Niall Lennon

Publications (61) View all

• Article: Medulloblastoma exome sequencing uncovers subtype-specific somatic mutations.

  Trevor J Pugh, Shyamal Dilhan Weeraratne, Tenley C Archer, Daniel A Pomeranz Krummel, Daniel Auclair, James Bochicchio, Mauricio O Carneiro, Scott L Carter, Kristian Cibulskis, Rachel L Erlich, [......], Stacey B Gabriel, Gad Getz, Natalie Jäger, David T W Jones, Peter Lichter, Stefan M Pfister, Thomas M Roberts, Matthew Meyerson, Scott L Pomeroy, Yoon-Jae Cho
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  ABSTRACT: Medulloblastomas are the most common malignant brain tumours in children. Identifying and understanding the genetic events that drive these tumours is critical for the development of more effective diagnostic, prognostic and therapeutic strategies. Recently, our group and others described distinct molecular subtypes of medulloblastoma on the basis of transcriptional and copy number profiles. Here we use whole-exome hybrid capture and deep sequencing to identify somatic mutations across the coding regions of 92 primary medulloblastoma/normal pairs. Overall, medulloblastomas have low mutation rates consistent with other paediatric tumours, with a median of 0.35 non-silent mutations per megabase. We identified twelve genes mutated at statistically significant frequencies, including previously known mutated genes in medulloblastoma such as CTNNB1, PTCH1, MLL2, SMARCA4 and TP53. Recurrent somatic mutations were newly identified in an RNA helicase gene, DDX3X, often concurrent with CTNNB1 mutations, and in the nuclear co-repressor (N-CoR) complex genes GPS2, BCOR and LDB1. We show that mutant DDX3X potentiates transactivation of a TCF promoter and enhances cell viability in combination with mutant, but not wild-type, β-catenin. Together, our study reveals the alteration of WNT, hedgehog, histone methyltransferase and now N-CoR pathways across medulloblastomas and within specific subtypes of this disease, and nominates the RNA helicase DDX3X as a component of pathogenic β-catenin signalling in medulloblastoma.
  Nature 07/2012; 488(7409):106-10. · 36.28 Impact Factor
• Source

  Available from: Gilberto A. Santiago

  Article: A phylogenetic analysis using full-length viral genomes of South American dengue serotype 3 in consecutive Venezuelan outbreaks reveals a novel NS5 mutation.

  D J Schmidt, B E Pickett, D Camacho, G Comach, K Xhaja, N J Lennon, K Rizzolo, N de Bosch, A Becerra, M L Nogueira, [......], E V da Silva, P F Vasconcelos, J L Muñoz-Jordán, G A Santiago, R Ocazionez, L Gehrke, E J Lefkowitz, B W Birren, M R Henn, I Bosch
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  ABSTRACT: Dengue virus currently causes 50-100 million infections annually. Comprehensive knowledge about the evolution of Dengue in response to selection pressure is currently unavailable, but would greatly enhance vaccine design efforts. In the current study, we sequenced 187 new dengue virus serotype 3 (DENV-3) genotype III whole genomes isolated from Asia and the Americas. We analyzed them together with previously-sequenced isolates to gain a more detailed understanding of the evolutionary adaptations existing in this prevalent American serotype. In order to analyze the phylogenetic dynamics of DENV-3 during outbreak periods; we incorporated datasets of 48 and 11 sequences spanning two major outbreaks in Venezuela during 2001 and 2007-2008, respectively. Our phylogenetic analysis of newly sequenced viruses shows that subsets of genomes cluster primarily by geographic location, and secondarily by time of virus isolation. DENV-3 genotype III sequences from Asia are significantly divergent from those from the Americas due to their geographical separation and subsequent speciation. We measured amino acid variation for the E protein by calculating the Shannon entropy at each position between Asian and American genomes. We found a cluster of seven amino acid substitutions having high variability within E protein domain III, which has previously been implicated in serotype-specific neutralization escape mutants. No novel mutations were found in the E protein of sequences isolated during either Venezuelan outbreak. Shannon entropy analysis of the NS5 polymerase mature protein revealed that a G374E mutation, in a region that contributes to interferon resistance in other flaviviruses by interfering with JAK-STAT signaling was present in both the Asian and American sequences from the 2007-2008 Venezuelan outbreak, but was absent in the sequences from the 2001 Venezuelan outbreak. In addition to E, several NS5 amino acid changes were unique to the 2007-2008 epidemic in Venezuela and may give additional insight into the adaptive response of DENV-3 at the population level.
  Infection, genetics and evolution: journal of molecular epidemiology and evolutionary genetics in infectious diseases 09/2011; 11(8):2011-9. · 3.22 Impact Factor
• Article: Dysferlin Interacts with Annexins A1 and A2 and Mediates Sarcolemmal Wound-healing

