HMPP_Proposal.pdf – National Human Genome Research

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Pilot Project to Expand the Number of Sequences of Culturable Microbes from the 
                                 Human Body 

                     George Weinstock, Richard Gibbs 
          Human Genome Sequencing Center, Baylor College of Medicine 

                 Richard Wilson, Jeffrey Gordon, Sandra Clifton 
                Genome Sequencing Center, Washington University 

                          Bruce Birren, Chad Nusbaum 
                     The Broad Institute of MIT and Harvard
Summary 

We propose a Human Microbiome Pilot Project (HMPP) to generate key data that are 
needed to design a cost effective large scale Human Microbiome Project.  Specifically, 
this pilot will: 

1.  Create reference genome sequences of representatives of divisions (superkingdoms) of 
bacteria and archaea in targeted human host habitats to assist assembly and/or 
interpretation of metagenomic sequence data. 
2.  Define the quality of the sequence and annotation required for these references and the 
appropriate technologies with which to produce it. 
3.  Collect data needed to design effective largescale metagenomic sampling methods, 
including: 
4.  Determine the extent and nature of diversity within members of individual `species' in 
a single host's habitats, and between different hosts 
5.  Define the variation in prevalence of these different phylotypes and hence the required 
sensitivity of sampling methods. 
6.  Establish the relative levels of bacterial, archaeal and eukaryotic microbes and viruses 
in these communities. 
7.  Explore new methods for storing, displaying, and analyzing these data as necessary to 
enable rapid progress to a full scale Human Microbiome Project. 

The project will be performed by the three NHGRIfunded Genome Centers with 
coordination and advice from the NHGRI staff and an HMPP Advisory Panel. The 
project will also coordinate with other groups engaged in human microbiome work and 
with data repositories that are involved in collecting and presenting human microbiome 
data.




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Introduction 

The collection of trillions of microorganisms resident in the human body form complex 
communities primarily concentrated in a few body sites (Table 1) (Paustian, 2006 
Tierno, 2001). These communities contribute to our normal postnatal development, play a 
significant role in defining our physiology, and vary according to gender, age, 
environment, diet, and disease states. The key determinants and the degree of variation 
are not well understood. 

                     Table 1. The Normal Human Microbiota 
                  Body Site           bacteria/ml or   # 
                                      gram             species 

                  Respiratory                                   ? 
                                             3    4 
                  Nose                    10  10 
                                            10 
                  Oral                    10   total            >700 
                                            8    10 
                  Saliva                  10  10 
                                            12 
                  Gingival crevice        10 
                                            11 
                  Tooth surface           10 
                                            14 
                  Gastrointestinal        10    total           >1000 
                  Tract 
                                            0   4 
                  Stomach                 10  10 
                                            4   7 
                  Small intestines        10  10 
                                            11    12 
                  Colon (feces)           10   10 
                                            12 
                  Skin                    10   total            ? 
                                            5 
                  Surface                 10 

                  Urogenital                                    ? 
                                             9 
                  Vagina                  10 
                                            13 
                  Human cells             10    total 

While most thinking about the microbial origins of causes of disease has focused on 
invasion by pathogens, increasing attention is being paid to the idea that the normal 
microbiota affects predisposition to and can be a critical contributor to a number of 
pathologic states. Some of the better understood examples, such as dental caries, 
gingivitis, and vaginitis, result from changes in the composition of the oral and vaginal 
microbiota with associated host inflammatory responses. These can be thought of as 
"ecological diseases" which result from alteration of the normal balance of microbes in a 
community. 

More novel mechanisms are being discovered as well. For example, recent studies 
(Turnbaugh et al., 2006 Ley et al., 2006) show a correlation between the abundance of


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different bacterial divisions in the gut and obesity. In this case, the amount of energy 
harvested from the diet is affected by the microbial community structure. Additional 
discussion of the importance of the gut microbiota was presented in a previous white 
paper to the NHGRI (Gordon et al., 2005). One hopes that an understanding of the 
connection between microbial communities and human health will lead to new therapies 
and diagnostics. Therapies could involve manipulating the composition of microbial 
communities, or the human genes and gene products whose expression and activities are 
found to be regulated by the microbiota, or using the chemical entities produced by 
microbial communities as therapeutic agents. Diagnostics could involve the ideas 
borrowed from ecology, such as  "sentinel species"  organisms whose population 
dynamics are particularly sensitive to environmental changes (eg, changes in host 
physiology) and indicative of impending conditions. 

