The Experts below are selected from a list of 31011 Experts worldwide ranked by ideXlab platform
Curtis Huttenhower - One of the best experts on this subject based on the ideXlab platform.
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strain level epidemiology of microbial communities and the Human Microbiome
Genome Medicine, 2020Co-Authors: Curtis Huttenhower, Eric A Franzosa, Yan Yan, Long H NguyenAbstract:The biological importance and varied metabolic capabilities of specific microbial strains have long been established in the scientific community. Strains have, in the past, been largely defined and characterized based on microbial isolates. However, the emergence of new technologies and techniques has enabled assessments of their ecology and phenotypes within microbial communities and the Human Microbiome. While it is now more obvious how pathogenic strain variants are detrimental to Human health, the consequences of subtle genetic variation in the Microbiome have only recently been exposed. Here, we review the operational definitions of strains (e.g., genetic and structural variants) as they can now be identified from microbial communities using different high-throughput, often culture-independent techniques. We summarize the distribution and diversity of strains across the Human body and their emerging links to health maintenance, disease risk and progression, and biochemical responses to perturbations, such as diet or drugs. We list methods for identifying, quantifying, and tracking strains, utilizing high-throughput sequencing along with other molecular and “culturomics” technologies. Finally, we discuss implications of population studies in bridging experimental gaps and leading to a better understanding of the health effects of strains in the Human Microbiome.
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functional and phylogenetic assembly of microbial communities in the Human Microbiome
Trends in Microbiology, 2014Co-Authors: Afrah Shafquat, Regina Joice, Sheri L Simmons, Curtis HuttenhowerAbstract:Microbial communities associated with the Human body, that is, the Human Microbiome, are complex ecologies critical for normal development and health. The taxonomic and phylogenetic composition of these communities tends to significantly differ among individuals, precluding the definition of a simple, shared set of ‘core' microbes. Here, we review recent evidence and ecological theory supporting the assembly of host-associated microbial communities in terms of functional traits rather than specific organisms. That is, distinct microbial species may be responsible for specific host-associated functions and phenotypes in distinct hosts. We discuss how ecological processes (selective and stochastic forces) governing the assembly of metazoan communities can be adapted to describe microbial ecologies in host-associated environments, resulting in both niche-specific and ‘core' metabolic and other pathways maintained throughout the Human Microbiome. The extent to which phylogeny and functional traits are linked in host-associated microbes, as opposed to unlinked by mechanisms, such as lateral transfer, remains to be determined. However, the definition of these functional assembly rules within microbial communities using controlled model systems and integrative ‘omics' represents a fruitful opportunity for molecular systems ecology.
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a guide to enterotypes across the Human body meta analysis of microbial community structures in Human Microbiome datasets
PLOS Computational Biology, 2013Co-Authors: Omry Koren, Dan Knights, Rob Knight, Nicola Segata, Levi Waldron, Antonio Gonzalez, Curtis HuttenhowerAbstract:Recent analyses of Human-associated bacterial diversity have categorized individuals into ‘enterotypes’ or clusters based on the abundances of key bacterial genera in the gut microbiota. There is a lack of consensus, however, on the analytical basis for enterotypes and on the interpretation of these results. We tested how the following factors influenced the detection of enterotypes: clustering methodology, distance metrics, OTU-picking approaches, sequencing depth, data type (whole genome shotgun (WGS) vs.16S rRNA gene sequence data), and 16S rRNA region. We included 16S rRNA gene sequences from the Human Microbiome Project (HMP) and from 16 additional studies and WGS sequences from the HMP and MetaHIT. In most body sites, we observed smooth abundance gradients of key genera without discrete clustering of samples. Some body habitats displayed bimodal (e.g., gut) or multimodal (e.g., vagina) distributions of sample abundances, but not all clustering methods and workflows accurately highlight such clusters. Because identifying enterotypes in datasets depends not only on the structure of the data but is also sensitive to the methods applied to identifying clustering strength, we recommend that multiple approaches be used and compared when testing for enterotypes.
