skip to main content
DOE PAGES title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: Linking secondary metabolites to gene clusters through genome sequencing of six diverse Aspergillus species

Abstract

The fungal genus of Aspergillus is highly interesting, containing everything from industrial cell factories, model organisms, and human pathogens. In particular, this group has a prolific production of bioactive secondary metabolites (SMs). In this work, four diverse Aspergillus species (A. campestris, A. novofumigatus, A. ochraceoroseus, and A. steynii) have been whole-genome PacBio sequenced to provide genetic references in three Aspergillus sections. A. taichungensis and A. candidus also were sequenced for SM elucidation. Thirteen Aspergillus genomes were analyzed with comparative genomics to determine phylogeny and genetic diversity, showing that each presented genome contains 15–27% genes not found in other sequenced Aspergilli. In particular, A. novofumigatus was compared with the pathogenic species A. fumigatus. This suggests that A. novofumigatus can produce most of the same allergens, virulence, and pathogenicity factors as A. fumigatus, suggesting that A. novofumigatus could be as pathogenic as A. fumigatus. Furthermore, SMs were linked to gene clusters based on biological and chemical knowledge and analysis, genome sequences, and predictive algorithms. We thus identify putative SM clusters for aflatoxin, chlorflavonin, and ochrindol in A. ochraceoroseus, A. campestris, and A. steynii, respectively, and novofumigatonin, ent-cycloechinulin, and epi-aszonalenins in A. novofumigatus. Our study delivers six fungal genomes, showing the large diversitymore » found in the Aspergillus genus; highlights the potential for discovery of beneficial or harmful SMs; and supports reports of A. novofumigatus pathogenicity. It also shows how biological, biochemical, and genomic information can be combined to identify genes involved in the biosynthesis of specific SMs.« less

Authors:
; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; more »; ORCiD logo; ; ; ; ; ; ORCiD logo « less
Publication Date:
Research Org.:
Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Biological and Environmental Research (BER)
OSTI Identifier:
1416221
Alternate Identifier(s):
OSTI ID: 1439668; OSTI ID: 1465428
Report Number(s):
PNNL-SA-131168
Journal ID: ISSN 0027-8424; /pnas/115/4/E753.atom
Grant/Contract Number:  
AC02-05CH11231; AC05-76RL01830
Resource Type:
Published Article
Journal Name:
Proceedings of the National Academy of Sciences of the United States of America
Additional Journal Information:
Journal Name: Proceedings of the National Academy of Sciences of the United States of America Journal Volume: 115 Journal Issue: 4; Journal ID: ISSN 0027-8424
Publisher:
Proceedings of the National Academy of Sciences
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; Aspergillus; fumigatus; comparative genomics; secondary metabolism

