Harvard Center for Systems Biology

Oxford, MA, United States

Harvard Center for Systems Biology

Oxford, MA, United States
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Yang N.N.,University College London | Mazieres S.,University Paul Sabatier | Bravi C.,Instituto Multidisciplinario Of Biologia Celular | Ray N.,University of Geneva | And 23 more authors.
Annals of Human Genetics | Year: 2010

We report an integrated analysis of nuclear (autosomal, X- and Y-chromosome) short tandem repeat (STR) data and mtDNA D-loop sequences obtained in the same set of 22 Native populations from across the Americas. A north to south gradient of decreasing population diversity was observed, in agreement with a settlement of the Americas from the extreme northwest of the continent. This correlation is stronger with "least cost distances," which consider the coasts as facilitators of migration. Continent-wide estimates of population structure are highest for the Y-chromosome and lowest for the autosomes, consistent with the effective size of the different marker systems examined. Population differentiation is highest in East South America and lowest in Meso America and the Andean region. Regional analyses suggest a deviation from mutation-drift equilibrium consistent with population expansion in Meso America and the Andes and population contraction in Northwest and East South America. These data hint at an early divergence of Andean and non-Andean South Americans and at a contrasting demographic history for populations from these regions. © 2010 The Authors Annals of Human Genetics © 2010 Blackwell Publishing Ltd/University College London.

Zafra O.,CSIC - National Center for Biotechnology | Zafra O.,CSIC - National Institute of Aerospace Technology | Fraile S.,CSIC - National Center for Biotechnology | Gutierrez C.,University of Veterinary and Animal Sciences | And 6 more authors.
Environmental Microbiology | Year: 2011

Functional studies of biodegradative activities in environmental microorganisms require molecular tools for monitoring catabolic enzymes in the members of the native microbiota. To this end, we have generated repertories of single-domain VHH fragments of camel immunoglobulins (nanobodies) able to interact with multiple proteins that are descriptors of environmentally relevant processes. For this, we immunized Camelus dromedarius with a cocktail of up to 12 purified enzymes that are representative of major types of detoxifying activities found in aerobic and anaerobic microorganisms. Following the capture of the antigen-binding modules from the mRNA of the camel lymphocytes and the selection of sub-libraries for each of the enzymes in a phage display system we found a large number of VHH modules that interacted with each of the antigens. Those associated to the enzyme 2,3 dihydroxybiphenyl dioxygenase of Burkholderia xenovorans LB400 (BphC) and the arsenate reductase of Staphylococcus aureus (ArsC) were examined in detail and found to hold different qualities that were optimal for distinct protein recognition procedures. The repertory of anti-BphC VHHs included variants with a strong affinity and specificity for linear epitopes of the enzyme. When the anti-BphC VHH library was recloned in a prokaryotic intracellular expression system, some nanobodies were found to inhibit the dioxygenase activity in vivo. Furthermore, anti-ArsC VHHs were able to discriminate between proteins stemming from different enzyme families. The easiness of generating large collections of binders with different properties widens considerably the molecular toolbox for analysis of biodegradative bacteria and opens fresh possibilities of monitoring protein markers and activities in the environment. © 2011 Society for Applied Microbiology and Blackwell Publishing Ltd.

Ferguson L.,University of Cambridge | Lee S.F.,University of Melbourne | Chamberlain N.,Harvard Center for Systems Biology | Nadeau N.,University of Cambridge | And 13 more authors.
Molecular Ecology | Year: 2010

The mimetic wing patterns of Heliconius butterflies are an excellent example of both adaptive radiation and convergent evolution. Alleles at the HmYb and HmSb loci control the presence/absence of hindwing bar and hindwing margin phenotypes respectively between divergent races of Heliconius melpomene, and also between sister species. Here, we used fine-scale linkage mapping to identify and sequence a BAC tilepath across the HmYb/Sb loci. We also generated transcriptome sequence data for two wing pattern forms of H. melpomene that differed in HmYb/Sb alleles using 454 sequencing technology. Custom scripts were used to process the sequence traces and generate transcriptome assemblies. Genomic sequence for the HmYb/Sb candidate region was annotated both using the MAKER pipeline and manu2ally using transcriptome sequence reads. In total, 28 genes were identified in the HmYb/Sb candidate region, six of which have alternative splice forms. None of these are orthologues of genes previously identified as being expressed in butterfly wing pattern development, implying previously undescribed molecular mechanisms of pattern determination on Heliconius wings. The use of next-generation sequencing has therefore facilitated DNA annotation of a poorly characterized genome, and generated hypotheses regarding the identity of wing pattern at the HmYb/Sb loci. © 2010 Blackwell Publishing Ltd.

