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2.  Genetic diversity in cultured and wild marine cyanomyoviruses reveals phosphorus stress as a strong selective agent 
The ISME Journal  2013;7(9):1827-1841.
Viruses that infect marine cyanobacteria–cyanophages–often carry genes with orthologs in their cyanobacterial hosts, and the frequency of these genes can vary with habitat. To explore habitat-influenced genomic diversity more deeply, we used the genomes of 28 cultured cyanomyoviruses as references to identify phage genes in three ocean habitats. Only about 6–11% of genes were consistently observed in the wild, revealing high gene-content variability in these populations. Numerous shared phage/host genes differed in relative frequency between environments, including genes related to phosphorous acquisition, photorespiration, photosynthesis and the pentose phosphate pathway, possibly reflecting environmental selection for these genes in cyanomyovirus genomes. The strongest emergent signal was related to phosphorous availability; a higher fraction of genomes from relatively low-phosphorus environments–the Sargasso and Mediterranean Sea–contained host-like phosphorus assimilation genes compared with those from the N. Pacific Gyre. These genes are known to be upregulated when the host is phosphorous starved, a response mediated by pho box motifs in phage genomes that bind a host regulatory protein. Eleven cyanomyoviruses have predicted pho boxes upstream of the phosphate-acquisition genes pstS and phoA; eight of these have a conserved cyanophage-specific gene (PhCOG173) between the pho box and pstS. PhCOG173 is also found upstream of other shared phage/host genes, suggesting a unique regulatory role. Pho boxes are found upstream of high light-inducible (hli) genes in cyanomyoviruses, suggesting that this motif may have a broader role than regulating phosphorous-stress responses in infected hosts or that these hlis are involved in the phosphorous-stress response.
PMCID: PMC3749497  PMID: 23657361
cyanophage; cyanobacteria; phosphate; selective pressure
3.  ProPortal: a resource for integrated systems biology of Prochlorococcus and its phage 
Nucleic Acids Research  2011;40(Database issue):D632-D640.
ProPortal ( is a database containing genomic, metagenomic, transcriptomic and field data for the marine cyanobacterium Prochlorococcus. Our goal is to provide a source of cross-referenced data across multiple scales of biological organization—from the genome to the ecosystem—embracing the full diversity of ecotypic variation within this microbial taxon, its sister group, Synechococcus and phage that infect them. The site currently contains the genomes of 13 Prochlorococcus strains, 11 Synechococcus strains and 28 cyanophage strains that infect one or both groups. Cyanobacterial and cyanophage genes are clustered into orthologous groups that can be accessed by keyword search or through a genome browser. Users can also identify orthologous gene clusters shared by cyanobacterial and cyanophage genomes. Gene expression data for Prochlorococcus ecotypes MED4 and MIT9313 allow users to identify genes that are up or downregulated in response to environmental stressors. In addition, the transcriptome in synchronized cells grown on a 24-h light–dark cycle reveals the choreography of gene expression in cells in a ‘natural’ state. Metagenomic sequences from the Global Ocean Survey from Prochlorococcus, Synechococcus and phage genomes are archived so users can examine the differences between populations from diverse habitats. Finally, an example of cyanobacterial population data from the field is included.
PMCID: PMC3245167  PMID: 22102570
4.  Ecology of uncultured Prochlorococcus clades revealed through single-cell genomics and biogeographic analysis 
The ISME Journal  2012;7(1):184-198.
