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Next-Gen Sequencers to Power Much of Human Microbiome Projects

The National Institutes of Health last month approved an undisclosed amount of funding to support a five-year Human Microbiome Project under its Roadmap program “to characterize the microbial content of sites in the human body and examine whether changes in the microbiome can be related to disease.”
Leading up to this project, for which the NIH plans to issue requests for applications in the near future, is an NHGRI-funded Human Microbiome Pilot Project that took shape this year. In that pilot, the three large-scale sequencing centers aim to sequence at least 300 bacteria, create metagenomic data, test new sequencing technologies, and create standards for draft genomes.
Once that project is completed and the researchers have figured out which technologies are most cost-effective, “the spigot will open and we will do hundreds of genomes,” George Weinstock, co-director of the Baylor College of Medicine Human Genome Sequencing Center, who spearheaded the HMPP, said in an e-mail last week.
In addition, several research consortia around the world are currently embarking on large-scale projects to sequence and analyze microbes residing in the human body.
Although there has been much talk about an international human microbiome for years, the idea was only “seriously discussed as a large project” during a scientific meeting in Paris in 2005, said Weinstock. That meeting, whose attendees included international academic and industrial researchers and government funding agencies, resulted in a white paper that formalized the goals for a large-scale human microbiome project. Different countries are now adopting these in various local projects.  
In the US, the National Human Genome Research Institute approved a study by Washington University’s genome sequencing center in 2005 to sequence 100 gut bacteria by traditional Sanger sequencing to increase the number of reference genomes of the gut microbiome (see In Sequence 4/10/2007).
This year, the other two NHGRI-funded large-scale sequencing centers, at Baylor College of Medicine and the Broad Institute, joined Wash U to scale up the project into the Human Microbiome Pilot Project.
Funded with an as-yet undetermined amount contributed by the three centers, the HMPP aims to sequence at least 300 bacteria from the intestinal and urogenital tracts, and to produce metagenomic datasets from samples of these sites.
“All of these activities are to take advantage of new sequencing technologies to increase throughput and reduce costs,” according to Weinstock, who said part of the project will be “a serious comparison of different sequencing technologies” for both genome sequencing and metagenomic sequencing. The researchers also plan to establish standards for draft genome quality and their annotation.
When Wash U started sequencing gut microbes two year ago, 454 was just appearing on the scene and the plan was to sequence these bacteria by Sanger sequencing, Weinstock said.
“However, over the last two years, 454 has seriously challenged the Sanger methods for sequencing of bacterial-sized genomes, and with Solexa instruments at all the centers, and SOLiD to come out in Q4 of this year, there is now a lot of interest in seeing which of these methods will allow bacterial genomes to be sequenced most rapidly and inexpensively,” he said.
“And given the progress, particularly with 454 sequencing, in doing de novo genome sequences of microbes, there is increasing confidence in the ability to produce hundreds of genome sequences in the near term.”

“All of these activities are to take advantage of new sequencing technologies to increase throughput and reduce costs.”

To date, the centers have produced about 50 genomes, most of them at Washington University.
“The culmination of this two years of activity was the approval of the Human Microbiome Project as a Roadmap project” this May, Weinstock said, following a number of meetings and workshops in 2006, organized by several NIH institutes.
Neither details of the project nor its budget have been disclosed, but the project will likely last at least five, and maybe 10 years, according to Weinstock. “This will be the nucleus of the HMP, and the real start of it,” he said.
The NHGRI-funded sequencing centers have “a continuing dialogue” with the Wellcome Trust Sanger Institute, which also has human microbial sequencing activities going, according to Weinstock.
At least two other projects will contribute to the HMP, which does currently not exist as a centralized international project.
In Europe, a research consortium is waiting for approval this fall for a four-year, €19 million ($25.5 million) project to study microbes in the human intestinal tract. The project is slated to be funded with €12 million from the European Union and €7 million from participants.
Two European sequencing centers — the Wellcome Trust Sanger Institute and Genoscope in France —  will be involved, in addition to researchers from the European Molecular Biology Laboratory, Danish Polytechnical University, Odense University in Denmark, Novo Nordisk Steno Diabetes Center in Denmark, Vel d'Hebron Hospital in Barcelona, Institut National de la Recherche Agronomique in France, and Wageningen Research Center in the Netherlands.
The consortium plans to sequence the genomes of reference microbes as well as to generate metagenomic sequence data of samples from the human gut, according to Dusko Ehrlich, a researcher at INRA who coordinates the project.
“The extent of the sequencing that we foresee is on the order of one human genome,” he said. His consortium also plans to analyze variability of the human gut microbiome in the context of obesity and diseases.
Additionally, a joint Chinese-French metagenomics project aims to study and compare intestinal microbial samples from both countries, and to see how changes in diet alters intestinal flora. The project, which expects €4 million in funding for the first year, will be led by the Chinese Ministry of Science and the Chinese Academy of Sciences as well as Agence Nationale de la Recherche in France. Funding could be renewed for an additional two years. A funding decision is expected by mid-July, according to Ehrlich.

All three projects are planning to work together closely, so they do not duplicate each other’s efforts. “We expect very close coordination,” Ehrlich said.

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