Citation Formats

Kjærbølling, Inge, Vesth, Tammi C., Frisvad, Jens C., Nybo, Jane L., Theobald, Sebastian, Kuo, Alan, Bowyer, Paul, Matsuda, Yudai, Mondo, Stephen, Lyhne, Ellen K., Kogle, Martin E., Clum, Alicia, Lipzen, Anna, Salamov, Asaf, Ngan, Chew Yee, Daum, Chris, Chiniquy, Jennifer, Barry, Kerrie, LaButti, Kurt, Haridas, Sajeet, Simmons, Blake A., Magnuson, Jon K., Mortensen, Uffe H., Larsen, Thomas O., Grigoriev, Igor V., Baker, Scott E., and Andersen, Mikael R.. Linking secondary metabolites to gene clusters through genome sequencing of six diverse Aspergillus species. United States: N. p., 2018. Web. https://doi.org/10.1073/pnas.1715954115.
Kjærbølling, Inge, Vesth, Tammi C., Frisvad, Jens C., Nybo, Jane L., Theobald, Sebastian, Kuo, Alan, Bowyer, Paul, Matsuda, Yudai, Mondo, Stephen, Lyhne, Ellen K., Kogle, Martin E., Clum, Alicia, Lipzen, Anna, Salamov, Asaf, Ngan, Chew Yee, Daum, Chris, Chiniquy, Jennifer, Barry, Kerrie, LaButti, Kurt, Haridas, Sajeet, Simmons, Blake A., Magnuson, Jon K., Mortensen, Uffe H., Larsen, Thomas O., Grigoriev, Igor V., Baker, Scott E., & Andersen, Mikael R.. Linking secondary metabolites to gene clusters through genome sequencing of six diverse Aspergillus species. United States. https://doi.org/10.1073/pnas.1715954115
Kjærbølling, Inge, Vesth, Tammi C., Frisvad, Jens C., Nybo, Jane L., Theobald, Sebastian, Kuo, Alan, Bowyer, Paul, Matsuda, Yudai, Mondo, Stephen, Lyhne, Ellen K., Kogle, Martin E., Clum, Alicia, Lipzen, Anna, Salamov, Asaf, Ngan, Chew Yee, Daum, Chris, Chiniquy, Jennifer, Barry, Kerrie, LaButti, Kurt, Haridas, Sajeet, Simmons, Blake A., Magnuson, Jon K., Mortensen, Uffe H., Larsen, Thomas O., Grigoriev, Igor V., Baker, Scott E., and Andersen, Mikael R.. Tue . "Linking secondary metabolites to gene clusters through genome sequencing of six diverse Aspergillus species". United States. https://doi.org/10.1073/pnas.1715954115.
@article{osti_1416221,
title = {Linking secondary metabolites to gene clusters through genome sequencing of six diverse Aspergillus species},
author = {Kjærbølling, Inge and Vesth, Tammi C. and Frisvad, Jens C. and Nybo, Jane L. and Theobald, Sebastian and Kuo, Alan and Bowyer, Paul and Matsuda, Yudai and Mondo, Stephen and Lyhne, Ellen K. and Kogle, Martin E. and Clum, Alicia and Lipzen, Anna and Salamov, Asaf and Ngan, Chew Yee and Daum, Chris and Chiniquy, Jennifer and Barry, Kerrie and LaButti, Kurt and Haridas, Sajeet and Simmons, Blake A. and Magnuson, Jon K. and Mortensen, Uffe H. and Larsen, Thomas O. and Grigoriev, Igor V. and Baker, Scott E. and Andersen, Mikael R.},
abstractNote = {The fungal genus of Aspergillus is highly interesting, containing everything from industrial cell factories, model organisms, and human pathogens. In particular, this group has a prolific production of bioactive secondary metabolites (SMs). In this work, four diverse Aspergillus species (A. campestris, A. novofumigatus, A. ochraceoroseus, and A. steynii) have been whole-genome PacBio sequenced to provide genetic references in three Aspergillus sections. A. taichungensis and A. candidus also were sequenced for SM elucidation. Thirteen Aspergillus genomes were analyzed with comparative genomics to determine phylogeny and genetic diversity, showing that each presented genome contains 15–27% genes not found in other sequenced Aspergilli. In particular, A. novofumigatus was compared with the pathogenic species A. fumigatus. This suggests that A. novofumigatus can produce most of the same allergens, virulence, and pathogenicity factors as A. fumigatus, suggesting that A. novofumigatus could be as pathogenic as A. fumigatus. Furthermore, SMs were linked to gene clusters based on biological and chemical knowledge and analysis, genome sequences, and predictive algorithms. We thus identify putative SM clusters for aflatoxin, chlorflavonin, and ochrindol in A. ochraceoroseus, A. campestris, and A. steynii, respectively, and novofumigatonin, ent-cycloechinulin, and epi-aszonalenins in A. novofumigatus. Our study delivers six fungal genomes, showing the large diversity found in the Aspergillus genus; highlights the potential for discovery of beneficial or harmful SMs; and supports reports of A. novofumigatus pathogenicity. It also shows how biological, biochemical, and genomic information can be combined to identify genes involved in the biosynthesis of specific SMs.},
doi = {10.1073/pnas.1715954115},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
number = 4,
volume = 115,
place = {United States},
year = {2018},
month = {1}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record
https://doi.org/10.1073/pnas.1715954115

Citation Metrics:
Cited by: 7 works
Citation information provided by
Web of Science

Figures / Tables:

Table 1 Table 1: Overview of sequencing and annotation data for the four investigated PacBio-sequenced species, plus two additional Illumina-sequenced species

Save / Share:

Works referenced in this record:

The InterPro protein families database: the classification resource after 15 years
journal, November 2014

  • Mitchell, Alex; Chang, Hsin-Yu; Daugherty, Louise
  • Nucleic Acids Research, Vol. 43, Issue D1
  • DOI: 10.1093/nar/gku1243

