Scientists map genetic diversity of microbes in human gut
A team of microbiologists and bioinformaticians from Harvard Medical School and Joslin Diabetes Center offer a first glimpse of the array of genes that make up the bacterial universe residing in each of us, in a study published in the journal Cell Host & Microbe.
Scientists estimate that the human microbiome contains trillions of bacteria, most of them harmless, many beneficial, and some disease causing. Mounting evidence has revealed the role of these microbes as powerful modulators of disease and health. Changes in both bacterial count and bacterial content have been linked to development of conditions ranging from garden variety dental caries and gut infections to more serious ones, including chronic inflammatory bowel disease, diabetes, and multiple sclerosis.
Most research to date has focused on mapping the types of bacteria that inhabit our bodies to determine whether and how the presence of a given bacterial species might affect disease risk. By contrast, the new research delves far deeper, looking at the genes that make up the various microbial species and strains.
Studying bacterial species alone is bound to provide only partial clues into these microorganisms' role in disease and health, the researchers say. Given that genetic content varies greatly between the same microbes, understanding how and whether individual microbial genes affect disease risk is just as important.
In the study, the researchers set out to estimate the size of the universe of microbial genes in the human body, gathering all publicly available DNA sequencing data on human oral and gut microbiomes. In total, they analyzed the DNA of some 3,500 human microbiome samples, of which more than 1,400 were obtained from people's mouths and 2,100 from people's guts.
There were nearly 46 million bacterial genes in the 3,500 samples--about 24 million in the oral microbiome and 22 million in the gut microbiome, the researchers found.
More than half of all the bacterial genes (23 million) occurred only once, rendering them unique to the individual. The researchers termed these unique genes "singletons." Of the 23 million singletons, 11.8 million came from oral samples and 12.6 million came from intestinal samples.
Compounding the intrigue, these singleton genes also appeared to behave differently from other genes, the researchers observed, in that they performed different functions.
Commonly shared genes, the analysis showed, appeared to be involved in basic functions critical to a microbe's day-to-day survival, such the consumption and breakdown of enzymes, energy conversion and metabolism. Unique genes, by contrast, tended to carry out more specialized functions, such as gaining resistance against antibiotics and other pressures and helping to build a microbe's protective cell wall, which shields it from external assaults.
This finding suggests that singleton genes are key parts of a microbe's evolutionary survival kit, according to Braden Tierney, PhD, the study’s first author.
"Some of these unique genes appear to be important in solving evolutionary challenges," Tierney said in a statement. "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."
More research is needed to understand what fuels gene diversity, though the team believes there are at least two drivers of genetic variation. One is the microbes' love of freely swapping DNA material with their neighbors, a phenomenon known as horizontal gene transfer. To test this hypothesis, the researchers performed a special type of analysis that detects the shared molecular content between two organisms. They found little evidence that horizontal gene transfer was a main source of genetic uniqueness. Indeed, less than 1 percent of unique genes detected in oral samples and just under 2 percent of those found in the gut appeared to have arisen through this neighborly gene exchange.
Therefore, the researchers hypothesize, another more powerful driver of genetic diversity could be bacteria's ability to evolve their DNA rapidly in response to changes in the host environment. The current study was not designed to detect the precise environmental changes that drive this variation, but examples of such changes may include what type of food a person consumes, what medication they use, the lifestyle choices they make, what environmental exposures they encounter, and any physiologic changes in the host, including upregulation and downregulation in various host genes or whether a person develops a disease.
By one calculation, that number could be around 232 million, the study estimated. Another estimate, however, yielded a number comparable to the number of atoms in the universe.