Prochlorococcus is the numerically dominant photosynthetic organism throughout much of the world's oceans, yet little is known about the ecology and genetic diversity of populations inhabiting tropical waters. To help close this gap, we examined natural Prochlorococcus communities in the tropical Pacific Ocean using a single-cell whole-genome amplification and sequencing. Analysis of the gene content of just 10 single cells from these waters added 394 new genes to the Prochlorococcus pan-genome—that is, genes never before seen in a Prochlorococcus cell. Analysis of marker genes, including the ribosomal internal transcribed sequence, from dozens of individual cells revealed several representatives from two uncultivated clades of Prochlorococcus previously identified as HNLC1 and HNLC2. While the HNLC clades can dominate Prochlorococcus communities under certain conditions, their overall geographic distribution was highly restricted compared with other clades of Prochlorococcus. In the Atlantic and Pacific oceans, these clades were only found in warm waters with low Fe and high inorganic P levels. Genomic analysis suggests that at least one of these clades thrives in low Fe environments by scavenging organic-bound Fe, a process previously unknown in Prochlorococcus. Furthermore, the capacity to utilize organic-bound Fe appears to have been acquired horizontally and may be exchanged among other clades of Prochlorococcus. Finally, one of the single Prochlorococcus cells sequenced contained a partial genome of what appears to be a prophage integrated into the genome.
PMCID: PMC3526172  PMID: 22895163
HNLC; Prochlorococcus; siderophore
5.  A framework for human microbiome research 
Methé, Barbara A. | Nelson, Karen E. | Pop, Mihai | Creasy, Heather H. | Giglio, Michelle G. | Huttenhower, Curtis | Gevers, Dirk | Petrosino, Joseph F. | Abubucker, Sahar | Badger, Jonathan H. | Chinwalla, Asif T. | Earl, Ashlee M. | FitzGerald, Michael G. | Fulton, Robert S. | Hallsworth-Pepin, Kymberlie | Lobos, Elizabeth A. | Madupu, Ramana | Magrini, Vincent | Martin, John C. | Mitreva, Makedonka | Muzny, Donna M. | Sodergren, Erica J. | Versalovic, James | Wollam, Aye M. | Worley, Kim C. | Wortman, Jennifer R. | Young, Sarah K. | Zeng, Qiandong | Aagaard, Kjersti M. | Abolude, Olukemi O. | Allen-Vercoe, Emma | Alm, Eric J. | Alvarado, Lucia | Andersen, Gary L. | Anderson, Scott | Appelbaum, Elizabeth | Arachchi, Harindra M. | Armitage, Gary | Arze, Cesar A. | Ayvaz, Tulin | Baker, Carl C. | Begg, Lisa | Belachew, Tsegahiwot | Bhonagiri, Veena | Bihan, Monika | Blaser, Martin J. | Bloom, Toby | Vivien Bonazzi, J. | Brooks, Paul | Buck, Gregory A. | Buhay, Christian J. | Busam, Dana A. | Campbell, Joseph L. | Canon, Shane R. | Cantarel, Brandi L. | Chain, Patrick S. | Chen, I-Min A. | Chen, Lei | Chhibba, Shaila | Chu, Ken | Ciulla, Dawn M. | Clemente, Jose C. | Clifton, Sandra W. | Conlan, Sean | Crabtree, Jonathan | Cutting, Mary A. | Davidovics, Noam J. | Davis, Catherine C. | DeSantis, Todd Z. | Deal, Carolyn | Delehaunty, Kimberley D. | Dewhirst, Floyd E. | Deych, Elena | Ding, Yan | Dooling, David J. | Dugan, Shannon P. | Dunne, Wm. Michael | Durkin, A. Scott | Edgar, Robert C. | Erlich, Rachel