Minimum Information about a Biosynthetic Gene cluster
journal, August 2015

  • Medema, Marnix H.; Kottmann, Renzo; Yilmaz, Pelin
  • Nature Chemical Biology, Vol. 11, Issue 9
  • DOI: 10.1038/nchembio.1890

Polyphasic taxonomy of Aspergillus fumigatus and related species
journal, November 2005


Clustered Pathway Genes in Aflatoxin Biosynthesis
journal, March 2004


Versatile and open software for comparing large genomes
journal, January 2004

  • Kurtz, Stefan; Phillippy, Adam; Delcher, Arthur L.
  • Genome Biology, Vol. 5, Issue 2, R12
  • DOI: 10.1186/gb-2004-5-2-r12

Ghlorflavonin, a new Antifungal Antibiotic
journal, January 1969


Fungal secondary metabolites – Strategies to activate silent gene clusters
journal, January 2011


Functions Encoded by Pyrrolnitrin Biosynthetic Genes from Pseudomonas fluorescens
journal, April 1998


Natural products of filamentous fungi: enzymes, genes, and their regulation
journal, January 2007

  • Hoffmeister, Dirk; Keller, Nancy P.
  • Nat. Prod. Rep., Vol. 24, Issue 2
  • DOI: 10.1039/b603084j

Characterization of the Aspergillus ochraceoroseus aflatoxin/sterigmatocystin biosynthetic gene cluster
journal, May 2009

  • Cary, J. W.; Ehrlich, K. C.; Beltz, S. B.
  • Mycologia, Vol. 101, Issue 3
  • DOI: 10.3852/08-173

Genome sequencing and analysis of Aspergillus oryzae
journal, December 2005

  • Machida, Masayuki; Asai, Kiyoshi; Sano, Motoaki
  • Nature, Vol. 438, Issue 7071
  • DOI: 10.1038/nature04300

The Aspergillus fumigatus cell wall integrity signaling pathway: drug target, compensatory pathways, and virulence
journal, April 2015


Aspergillus is monophyletic: Evidence from multiple gene phylogenies and extrolites profiles
journal, September 2016


Chemodiversity in the genus Aspergillus
journal, August 2015

  • Frisvad, Jens C.; Larsen, Thomas O.
  • Applied Microbiology and Biotechnology, Vol. 99, Issue 19
  • DOI: 10.1007/s00253-015-6839-z

SMURF: Genomic mapping of fungal secondary metabolite clusters
journal, September 2010

  • Khaldi, Nora; Seifuddin, Fayaz T.; Turner, Geoff
  • Fungal Genetics and Biology, Vol. 47, Issue 9
  • DOI: 10.1016/j.fgb.2010.06.003

Draft Genome Sequences of Two Closely Related Aflatoxigenic Aspergillus Species Obtained from the Ivory Coast
journal, December 2015

  • Moore, Geromy G.; Mack, Brian M.; Beltz, Shannon B.
  • Genome Biology and Evolution, Vol. 8, Issue 3
  • DOI: 10.1093/gbe/evv246

Phylogeny, identification and nomenclature of the genus Aspergillus
journal, June 2014


CVTree: a phylogenetic tree reconstruction tool based on whole genomes
journal, July 2004

  • Qi, J.; Luo, H.; Hao, B.
  • Nucleic Acids Research, Vol. 32, Issue Web Server
  • DOI: 10.1093/nar/gkh362

Invasive aspergillosis caused by cryptic Aspergillus species: a report of two consecutive episodes in a patient with leukaemia
journal, November 2012

  • Pelaez, T.; Alvarez-Perez, S.; Mellado, E.
  • Journal of Medical Microbiology, Vol. 62, Issue Pt_3
  • DOI: 10.1099/jmm.0.044867-0

Terrequinone A biosynthesis through L-tryptophan oxidation, dimerization and bisprenylation
journal, August 2007

  • Balibar, Carl J.; Howard-Jones, Annaleise R.; Walsh, Christopher T.
  • Nature Chemical Biology, Vol. 3, Issue 9
  • DOI: 10.1038/nchembio.2007.20

Secondary metabolism in fungi: does chromosomal location matter?
journal, August 2010