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biodiversity and functional genomics in the Human Microbiome
Trends in Genetics, 2013Co-Authors: Xochitl C Morgan, Curtis Huttenhower, Nicola SegataAbstract:Over the course of our lives, Humans are colonized by a tremendous diversity of commensal microbes, which comprise the Human Microbiome. The collective genetic potential (metagenome) of the Human Microbiome is orders of magnitude more than the Human genome, and it profoundly affects Human health and disease in ways we are only beginning to understand. Advances in computing and high-throughput sequencing have enabled population-level surveys such as MetaHIT and the recently released Human Microbiome Project, detailed investigations of the Microbiome in Human disease, and mechanistic studies employing gnotobiotic model organisms. The resulting knowledge of Human Microbiome composition, function, and range of variation across multiple body sites has begun to assemble a rich picture of commensal host-microbe and microbe-microbe interactions as well as their roles in Human health and disease and their potential as diagnostic and therapeutic tools.
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The Human Microbiome Project: A Community Resource for the Healthy Human Microbiome
PLOS Biology, 2012Co-Authors: Dirk Gevers, Katherine H Huang, Rob Knight, Barbara A Methe, Karen E Nelson, Joseph F Petrosino, Amy L. Mcguire, Bruce W. Birren, Owen White, Curtis HuttenhowerAbstract:This manuscript describes the NIH Human Microbiome Project, including a brief review of Human Microbiome research, a history of the project, and a comprehensive overview of the consortium's recent collection of publications analyzing the Human Microbiome.
Rob Knight - One of the best experts on this subject based on the ideXlab platform.
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challenges in the construction of knowledge bases for Human Microbiome disease associations
Microbiome, 2019Co-Authors: Varsha D Badal, Dustin Wright, Yannis Katsis, Austin D Swafford, Rob KnightAbstract:The last few years have seen tremendous growth in Human Microbiome research, with a particular focus on the links to both mental and physical health and disease. Medical and experimental settings provide initial sources of information about these links, but individual studies produce disconnected pieces of knowledge bounded in context by the perspective of expert researchers reading full-text publications. Building a knowledge base (KB) consolidating these disconnected pieces is an essential first step to democratize and accelerate the process of accessing the collective discoveries of Human disease connections to the Human Microbiome. In this article, we survey the existing tools and development efforts that have been produced to capture portions of the information needed to construct a KB of all known Human Microbiome-disease associations and highlight the need for additional innovations in natural language processing (NLP), text mining, taxonomic representations, and field-wide vocabulary standardization in Human Microbiome research. Addressing these challenges will enable the construction of KBs that help identify new insights amenable to experimental validation and potentially clinical decision support.
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evaluating the information content of shallow shotgun metagenomics
bioRxiv, 2018Co-Authors: Benjamin Hillmann, Rob Knight, Gabriel A Alghalith, Robin R Shieldscutler, Qiyun Zhu, Daryl M Gohl, Kenneth B Beckman, Dan KnightsAbstract:Although microbial communities are associated with many aspects of Human, environmental, plant, and animal health, there exists no cost-efficient method for precisely characterizing the species and genes present in such communities. While deep whole-genome shotgun (WGS) sequencing provides the highest-level of taxonomic and functional resolution, it is often prohibitively expensive for large-scale studies. The prevailing alternative, high-throughput 16S rRNA gene amplicon sequencing (16S), often does not resolve taxonomy past the genus level and provides only moderately accurate predictions of the functional profile. Thus, there is currently no widely accepted approach to affordable, high-resolution, taxonomic and functional Microbiome analysis. We evaluated the information content of shallow shotgun sequencing with as low as 0.5 million sequences per sample as a possible alternative to 16S sequencing for large Human Microbiome studies. We describe a library preparation protocol that enables shallow shotgun sequencing at approximately the same per-sample cost as 16S. We used multiple real and simulated biological data sets, including two novel Human stool samples with ultra-deep sequencing of 2.5 billion sequences per sample, to demonstrate that shallow shotgun recovers accurate species-level taxonomic and functional profiles of the Human Microbiome. We also highlight some of the inherent limitations of shallow shotgun sequencing, and we note that 16S sequencing is still a valuable and important method for taxonomic profiling of novel environments. Although deep WGS remains the gold standard for high-resolution Human Microbiome analysis, we recommend that researchers consider shallow shotgun sequencing as an alternative to 16S for performing large-scale Human Microbiome research studies.