L. | Farmer, Candace N. | Farrell, Ruth M. | Faust, Karoline | Feldgarden, Michael | Felix, Victor M. | Fisher, Sheila | Fodor, Anthony A. | Forney, Larry | Foster, Leslie | Di Francesco, Valentina | Friedman, Jonathan | Friedrich, Dennis C. | Fronick, Catrina C. | Fulton, Lucinda L. | Gao, Hongyu | Garcia, Nathalia | Giannoukos, Georgia | Giblin, Christina | Giovanni, Maria Y. | Goldberg, Jonathan M. | Goll, Johannes | Gonzalez, Antonio | Griggs, Allison | Gujja, Sharvari | Haas, Brian J. | Hamilton, Holli A. | Harris, Emily L. | Hepburn, Theresa A. | Herter, Brandi | Hoffmann, Diane E. | Holder, Michael E. | Howarth, Clinton | Huang, Katherine H. | Huse, Susan M. | Izard, Jacques | Jansson, Janet K. | Jiang, Huaiyang | Jordan, Catherine | Joshi, Vandita | Katancik, James A. | Keitel, Wendy A. | Kelley, Scott T. | Kells, Cristyn | Kinder-Haake, Susan | King, Nicholas B. | Knight, Rob | Knights, Dan | Kong, Heidi H. | Koren, Omry | Koren, Sergey | Kota, Karthik C. | Kovar, Christie L. | Kyrpides, Nikos C. | La Rosa, Patricio S. | Lee, Sandra L. | Lemon, Katherine P. | Lennon, Niall | Lewis, Cecil M. | Lewis, Lora | Ley, Ruth E. | Li, Kelvin | Liolios, Konstantinos | Liu, Bo | Liu, Yue | Lo, Chien-Chi | Lozupone, Catherine A. | Lunsford, R. Dwayne | Madden, Tessa | Mahurkar, Anup A. | Mannon, Peter J. | Mardis, Elaine R. | Markowitz, Victor M. | Mavrommatis, Konstantinos | McCorrison, Jamison M. | McDonald, Daniel | McEwen, Jean | McGuire, Amy L. | McInnes, Pamela | Mehta, Teena | Mihindukulasuriya, Kathie A. | Miller, Jason R. | Minx, Patrick J. | Newsham, Irene | Nusbaum, Chad | O’Laughlin, Michelle | Orvis, Joshua | Pagani, Ioanna | Palaniappan, Krishna | Patel, Shital M. | Pearson, Matthew | Peterson, Jane | Podar, Mircea | Pohl, Craig | Pollard, Katherine S. | Priest, Margaret E. | Proctor, Lita M. | Qin, Xiang | Raes, Jeroen | Ravel, Jacques | Reid, Jeffrey G. | Rho, Mina | Rhodes, Rosamond | Riehle, Kevin P. | Rivera, Maria C. | Rodriguez-Mueller, Beltran | Rogers, Yu-Hui | Ross, Matthew C. | Russ, Carsten | Sanka, Ravi K. | Pamela Sankar, J. | Sathirapongsasuti, Fah | Schloss, Jeffery A. | Schloss, Patrick D. | Schmidt, Thomas M. | Scholz, Matthew | Schriml, Lynn | Schubert, Alyxandria M. | Segata, Nicola | Segre, Julia A. | Shannon, William D. | Sharp, Richard R. | Sharpton, Thomas J. | Shenoy, Narmada | Sheth, Nihar U. | Simone, Gina A. | Singh, Indresh | Smillie, Chris S. | Sobel, Jack D. | Sommer, Daniel D. | Spicer, Paul | Sutton, Granger G. | Sykes, Sean M. | Tabbaa, Diana G. | Thiagarajan, Mathangi | Tomlinson, Chad M. | Torralba, Manolito | Treangen, Todd J. | Truty, Rebecca M. | Vishnivetskaya, Tatiana A. | Walker, Jason | Wang, Lu | Wang, Zhengyuan | Ward, Doyle V. | Warren, Wesley | Watson, Mark A. | Wellington, Christopher | Wetterstrand, Kris A. | White, James R. | Wilczek-Boney, Katarzyna | Wu, Yuan Qing | Wylie, Kristine M. | Wylie, Todd | Yandava, Chandri | Ye, Liang | Ye, Yuzhen | Yooseph, Shibu | Youmans, Bonnie P. | Zhang, Lan | Zhou, Yanjiao | Zhu, Yiming | Zoloth, Laurie | Zucker, Jeremy D. | Birren, Bruce W. | Gibbs, Richard A. | Highlander, Sarah K. | Weinstock, George M. | Wilson, Richard K. | White, Owen
Nature  2012;486(7402):215-221.