Aspergillus fumigatus and Aspergillosis
journal, April 1999


Alignment of whole genomes
journal, January 1999

  • Delcher, A. L.; Kasif, S.; Fleischmann, R. D.
  • Nucleic Acids Research, Vol. 27, Issue 11
  • DOI: 10.1093/nar/27.11.2369

Aflatoxin biosynthesis gene clusters and flanking regions
journal, September 2005


Whole genome comparison of the A. fumigatus family
journal, January 2006


Comprehensive annotation of secondary metabolite biosynthetic genes and gene clusters of Aspergillus nidulans, A. fumigatus, A. niger and A. oryzae
journal, January 2013

  • Inglis, Diane O.; Binkley, Jonathan; Skrzypek, Marek S.
  • BMC Microbiology, Vol. 13, Issue 1
  • DOI: 10.1186/1471-2180-13-91

Transcriptional Regulation of Chemical Diversity in Aspergillus fumigatus by LaeA
journal, January 2007


Secondary metabolic gene clusters: evolutionary toolkits for chemical innovation
journal, October 2010


The chalcone synthase superfamily of type III polyketide synthases
journal, December 2002

  • Austin, Michael B.; Noel, Joseph P.
  • Natural Product Reports, Vol. 20, Issue 1
  • DOI: 10.1039/b100917f

On K-peptide length in composition vector phylogeny of prokaryotes
journal, December 2014


Fungal type III polyketide synthases
journal, January 2014

  • Hashimoto, Makoto; Nonaka, Takamasa; Fujii, Isao
  • Nat. Prod. Rep., Vol. 31, Issue 10
  • DOI: 10.1039/C4NP00096J

Re-identification of Aspergillus fumigatus sensu lato based on a new concept of species delimitation
journal, October 2010


Cryptic chlorination by a non-haem iron enzyme during cyclopropyl amino acid biosynthesis
journal, August 2005

  • Vaillancourt, Frédéric H.; Yeh, Ellen; Vosburg, David A.
  • Nature, Vol. 436, Issue 7054
  • DOI: 10.1038/nature03797

Cross-reactivity of IgE antibodies to allergens
journal, June 2001


Fumigatonin, a new meroterpenoid from
journal, January 1984


Dereplication of Microbial Natural Products by LC-DAD-TOFMS
journal, November 2011

  • Nielsen, Kristian F.; Månsson, Maria; Rank, Christian
  • Journal of Natural Products, Vol. 74, Issue 11
  • DOI: 10.1021/np200254t

Phylogenetic analysis of Aspergillus species using DNA sequences from four loci
journal, March 2008


Extrolites of Aspergillus fumigatus and Other Pathogenic Species in Aspergillus Section Fumigati
journal, January 2016


Fast algorithms for large-scale genome alignment and comparison
journal, June 2002


Novofumigatonin, a New Orthoester Meroterpenoid from Aspergillus novofumigatus
journal, February 2008

  • Rank, Christian; Phipps, Richard K.; Harris, Pernille
  • Organic Letters, Vol. 10, Issue 3
  • DOI: 10.1021/ol7026834

Polyphasic taxonomy of Aspergillus section Candidi based on molecular, morphological and physiological data
journal, January 2007


Widespread adenine N6-methylation of active genes in fungi
journal, May 2017

  • Mondo, Stephen J.; Dannebaum, Richard O.; Kuo, Rita C.
  • Nature Genetics, Vol. 49, Issue 6
  • DOI: 10.1038/ng.3859

Genes y moléculas implicados en la virulencia de Aspergillus fumigatus
journal, March 2005

  • Rementeria, Aitor; López-Molina, Nuria; Ludwig, Alfred
  • Revista Iberoamericana de Micología, Vol. 22, Issue 1
  • DOI: 10.1016/S1130-1406(05)70001-2

Biosynthesis of chlorflavonin in aspergillus candidus: a novel fungal route to flavonoids
journal, January 1979

  • Burns, Michael K.; Coffin, Jane M.; Kurobane, Itsuo
  • Journal of the Chemical Society, Chemical Communications, Issue 9
  • DOI: 10.1039/c39790000426

Genomic sequence of the pathogenic and allergenic filamentous fungus Aspergillus fumigatus
journal, December 2005

  • Nierman, William C.; Pain, Arnab; Anderson, Michael J.
  • Nature, Vol. 438, Issue 7071, p. 1151-1156
  • DOI: 10.1038/nature04332