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current understanding of the Human Microbiome
Nature Medicine, 2018Co-Authors: Martin J Blaser, Gregory J Caporaso, Jack A Gilbert, Susan V Lynch, Janet K Jansson, Rob KnightAbstract:Our understanding of the link between the Human Microbiome and disease, including obesity, inflammatory bowel disease, arthritis and autism, is rapidly expanding. Improvements in the throughput and accuracy of DNA sequencing of the genomes of microbial communities that are associated with Human samples, complemented by analysis of transcriptomes, proteomes, metabolomes and immunomes and by mechanistic experiments in model systems, have vastly improved our ability to understand the structure and function of the Microbiome in both diseased and healthy states. However, many challenges remain. In this review, we focus on studies in Humans to describe these challenges and propose strategies that leverage existing knowledge to move rapidly from correlation to causation and ultimately to translation into therapies.
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a guide to enterotypes across the Human body meta analysis of microbial community structures in Human Microbiome datasets
PLOS Computational Biology, 2013Co-Authors: Omry Koren, Dan Knights, Rob Knight, Nicola Segata, Levi Waldron, Antonio Gonzalez, Curtis HuttenhowerAbstract:Recent analyses of Human-associated bacterial diversity have categorized individuals into ‘enterotypes’ or clusters based on the abundances of key bacterial genera in the gut microbiota. There is a lack of consensus, however, on the analytical basis for enterotypes and on the interpretation of these results. We tested how the following factors influenced the detection of enterotypes: clustering methodology, distance metrics, OTU-picking approaches, sequencing depth, data type (whole genome shotgun (WGS) vs.16S rRNA gene sequence data), and 16S rRNA region. We included 16S rRNA gene sequences from the Human Microbiome Project (HMP) and from 16 additional studies and WGS sequences from the HMP and MetaHIT. In most body sites, we observed smooth abundance gradients of key genera without discrete clustering of samples. Some body habitats displayed bimodal (e.g., gut) or multimodal (e.g., vagina) distributions of sample abundances, but not all clustering methods and workflows accurately highlight such clusters. Because identifying enterotypes in datasets depends not only on the structure of the data but is also sensitive to the methods applied to identifying clustering strength, we recommend that multiple approaches be used and compared when testing for enterotypes.
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The Human Microbiome Project: A Community Resource for the Healthy Human Microbiome
PLOS Biology, 2012Co-Authors: Dirk Gevers, Katherine H Huang, Rob Knight, Barbara A Methe, Karen E Nelson, Joseph F Petrosino, Amy L. Mcguire, Bruce W. Birren, Owen White, Curtis HuttenhowerAbstract:This manuscript describes the NIH Human Microbiome Project, including a brief review of Human Microbiome research, a history of the project, and a comprehensive overview of the consortium's recent collection of publications analyzing the Human Microbiome.
Jay L Mellies - One of the best experts on this subject based on the ideXlab platform.
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myoviridae phage pdx kills enteroaggregative escherichia coli without Human Microbiome dysbiosis
Journal of Medical Microbiology, 2020Co-Authors: Leah C S Cepko, Eliotte E Garling, Madeline J Dinsdale, William P Scott, Loralee Bandy, Timothy J Nice, Joshua J Faberhammond, Jay L MelliesAbstract:Introduction. Bacteriophage therapy can be developed to target emerging diarrhoeal pathogens, but doing so in the absence of Microbiome disruption, which occurs with antibiotic treatment, has not been established. Aim. Identify a therapeutic bacteriophage that kills diarrhoeagenic enteroaggregative Escherichia coli (EAEC) while leaving the Human Microbiome intact. Methodology. Phages from wastewater in Portland, OR, USA were screened for bacteriolytic activity by overlay assay. One isolated phage, PDX, was classified by electron microscopy and genome sequencing. A mouse model of infection determined whether the phage was therapeutic against EAEC. 16S metagenomic analysis of anaerobic cultures determined whether a normal Human Microbiome was altered by treatment. Results. Escherichia virus PDX, a member of the strictly lytic family Myoviridae, killed a case-associated EAEC isolate from a child in rural Tennessee in a dose-dependent manner, and killed EAEC isolates from Columbian children. A single dose of PDX (multiplicity of infection: 100) 1 day post-infection reduced EAEC recovered from mouse faeces. PDX also killed EAEC when cultured anaerobically in the presence of Human faecal bacteria. While the addition of EAEC reduced the β-diversity of the Human microbiota, that of the cultures with either faeces alone, faeces with EAEC and PDX, or with just PDX phage was not different statistically. Conclusion. PDX killed EAEC isolate EN1E-0007 in vivo and in vitro, while not altering the diversity of normal Human microbiota in anaerobic culture, and thus could be part of an effective therapy for children in developing countries and those suffering from EAEC-mediated traveller’s diarrhoea without causing dysbiosis.
