number of genetic elements within every bacterial species, and theoretical approximations start at a perhaps conservative one billion genes. “Within the human gut microbiome, up to 10 million non-redundant genes have been identified by major sequencing consortiums using de novo approaches,” the researchers pointed out. However, they continued, prior sequencing efforts have been almost exclusively centered on the gut microbiome, are relatively limited in terms of sample sizes, and haven’t focused on the overall rarity of genes across a population.

For their reported research, the Harvard Medical School team, working with researchers at the Joslin Diabetes Center; University of Waterloo, Ontario; University of Alberta, Edmonton; and University of California, Berkeley, collected all publicly available DNA sequencing data on human oral and gut microbiomes. In total, they assessed the DNA of some 3,500 human microbiome samples, of which more than 1,400 were obtained from people’s mouths and about 2,100 from the gut.

Microbiome Graphical Abstract
Source: Tierney BT, et al Cell Host & Microbe, Volume 26, Issue 2, P283-295.E8

Their analyses identified nearly 46 million genes in total. “We found staggering genetic heterogeneity in the dataset, identifying a total of 45,666,334 non-redundant genes (23,961,508 oral and 22,254,436 gut),” they noted. More than half of the genes were found in only one sample, and so were unique to that individual. The researchers termed these genes “singletons”. “The oral gene catalog contained 11,891,670 (49.6%) singletons and 12,069,838 (50.4%) non-singletons, whereas the gut gene catalog contained 12,621,933 (56.7%) singletons and 9,632,503 (43.2%) non-singletons. On average, 2.9% of the genes in each sample were singletons.”

Interestingly, commonly shared genes tended to be involved in microbial day-to-day functioning, such as enzyme use and energy conversion and metabolism. in contrast, the singleton genes were often involved with more specialized functions. “We found that singleton genes are enriched in functionality for a variety of unrelated metabolic functions compared with non-singletons, which were enriched in more conserved bacterial processes,” the investigators stated. However, functions encoded by singletons are not irrelevant. We identified a number of pathways (e.g., antibiotic resistance and cell wall biosynthesis), that might affect both the structure of the microbiome and host health.”

They speculate that singleton genes may arise to help the organisms meet new or changing environmental pressures. “… given the functional variety encoded within singleton genes, we propose that singletons form an evolutionary organ within the microbiome, one that can be leveraged by microbes to adapt readily to environmental conditions.”

“Some of these unique genes appear to be important in solving evolutionary challenges,” Tierney said. “If a microbe needs to become resistant to an antibiotic because of exposure to drugs or suddenly faces a new selective pressure, the singleton genes may be the wellspring of genetic diversity the microbe can pull from to adapt.”

The authors suggested two possible mechanisms by which these unique singleton genes may emerge: either through horizontal gene transfer—the ability of bacteria to swap genetic material with their neighbors—or from extremely rare microbial species or strains. Results from gene mapping analyses indicated that horizontal gene transfer was unlikely to explain this genetic diversity. In fact, less than 1% of unique genes detected in the oral samples, and just under 2% of unique genes in the gut appeared to have arisen through horizontal gene transfer. Rather, the investigators suggest that microbial genetic diversity may be driven by the ability of bacteria to evolve their DNA rapidly in response to environmental changes—such as the host’s diet, medication, physiological changes, or disease and alterations to host gene expression.

They state that the catalog of genes generated through their study may only be representative of 8–72% and 4–50% of the total potential genetic diversity of the gut and oral microbiomes, respectively. “This analysis uncovered a universe of prokaryotic genes massive in scale,” they noted, further commenting that the landscape of the human microbiome is “immense” and displays “staggering” diversity across people.

The researchers are making their gene catalog available through a resource that can be accessed at https://microbial-genes.bio. “We hope the scientific community will be able to use the set of resources provided here to deepen the field’s understanding of the relationship between taxonomy and microbial genetic variation,” they wrote.

As to how many genes there are in the collective human microbiome, one calculation puts the figure at around 232 million, whereas another resulted in a number comparable to the number of atoms in the universe. Perhaps the bottom line is that the actual number may be something that we can’t ever find out, Patel suggested. “Whatever it may be, we hope that our catalog, along with a searchable web application, will have many practical uses and seed many directions of research in the field of host-microbe relationships.”

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