A variety of microbial communities and their genes (microbiome) exist throughout the human body, playing fundamental roles in human health and disease. The NIH funded Human Microbiome Project (HMP) Consortium has established a population-scale framework which catalyzed significant development of metagenomic protocols resulting in a broad range of quality-controlled resources and data including standardized methods for creating, processing and interpreting distinct types of high-throughput metagenomic data available to the scientific community. Here we present resources from a population of 242 healthy adults sampled at 15 to 18 body sites up to three times, which to date, have generated 5,177 microbial taxonomic profiles from 16S rRNA genes and over 3.5 Tb of metagenomic sequence. In parallel, approximately 800 human-associated reference genomes have been sequenced. Collectively, these data represent the largest resource to date describing the abundance and variety of the human microbiome, while providing a platform for current and future studies.
PMCID: PMC3377744  PMID: 22699610
6.  MicrobesOnline: an integrated portal for comparative and functional genomics 
Nucleic Acids Research  2009;38(Database issue):D396-D400.
Since 2003, MicrobesOnline ( has been providing a community resource for comparative and functional genome analysis. The portal includes over 1000 complete genomes of bacteria, archaea and fungi and thousands of expression microarrays from diverse organisms ranging from model organisms such as Escherichia coli and Saccharomyces cerevisiae to environmental microbes such as Desulfovibrio vulgaris and Shewanella oneidensis. To assist in annotating genes and in reconstructing their evolutionary history, MicrobesOnline includes a comparative genome browser based on phylogenetic trees for every gene family as well as a species tree. To identify co-regulated genes, MicrobesOnline can search for genes based on their expression profile, and provides tools for identifying regulatory motifs and seeing if they are conserved. MicrobesOnline also includes fast phylogenetic profile searches, comparative views of metabolic pathways, operon predictions, a workbench for sequence analysis and integration with RegTransBase and other microbial genome resources. The next update of MicrobesOnline will contain significant new functionality, including comparative analysis of metagenomic sequence data. Programmatic access to the database, along with source code and documentation, is available at
PMCID: PMC2808868  PMID: 19906701
7.  Analysis of a Ferric Uptake Regulator (Fur) Mutant of Desulfovibrio vulgaris Hildenborough▿  
Applied and Environmental Microbiology  2007;73(17):5389-5400.
Previous experiments examining the transcriptional profile of the anaerobe Desulfovibrio vulgaris demonstrated up-regulation of the Fur regulon in response to various environmental stressors. To test the involvement of Fur in the growth response and transcriptional regulation of D. vulgaris, a targeted mutagenesis procedure was used for deleting the fur gene. Growth of the resulting Δfur mutant (JW707) was not affected by iron availability, but the mutant did exhibit increased sensitivity to nitrite and osmotic stresses compared to the wild type. Transcriptional profiling of JW707 indicated that iron-bound Fur acts as a traditional repressor for ferrous iron uptake genes (feoAB) and other genes containing a predicted Fur binding site within their promoter. Despite the apparent lack of siderophore biosynthesis genes within the D. vulgaris genome, a large 12-gene operon encoding orthologs to TonB and TolQR also appeared to be repressed by iron-bound Fur. While other genes predicted to be involved in iron homeostasis were unaffected by the presence or absence of Fur, alternative expression patterns that could be interpreted as repression or activation by iron-free Fur were observed. Both the physiological and transcriptional data implicate a global regulatory role for Fur in the sulfate-reducing bacterium D. vulgaris.