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myoviridae phage pdx kills enteroaggregative escherichia coli without Human Microbiome dysbiosis
bioRxiv, 2019Co-Authors: Leah C S Cepko, Eliotte E Garling, Madeline J Dinsdale, William P Scott, Loralee Bandy, Timothy J Nice, Joshua J Faberhammond, Jay L MelliesAbstract:Abstract Purpose To identify therapeutic a bacteriophage that kills diarrheagenic enteroaggregative Escherichia coli (EAEC) while leaving the Human Microbiome intact. Methodology Phages from wastewater in Portland, OR, were screened for bacteriolytic activity using an overlay assay, and isolated in a sequential procedure to enrich for the recognition of core bacterial antigens. Electron microscopy and genome sequencing were performed to classify the isolated phage, and the host range was determined by spot tests and plaque assays. One-step growth curves and time-kill assays were conducted to characterize the life cycle of the phage, and to interrogate the multiplicity of infection (MOI) necessary for killing. A mouse model of infection was used to determine whether the phage could be used therapeutically against EAEC in vivo. Anaerobic culture in the presence of Human fecal bacteria determined whether the phage could kill EAEC in vitro, and to assess whether the Microbiome had been altered. Results The isolated phage, termed Escherichia virus PDX, is a member of the strictly lytic Myoviridae family of viruses. Phage PDX killed EAEC isolate EN1E-0227, a case-associated isolate from a child in rural Tennessee, in a dose-dependent manner, and also formed plaques on case-associated clinical EAEC isolates from Columbian children suffering from diarrhea. A single dose of PDX, at a MOI of 100, one day post infection, reduced the population of recovered EAEC isolate EN1E-0227 bacteria in fecal pellets in a mouse model of colonization, over a five-day period. Phage PDX also killed EAEC EN1E-0227 when cultured anaerobically in vitro in the presence of Human fecal bacteria. While the addition of EAEC EN1E-0227 reduced the α-diversity of the Human microbiota, that of the cultures with either feces alone, feces with EAEC and PDX, or with just the PDX phage were not different statistically, as measured by Chao1 and Shannon diversity indices. Additionally, β-diversity and differential abundance analyses show that conditions with PDX added were not different from feces alone, but all groups were significantly different from feces + EAEC. Conclusions The strictly bacteriolytic, Myoviridae Escherichia virus PDX killed EAEC isolate EN1E-0227 bacteria both in vivo and in vitro, while simultaneously not altering the diversity of normal Human microbiota in anaerobic culture. Thus, the PDX phage could be part of an effective therapeutic intervention for children in developing countries who suffer from acute, or persistent EAEC-mediated diarrhea, and to help reduce the serious effects of environmental enteropathy. Because the emerging pathogen EAEC is now the second leading cause of traveler’s diarrhea, PDX could also provide therapeutic relief for these individuals, particularly in light of the growing crisis of antibiotic resistances.
Mark J Daly - One of the best experts on this subject based on the ideXlab platform.