  Niall J. Lennon, Alvin Kho, Brian J. Bacskai, Sarah L. Perlmutter, Bradley T. Hyman, Jr. Robert H. Brown
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  ABSTRACT: Mutations in the dysferlin gene cause limb girdle muscular dystrophy type 2B and Miyoshi myopathy. We report here the results of expression profile analyses and in vitro investigations that point to an interaction between dysferlin and the Ca2+ and lipid-binding proteins, annexins A1 and A2, and define a role for dysferlin in Ca2+-dependent repair of sarcolemmal injury through a process of vesicle fusion. Expression profiling identified a network of genes that are co-regulated in dysferlinopathic mice. Co-immunofluorescence, co-immunoprecipitation, and fluorescence lifetime imaging microscopy revealed that dysferlin normally associates with both annexins A1 and A2 in a Ca2+ and membrane injury-dependent manner. The distribution of the annexins and the efficiency of sarcolemmal wound-healing are significantly disrupted in dysferlin-deficient muscle. We propose a model of muscle membrane healing mediated by dysferlin that is relevant to both normal and dystrophic muscle and defines the annexins as potential muscular dystrophy genes.
  Journal of Biological Chemistry 12/2003; 278(50):50466-50473. · 4.77 Impact Factor
• Source

  Available from: József Geml

  Article: An arctic community of symbiotic fungi assembled by long‐distance dispersers: phylogenetic diversity of ectomycorrhizal basidiomycetes in Svalbard based on soil and sporocarp DNA

  József Geml, Ina Timling, Clare H. Robinson, Niall Lennon, H. Chad Nusbaum, Christian Brochmann, Machiel E. Noordeloos, D. Lee Taylor
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  ABSTRACT: Aim  Current evidence from temperate studies suggests that ectomycorrhizal (ECM) fungi require overland routes for migration because of their obligate symbiotic associations with woody plants. Despite their key roles in arctic ecosystems, the phylogenetic diversity and phylogeography of arctic ECM fungi remains little known. Here we assess the phylogenetic diversity of ECM communities in an isolated, formerly glaciated, high arctic archipelago, and provide explanations for their phylogeographic origins.Location  Svalbard.Methods  We generated and analysed internal transcribed spacer (ITS) nuclear ribosomal DNA sequences from both curated sporocarp collections (from Svalbard) and soil polymerase chain reaction (PCR) clone libraries (from Svalbard and the North American Arctic), compared these with publicly available sequences in GenBank, and estimated the phylogenetic diversity of ECM fungi in Svalbard. In addition, we conducted coalescent analyses to estimate migration rates in selected species.Results  Despite Svalbard’s geographic isolation and arctic climate, its ECM fungi are surprisingly diverse, with at least 72 non-singleton operational taxonomic units (soil) and 109 phylogroups (soil + sporocarp). The most species-rich genera are Thelephora/Tomentella, Cortinarius and Inocybe, followed by Hebeloma, Russula, Lactarius, Entoloma, Sebacina, Clavulina, Laccaria, Leccinum and Alnicola. Despite the scarcity of available reference data from other arctic regions, the majority of the phylogroups (73.4%) were also found outside Svalbard. At the same time, all putative Svalbard ‘endemics’ were newly sequenced taxa from diverse genera with massive undocumented diversity. Overall, our results support long-distance dispersal more strongly than vicariance and glacial survival. However, because of the high variation in nucleotide substitution rates among fungi, allopatric persistence since the Pliocene, although unlikely, cannot be statistically rejected. Results from the coalescent analyses suggest recent gene flow among different arctic areas.Main conclusions  Our results indicate numerous recent colonization events and suggest that long-distance, transoceanic dispersal is widespread in arctic ECM fungi, which differs markedly from the currently prevailing view on the dispersal capabilities of ECM fungi. Our molecular evidence indicates that long-distance dispersal has probably played a major role in the phylogeographic history of some ECM fungi in the Northern Hemisphere. Our results may have implications for studies on the biodiversity, ecology and conservation of arctic fungi in general.
  Journal of Biogeography 08/2011; 39(1):74 - 88. · 4.54 Impact Factor
• Article: Evolution of genes and genomes on the Drosophila phylogeny

  Andrew G. Clark, Michael B. Eisen, Douglas R. Smith, Casey M. Bergman, Brian Oliver, Therese A. Markow, Thomas C. Kaufman, Manolis Kellis, William Gelbart, Venky N. Iyer, [......], Andrew Zimmer, Zac Zwirko, Pablo Alvarez, Will Brockman, Jonathan Butler, CheeWhye Chin, Manfred Grabherr, Michael Kleber, Evan Mauceli, Iain MacCallum
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  ABSTRACT: Comparative analysis of multiple genomes in a phylogenetic framework dramatically improves the precision and sensitivity of evolutionary inference, producing more robust results than single-genome analyses can provide. The genomes of 12 Drosophila species, ten of which are presented here for the first time (sechellia, simulans, yakuba, erecta, ananassae, persimilis, willistoni, mojavensis, virilis and grimshawi), illustrate how rates and patterns of sequence divergence across taxa can illuminate evolutionary processes on a genomic scale. These genome sequences augment the formidable genetic tools that have made Drosophila melanogaster a pre-eminent model for animal genetics, and will further catalyse fundamental research on mechanisms of development, cell biology, genetics, disease, neurobiology, behaviour, physiology and evolution. Despite remarkable similarities among these Drosophila species, we identified many putatively non-neutral changes in protein-coding genes, non-coding RNA genes, and cis-regulatory regions. These may prove to underlie differences in the ecology and behaviour of these diverse species.
  Nature 11/2007; 450(7167):203-218. · 36.28 Impact Factor