From Trash to Treasure

Neuron
Scientists at UCSF and Stanford collect saliva samples from the Khoe-San in southern Africa. Each of these saliva samples contain up to 60% microbial DNA, which Gladstone scientists are now using to study the Khoe-San microbiome.

How a chance meeting between scientists is setting the stage for the next phase in human genomics.

By ANNE D. HOLDEN, PhD

June 17, 2013: “Almost half of every saliva sample we collected contained contaminants.”

Chris Gignoux, University of California, San Francisco (UCSF) graduate student, was speaking to a group of like-minded geneticists at a weekly research meeting on campus. Among the group were Gladstone Investigator Katie Pollard, PhD, and Bioinformatics Fellow, Tom Sharpton, PhD. And all were listening to Gignoux as he described the difficult process of collecting, sequencing and analyzing the DNA of the Khoe-San, a traditional population from southern Africa. Along with collaborators at Stanford University, Gignoux was analyzing the Khoe-San’s DNA in an attempt to piece together their genetic history.

The team had recently returned from the field, where they had collected saliva samples for analysis back in the lab. But getting the DNA ready for analysis was proving difficult—the samples contained not only human DNA, but also so-called “contaminants,” largely made up of microbes that also resided in the saliva of the Khoe-san. To Gignoux and his colleagues, these microbes were getting in the way. But to Pollard and Sharpton, these microbes could be the key to a question that they had been trying to answer.

Pollard, Sharpton and others at Gladstone have been examining the human “microbiome,” that is, the vast array of microorganisms—which include many species of bacteria or viruses—that dwell in or on the human body and comprise up to ten pounds of our body weight. They were part of the NIH-backed Human Microbiome Project, which sought to categorize the hundreds of thousands of microbe species of microbes. The end goal was to discover the role that these microbes play in human health and disease.

The Gladstone team had been studying microbes that reside in the human gut, based on fecal samples taken from people living in the United States. There are thousands of microbe species living in the human gut, and scientists are just beginning to understand how these species are essential for keeping the intestinal tract healthy and disease-free.

But they wondered whether the microbial makeup of people living in industrialized countries was different from that in the developing world, and if so, whether these differences influenced one’s risk for developing a particular disease. They only needed some samples to test their hypothesis.

Neuron
Southwestern Africa is home the Khoe-San, one of the oldest and most diverse populations on Earth.

“Trying to secure funding to travel halfway around the world to collect samples would be difficult, so we had put the idea on the backburner,” Sharpton explained. “So when Chris mentioned the microbial contaminants in their samples, we jumped at the chance to study them.”

And as so often happens in science, a collaboration emerged. Gignoux and his colleagues would hand over the microbes and focus on analzying the human DNA. The UCSF-Stanford team would trace the genetic history of the Khoe-San people, while the Gladstone team would focus on the Khoe-San microbiome.

“What we were looking for was whether the Khoe-San’s mouths contained different microbes than your average American,” said Pollard. “If so, we could then begin to study whether these microbial differences revealed key differences in human health and diseases between the two groups.”

Anthropologists often view the Khoe-San, or Bushmen, as a window into the evolution of our species. They are among the most genetically and linguistically diverse of all human populations—and they are also among the most ancient. Over the past several years, the Khoe-San’s DNA has been of particular interest to geneticists interested in this group’s evolutionary history.

“We hypothesized that the Khoe-San microbiome would therefore also be of particular interest, and might give us clues as to the origins of particular microbiome-related diseases,” Pollard added. “For example, we’ve been researching how the concentrations of particular microbe species in the gut may influence one’s risk for developing inflammatory bowel disease, or IBD.”

IBD—the two most common forms of which are ulcerative colitis and Crohn’s disease—affects approximately 1.4 million Americans, but is virtually absent in the Khoe-San. Because the Khoe-San have little or no access to antibiotics or processed foods, Pollard and her team have hypothesized that the Khoe-San’s microbiome may be closer to our species’ “ancestral” microbiome, and may therefore lend clues as to how the presence or absence of particular microbe species could influence one’s risk for developing IBD.

Analyzing the Khoe-San microbiome as it relates to IBD would require additional fecal sample collection. However, the Gladstone team’s initial analysis is already revealing interesting results.

“The types of microbe species living in the Khoe-San mouths are quite different from those living in the mouths of Americans—so this initial research is really a proof of principle that two genetically distinct populations can also be distinct from each other at the microbial level,” continued Sharpton. “As we continue to study the microbes of these and other populations around the world, we’re optimistic that we can map the evolutionary history of the human microbiome.”

This serendipitous collaboration between geneticists may be the first of many. Just as the past thirty years has yielded a wealth of information on the human genome, the next thirty could yield new insights into the human microbiome, and how this microbiome is a key player in defining who we are, and where we come from.