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host genetic variation and its Microbiome interactions within the Human Microbiome project
Genome Medicine, 2018Co-Authors: Raivo Kolde, Gholamali Rahnavard, Eric A Franzosa, Andrew Brantley Hall, Hera Vlamakis, Christine Stevens, Mark J DalyAbstract:Despite the increasing recognition that microbial communities within the Human body are linked to health, we have an incomplete understanding of the environmental and molecular interactions that shape the composition of these communities. Although host genetic factors play a role in these interactions, these factors have remained relatively unexplored given the requirement for large population-based cohorts in which both genotyping and Microbiome characterization have been performed. We performed whole-genome sequencing of 298 donors from the Human Microbiome Project (HMP) healthy cohort study to accompany existing deep characterization of their Microbiomes at various body sites. This analysis yielded an average sequencing depth of 32x, with which we identified 27 million (M) single nucleotide variants and 2.3 M insertions-deletions. Taxonomic composition and functional potential of the Microbiome covaried significantly with genetic principal components in the gastrointestinal tract and oral communities, but not in the nares or vaginal microbiota. Example associations included validation of known associations between FUT2 secretor status, as well as a variant conferring hypolactasia near the LCT gene, with Bifidobacterium longum abundance in stool. The associations of microbial features with both high-level genetic attributes and single variants were specific to particular body sites, highlighting the opportunity to find unique genetic mechanisms controlling Microbiome properties in the microbial communities from multiple body sites. This study adds deep sequencing of host genomes to the body-wide Microbiome sequences already extant from the HMP healthy cohort, creating a unique, versatile, and well-controlled reference for future studies seeking to identify host genetic modulators of the Microbiome.
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host genetic variation and its Microbiome interactions within the Human Microbiome project
Genome Medicine, 2018Co-Authors: Raivo Kolde, Gholamali Rahnavard, Eric A Franzosa, Andrew Brantley Hall, Hera Vlamakis, Christine Stevens, Mark J DalyAbstract:Despite the increasing recognition that microbial communities within the Human body are linked to health, we have an incomplete understanding of the environmental and molecular interactions that shape the composition of these communities. Although host genetic factors play a role in these interactions, these factors have remained relatively unexplored given the requirement for large population-based cohorts in which both genotyping and Microbiome characterization have been performed. We performed whole-genome sequencing of 298 donors from the Human Microbiome Project (HMP) healthy cohort study to accompany existing deep characterization of their Microbiomes at various body sites. This analysis yielded an average sequencing depth of 32x, with which we identified 27 million (M) single nucleotide variants and 2.3 M insertions-deletions. Taxonomic composition and functional potential of the Microbiome covaried significantly with genetic principal components in the gastrointestinal tract and oral communities, but not in the nares or vaginal microbiota. Example associations included validation of known associations between FUT2 secretor status, as well as a variant conferring hypolactasia near the LCT gene, with Bifidobacterium longum abundance in stool. The associations of microbial features with both high-level genetic attributes and single variants were specific to particular body sites, highlighting the opportunity to find unique genetic mechanisms controlling Microbiome properties in the microbial communities from multiple body sites. This study adds deep sequencing of host genomes to the body-wide Microbiome sequences already extant from the HMP healthy cohort, creating a unique, versatile, and well-controlled reference for future studies seeking to identify host genetic modulators of the Microbiome.
Eric A Franzosa - One of the best experts on this subject based on the ideXlab platform.
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metatranscriptomics for the Human Microbiome and microbial community functional profiling
Social Science Research Network, 2021Co-Authors: Yan Yan, Long H Nguyen, Yancong Zhang, Kelsey N Thompson, Tobyn Branck, Eric A FranzosaAbstract:Shotgun metatranscriptomics (MTX) is an increasingly practical way to survey microbial community gene function and regulation at scale. This review begins by summarizing the motivations for community transcriptomics and the history of the field. We then explore the principles, best practices, and challenges of contemporary MTX workflows: beginning with laboratory methods for isolation and sequencing of community RNA, followed by informatics methods for quantifying RNA features, and finally statistical methods for detecting differential expression in a community context. In thesecond half of the review, we survey important biological findings from the MTX literature, drawing examples from the Human Microbiome, other (nonHuman) host-associated Microbiomes, and the environment. Across these examples, MTX methods prove invaluable for probing microbe-microbe and host-microbe interactions, the dynamics of energy harvest and chemical cycling, and responses to environmental stresses. We conclude with a review of open challenges in the MTX field, including making assays and analyses more robust, accessible, and adaptable to new technologies; deciphering roles for millions of uncharacterized microbial transcripts; and solving applied problems such as biomarker discovery and development of microbial therapeutics.