PMCID: PMC2042090  PMID: 17630305
8.  Energetic Consequences of Nitrite Stress in Desulfovibrio vulgaris Hildenborough, Inferred from Global Transcriptional Analysis†  
Many of the proteins that are candidates for bioenergetic pathways involved with sulfate respiration in Desulfovibrio spp. have been studied, but complete pathways and overall cell physiology remain to be resolved for many environmentally relevant conditions. In order to understand the metabolism of these microorganisms under adverse environmental conditions for improved bioremediation efforts, Desulfovibrio vulgaris Hildenborough was used as a model organism to study stress response to nitrite, an important intermediate in the nitrogen cycle. Previous physiological studies demonstrated that growth was inhibited by nitrite and that nitrite reduction was observed to be the primary mechanism of detoxification. Global transcriptional profiling with whole-genome microarrays revealed coordinated cascades of responses to nitrite in pathways of energy metabolism, nitrogen metabolism, oxidative stress response, and iron homeostasis. In agreement with previous observations, nitrite-stressed cells showed a decrease in the expression of genes encoding sulfate reduction functions in addition to respiratory oxidative phosphorylation and ATP synthase activity. Consequently, the stressed cells had decreased expression of the genes encoding ATP-dependent amino acid transporters and proteins involved in translation. Other genes up-regulated in response to nitrite include the genes in the Fur regulon, which is suggested to be involved in iron homeostasis, and genes in the Per regulon, which is predicted to be responsible for oxidative stress response.
PMCID: PMC1489655  PMID: 16751553
9.  A novel method for accurate operon predictions in all sequenced prokaryotes 
Nucleic Acids Research  2005;33(3):880-892.
We combine comparative genomic measures and the distance separating adjacent genes to predict operons in 124 completely sequenced prokaryotic genomes. Our method automatically tailors itself to each genome using sequence information alone, and thus can be applied to any prokaryote. For Escherichia coli K12 and Bacillus subtilis, our method is 85 and 83% accurate, respectively, which is similar to the accuracy of methods that use the same features but are trained on experimentally characterized transcripts. In Halobacterium NRC-1 and in Helicobacter pylori, our method correctly infers that genes in operons are separated by shorter distances than they are in E.coli, and its predictions using distance alone are more accurate than distance-only predictions trained on a database of E.coli transcripts. We use microarray data from six phylogenetically diverse prokaryotes to show that combining intergenic distance with comparative genomic measures further improves accuracy and that our method is broadly effective. Finally, we survey operon structure across 124 genomes, and find several surprises: H.pylori has many operons, contrary to previous reports; Bacillus anthracis has an unusual number of pseudogenes within conserved operons; and Synechocystis PCC 6803 has many operons even though it has unusually wide spacings between conserved adjacent genes.
PMCID: PMC549399  PMID: 15701760
10.  Genomic analysis of oceanic cyanobacterial myoviruses compared with T4-like myoviruses from diverse hosts and environments 
Environmental Microbiology  2010;12(11):3035-3056.
T4-like myoviruses are ubiquitous, and their genes are among the most abundant documented in ocean systems. Here we compare 26 T4-like genomes, including 10 from non-cyanobacterial myoviruses, and 16 from marine cyanobacterial myoviruses (cyanophages) isolated on diverse Prochlorococcus or Synechococcus hosts. A core genome of 38 virion construction and DNA replication genes was observed in all 26 genomes, with 32 and 25 additional genes shared among the non-cyanophage and cyanophage subsets, respectively. These hierarchical cores are highly syntenic across the genomes, and sampled to saturation. The 25 cyanophage core genes include six previously described genes with putative functions (psbA, mazG, phoH, hsp20, hli03, cobS), a hypothetical protein with a potential phytanoyl-CoA dioxygenase domain, two virion structural genes, and 16 hypothetical genes. Beyond previously described cyanophage-encoded photosynthesis and phosphate stress genes, we observed core genes that may play a role in nitrogen metabolism during infection through modulation of 2-oxoglutarate. Patterns among non-core genes that may drive niche diversification revealed that phosphorus-related gene content reflects source waters rather than host strain used for isolation, and that carbon metabolism genes appear associated with putative mobile elements. As well, phages isolated on Synechococcus had higher genome-wide %G+C and often contained different gene subsets (e.g. petE, zwf, gnd, prnA, cpeT) than those isolated on Prochlorococcus. However, no clear diagnostic genes emerged to distinguish these phage groups, suggesting blurred boundaries possibly due to cross-infection. Finally, genome-wide comparisons of both diverse and closely related, co-isolated genomes provide a locus-to-locus variability metric that will prove valuable for interpreting metagenomic data sets.
PMCID: PMC3037559  PMID: 20662890

Results 1-10 (10)