As recognition of the importance of the normal microbiota of the human body has grown 
in recent years, several concepts have emerged. First is the idea that a microbial 
community is an important operational element itself. Although many organisms within a 
community cannot be cultured in isolation, they exist in the community environment, 
which includes not only microbial neighbors but also the host habitat. This community 
("biome"), can be thought of as a unit analogous to an organ, and its genome as a 
"metagenome" (using meta to denote something of a higher order) comprising the 
genomes of the included community organisms. This microbial metagenome 
(microbiome) has been referred to as the "second human genome" and the concept has 
been suggested of the human as a "superorganism" whose genetic and metabolic 
landscape is an amalgamation of microbial and human components (Gill et al., 2006). 
The interactions between components of this superorganism are poorly understood and 
offer an important area for future research. 

The Human Microbiome Project (HMP) has been proposed to further our understanding 
of this aspect of human biology. In the broadest terms the HMP would produce reference 
sequences for representative genomes of the human microbiota, and perform 
metagenomic analyses (sequencing of microbial communities as mixtures of genomes) of 
samples obtained from individuals representing different aspects of the human lifecycle 
(i.e. males and females of varying ages with various lifestyles and living conditions, and 
with physiologic and pathophyisologic states, etc.). The reference sequences would allow 
the component organisms to be identified in the metagenomic samples and comparison of 
the metagenomic data would allow correlations to be made between the content of 
organismal and gene lineages and the human condition, as in the obesity example cited 
above. 

The HMP is a very complex project, given the genetic/environmental/lifestyle variations 
that exist among humans, the variations in the composition of microbial communities that 
exist between individuals, the importance of considering space and time when sampling 
diversity in a given host habitat, the question of whether the species concept can be 
meaningfully applied to the microbial world, technical challenges in deep community 
sampling given the enormous range of abundance of different microbial phylotypes 
within some host habitats, the inability to culture most members of a microbiota using



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current methods, and  many other issues. Nevertheless, while still at the conceptual stage, 
the HMP has gained much momentum over the last year, in part because of the 
introduction of a new generation of highly parallel DNA sequencers, and in part by the 
development of new computational tools for comparing microbial communities whose 
composition has been described by 16S rRNA gene sequencebased enumeration. Within 
the NIH, several discussions have been held and most recently the HMP has been 
selected for further development as one of the next Roadmap initiatives. In Europe, a 
conference was held addressing the idea of an international HMP, and recently the 
European Union announced funding for this initiative (Eichinger, 2007). Outside of the 
EU, there has been a commitment to the project at the Wellcome Trust Sanger Institute, 
and genome centers in China, Japan, and elsewhere have indicated their enthusiasm to 
participate with local funding. Despite a need to clarify many technical details, the broad 
enthusiasm for the concept indicates that it will eventually become a reality. 

Establishing clear pilot studies at the appropriate scale to address key questions is 
critically important for the successful design of the HMP. NIH is currently funding 
several metagenomic projects. These include a RFA from the National Institute for 
Dental and Craniofacial Research (NIDCR) for metagenomic research of the oral cavity 
(currently being reissued) and a project at The Institute for Genomic Research (TIGR) 
funded by the National Institute for Allergies and Infectious Diseases (NIAID) for 
metagenomic studies of the vaginal flora. Last, but not least, the NHGRI approved the 
Human Gut Microbiome Initiative at the Genome Sequencing Center at Washington 
University in 2005 (Gordon et al., 2005). 

These initial projects are important, but not of comparable scale to earlier NHGRI pilot 
studies for the Human Genome Project (during 19961998) or the ENCODE project 
(currently being completed). In this proposal we seek to expand the existing NHGRI pilot 
project, expanding it to include all three NHGRIfunded Genome Centers and broaden 
the scope. The need to obtain more information for the HMP through such projects is 
becoming pressing as the NIH Roadmap and EU initiatives move forward.




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