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strain level epidemiology of microbial communities and the Human Microbiome
Genome Medicine, 2020Co-Authors: Curtis Huttenhower, Eric A Franzosa, Yan Yan, Long H NguyenAbstract:The biological importance and varied metabolic capabilities of specific microbial strains have long been established in the scientific community. Strains have, in the past, been largely defined and characterized based on microbial isolates. However, the emergence of new technologies and techniques has enabled assessments of their ecology and phenotypes within microbial communities and the Human Microbiome. While it is now more obvious how pathogenic strain variants are detrimental to Human health, the consequences of subtle genetic variation in the Microbiome have only recently been exposed. Here, we review the operational definitions of strains (e.g., genetic and structural variants) as they can now be identified from microbial communities using different high-throughput, often culture-independent techniques. We summarize the distribution and diversity of strains across the Human body and their emerging links to health maintenance, disease risk and progression, and biochemical responses to perturbations, such as diet or drugs. We list methods for identifying, quantifying, and tracking strains, utilizing high-throughput sequencing along with other molecular and “culturomics” technologies. Finally, we discuss implications of population studies in bridging experimental gaps and leading to a better understanding of the health effects of strains in the Human Microbiome.
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host genetic variation and its Microbiome interactions within the Human Microbiome project
Genome Medicine, 2018Co-Authors: Raivo Kolde, Gholamali Rahnavard, Eric A Franzosa, Andrew Brantley Hall, Hera Vlamakis, Christine Stevens, Mark J DalyAbstract:Despite the increasing recognition that microbial communities within the Human body are linked to health, we have an incomplete understanding of the environmental and molecular interactions that shape the composition of these communities. Although host genetic factors play a role in these interactions, these factors have remained relatively unexplored given the requirement for large population-based cohorts in which both genotyping and Microbiome characterization have been performed. We performed whole-genome sequencing of 298 donors from the Human Microbiome Project (HMP) healthy cohort study to accompany existing deep characterization of their Microbiomes at various body sites. This analysis yielded an average sequencing depth of 32x, with which we identified 27 million (M) single nucleotide variants and 2.3 M insertions-deletions. Taxonomic composition and functional potential of the Microbiome covaried significantly with genetic principal components in the gastrointestinal tract and oral communities, but not in the nares or vaginal microbiota. Example associations included validation of known associations between FUT2 secretor status, as well as a variant conferring hypolactasia near the LCT gene, with Bifidobacterium longum abundance in stool. The associations of microbial features with both high-level genetic attributes and single variants were specific to particular body sites, highlighting the opportunity to find unique genetic mechanisms controlling Microbiome properties in the microbial communities from multiple body sites. This study adds deep sequencing of host genomes to the body-wide Microbiome sequences already extant from the HMP healthy cohort, creating a unique, versatile, and well-controlled reference for future studies seeking to identify host genetic modulators of the Microbiome.
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host genetic variation and its Microbiome interactions within the Human Microbiome project
Genome Medicine, 2018Co-Authors: Raivo Kolde, Gholamali Rahnavard, Eric A Franzosa, Andrew Brantley Hall, Hera Vlamakis, Christine Stevens, Mark J DalyAbstract:Despite the increasing recognition that microbial communities within the Human body are linked to health, we have an incomplete understanding of the environmental and molecular interactions that shape the composition of these communities. Although host genetic factors play a role in these interactions, these factors have remained relatively unexplored given the requirement for large population-based cohorts in which both genotyping and Microbiome characterization have been performed. We performed whole-genome sequencing of 298 donors from the Human Microbiome Project (HMP) healthy cohort study to accompany existing deep characterization of their Microbiomes at various body sites. This analysis yielded an average sequencing depth of 32x, with which we identified 27 million (M) single nucleotide variants and 2.3 M insertions-deletions. Taxonomic composition and functional potential of the Microbiome covaried significantly with genetic principal components in the gastrointestinal tract and oral communities, but not in the nares or vaginal microbiota. Example associations included validation of known associations between FUT2 secretor status, as well as a variant conferring hypolactasia near the LCT gene, with Bifidobacterium longum abundance in stool. The associations of microbial features with both high-level genetic attributes and single variants were specific to particular body sites, highlighting the opportunity to find unique genetic mechanisms controlling Microbiome properties in the microbial communities from multiple body sites. This study adds deep sequencing of host genomes to the body-wide Microbiome sequences already extant from the HMP healthy cohort, creating a unique, versatile, and well-controlled reference for future studies seeking to identify host genetic modulators of the Microbiome.