Gill et al. (2006) conducted the first metagenomic study of the human gut microbiome. Metagenomics describes the ability to sequence all the genetic material in a sample without initially having to cultivate the microbial species that are present. The development of these methods was a huge step forward over sequencing methods that were focused on a single phylogenetic marker (as was the case with 16S rRNA) and other methods that were dependent on a PCR (polymerase chain reaction) amplification step that is now known to potentially introduce significant bias. For the Gill et al. (2006) study, even though the researchers sampled from only two individuals, all that microbial diversity again elicited much excitement. At that time, the J. Craig Venter Institute (JCVI) had one of the largest sequencing centers in the world, running about 100 Sanger sequencing machines around the clock that generated about 1-2 megabases per day. Today, the newest high-throughput sequencing technology is capable of generating an entire human genome in about 4 hours.3 Nelson noted that her first microbial genome sequence project involving the genome of Thermotoga maritime took approximately 2 years and cost about $2 million. Today, the same project could probably be done in an afternoon for less than $200. She predicted that sequencing technology will continue to advance. “I believe that sequencing is going to become like PCR,” she said. “Every grad student is going to have their own sequencing machine on their desktop.”

The largest human microbiome sequencing study to date is the National Institutes of Health (NIH)-funded Human Microbiome Project (HMP), whose focus is on generating a metagenomic reference database for “normal” individuals to serve as a resource for researchers studying microbiome-disease associations and other phenomena. The reference dataset is based on a human cohort of 300 individuals, with microbial genome data being collected from five major body sites (nasal, oral, skin, GI, and urogenital environments). When the project started, the goal was to sequence 1,000 reference genomes. Today, the goal is to sequence 3,000 reference genomes. Results from the first 178 genomes sequenced were published in 2010 (Human Microbiome Jumpstart Reference Strains Consortium, 2010). In addition to its mostly bacteria-focused work, the HMP also has an initiative to sequence several viruses and microeukaryotes that are associated with the human body.

The Microbiome and Disease

In parallel to the HMP, a number of other organizations have been funding microbiome work focused on specific diseases, with many researchers taking systems biology approaches and integrating multiple -omics

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3 The human genome contains an estimated 3,000 megabases.



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