Belousoff M.J.,Weizmann Institute of Science | Davidovich C.,Weizmann Institute of Science | Zimmerman E.,Weizmann Institute of Science | Caspi Y.,Weizmann Institute of Science | And 12 more authors.
Biochemical Society Transactions | Year: 2010

Structural analysis, supported by biochemical, mutagenesis and computational evidence, indicates that the peptidyltransferase centre of the contemporary ribosome is a universal symmetrical pocket composed solely of rRNA. This pocket seems to be a relic of the proto-ribosome, an ancient ribozyme, which was a dimeric RNA assembly formed from self-folded RNA chains of identical, similar or different sequences. This could have occurred spontaneously by gene duplication or gene fusion. This pocket-like entity was capable of autonomously catalysing various reactions, including peptide bond formation and non-coded or semi-coded amino acid polymerization. Efforts toward the structural definition of the early entity capable of genetic decoding involve the crystallization of the small ribosomal subunit of a bacterial organism harbouring a single functional rRNA operon. ©The Authors.

Chen Y.,University of Oxford | Adams E.,University of Oxford | Regateiro F.S.,University of Oxford | Vaux D.J.,University of Oxford | And 4 more authors.
European Journal of Immunology | Year: 2012

Regulatory T (Treg) cells are critically important for the maintenance of immunological tolerance. Both centrally arising natural nTreg cells and those emerging in the periphery in response to TGF-β, iTreg cells, play a role in the control of unwanted immune responses. Treg cells adopt multiple mechanisms to inhibit effector T cells, yet it is unclear whether these mechanisms are shared by nTreg cells and iTreg cells alike. Here, we show that iTreg cells, like nTreg cells, are able to out-compete naïve T cells in clustering around dendritic cells (DCs). However, using both a tamoxifen-responsive inducible Foxp3 retroviral construct and TGF-β-induced iTreg cells from hCD2-Foxp3 knock in reporter mice, we show that it is prior antigen-induced activation rather than Foxp3 expression per se that determines the ability of iTreg cells to competitively cluster around DCs. We found no difference in the capacity of iTreg cells to displace naïve T cells around DCs to that of Tr1, Th1, Th2, or Th9 cells. An important difference was, however, that clustering of iTreg cells around DCs, just as for naïve T cells, did not effectively activate DCs.© 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Bouvier T.,Montpellier University | Maurice C.F.,Montpellier University | Maurice C.F.,Harvard Center for Systems Biology
Microbial Ecology | Year: 2011

Culture studies of phage-host systems have shown that phage proliferation strongly depends on the physiological state of the host, but it is still unclear to what extent this holds true within aquatic ecosystems. We used a combination of flow sorting and electron microscopy to explore how the frequency of bacterial cells with attached viruses (FCAV), of visibly infected cells, and the number of intracellular viruses are distributed within five physiologic categories: cells with high (HNA) and low (LNA) nucleic acid content, with a compromised membrane, in division, and with an intact-looking morphology. FCAV was not different between the cellular physiologic categories, suggesting low influence of host physiology on viral adsorption. Infected cells were found within all the physiologic categories, besides the dividing cells, but showed different levels of new virion production, with the abundance of intracellular viruses ranked as follows: HNA & intact-looking cells & LNA & compromised membrane cells. These results favor the physiological control hypothesis of viral progeny production. The calculation of viral production rate of the HNA and LNA cells show that viral infection of HNA cells likely accounts for the majority of viral production. It also show that cells considered as less active can still act as resources for phages, although they contain much less intracellular phage particles. © 2011 Springer Science+Business Media, LLC.

Maurice C.F.,Montpellier University | Maurice C.F.,Harvard Center for Systems Biology | Mouillot D.,Montpellier University | Bettarel Y.,Montpellier University | And 3 more authors.
ISME Journal | Year: 2011

Previous studies indicate that lysogeny is preponderant when environmental conditions are challenging for the bacterial communities and when their metabolism is reduced. Furthermore, it appears that lysogeny is more frequent within certain bacterial phylogenetic groups. In this comparative study from 10 freshwater reservoirs and 10 coastal lagoons, we aim to disentangle the influence of these different factors. In eight reservoirs and four lagoons, lysogeny was detected by induction assays with mitomycin C, and induction significantly modified the bacterial community composition (BCC), whereas community composition remained constant in ecosystems in which lysogeny was not observed. Among the phylogenetic groups studied, the most abundant ones were Bacteroidetes and α-proteobacteria in lagoons, and Β-proteobacteria and Bacteroidetes in reservoirs. These dominant groups comprised the highest proportions of inducible lysogens. In order to unravel the effects of bacterial metabolism from phylogeny on lysogeny, we measured bacterial community physiology and the specific activities of selected phylogenetic groups. The proportion of inducible lysogens within the α- and the Β-proteobacteria decreased with increasing group-specific metabolism in lagoons and reservoirs, respectively. In contrast, this relationship was not observed for the other lysogen-containing groups. Hence, both host physiology and phylogeny are critical for the establishment of lysogeny. This study illustrates the importance of lysogeny among the most abundant phylogenetic groups, and further suggests its strong structuring impact on BCC. © 2011 International Society for Microbial Ecology All rights reserved.

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