Molecular Genetic Characterization of a Cluster in A. terreus for Biosynthesis of the Meroterpenoid Terretonin
journal, November 2012

  • Guo, Chun-Jun; Knox, Benjamin P.; Chiang, Yi-Ming
  • Organic Letters, Vol. 14, Issue 22
  • DOI: 10.1021/ol302682z

Reconstitution of a fungal meroterpenoid biosynthesis reveals the involvement of a novel family of terpene cyclases
journal, August 2010

  • Itoh, Takayuki; Tokunaga, Kinya; Matsuda, Yudai
  • Nature Chemistry, Vol. 2, Issue 10
  • DOI: 10.1038/nchem.764

Ochrindoles A-D: New Bis-Indolyl Benzenoids from the Sclerotia of Aspergillus ochraceus NRRL 3519
journal, May 1994

  • de Guzman, Florecita S.; Bruss, Dan R.; Rippentrop, Jonathan M.
  • Journal of Natural Products, Vol. 57, Issue 5
  • DOI: 10.1021/np50107a011

Polyphasic taxonomy of Aspergillus fumigatus and related species
journal, November 2005


    Works referencing / citing this record:

    Safety of the fungal workhorses of industrial biotechnology: update on the mycotoxin and secondary metabolite potential of Aspergillus niger, Aspergillus oryzae, and Trichoderma reesei
    journal, October 2018

    • Frisvad, Jens C.; Møller, Lars L. H.; Larsen, Thomas O.
    • Applied Microbiology and Biotechnology, Vol. 102, Issue 22
    • DOI: 10.1007/s00253-018-9354-1

    Aspergillus nidulans in the post-genomic era: a top-model filamentous fungus for the study of signaling and homeostasis mechanisms
    journal, February 2019


    New voyages to explore the natural product galaxy
    journal, January 2019

    • Mouncey, Nigel J.; Otani, Hiroshi; Udwary, Daniel
    • Journal of Industrial Microbiology & Biotechnology, Vol. 46, Issue 3-4
    • DOI: 10.1007/s10295-018-02122-w

    Harnessing diverse transcriptional regulators for natural product discovery in fungi
    journal, January 2020

    • Lyu, Hai-Ning; Liu, Hong-Wei; Keller, Nancy P.
    • Natural Product Reports, Vol. 37, Issue 1
    • DOI: 10.1039/c8np00027a

    Recent advances in the genome mining of Aspergillus secondary metabolites (covering 2012–2018)
    journal, January 2019

    • Romsdahl, Jillian; Wang, Clay C. C.
    • MedChemComm, Vol. 10, Issue 6
    • DOI: 10.1039/c9md00054b

    Metabolic and regulatory insights from the experimental horizontal gene transfer of the aurofusarin and bikaverin gene clusters to Aspergillus nidulans
    journal, September 2019

    • Reus, Elise; Nielsen, Mikkel Rank; Frandsen, Rasmus John Normand
    • Molecular Microbiology, Vol. 112, Issue 6
    • DOI: 10.1111/mmi.14376

    Resistance Gene-Directed Genome Mining of 50 Aspergillus Species
    journal, May 2019


    Genomes and secretomes of Ascomycota fungi reveal diverse functions in plant biomass decomposition and pathogenesis
    journal, December 2019


    A 19-isolate reference-quality global pangenome for the fungal wheat pathogen Zymoseptoria tritici
    journal, February 2020


    How a fungus shapes biotechnology: 100 years of Aspergillus niger research
    journal, May 2018

    • Cairns, Timothy C.; Nai, Corrado; Meyer, Vera
    • Fungal Biology and Biotechnology, Vol. 5, Issue 1
    • DOI: 10.1186/s40694-018-0054-5

    Cpf1 enables fast and efficient genome editing in Aspergilli
    journal, May 2019

    • Vanegas, Katherina Garcia; Jarczynska, Zofia Dorota; Strucko, Tomas
    • Fungal Biology and Biotechnology, Vol. 6, Issue 1
    • DOI: 10.1186/s40694-019-0069-6

    Halophiles and Their Biomolecules: Recent Advances and Future Applications in Biomedicine
    journal, December 2019

    • Corral, Paulina; Amoozegar, Mohammad A.; Ventosa, Antonio
    • Marine Drugs, Vol. 18, Issue 1
    • DOI: 10.3390/md18010033

    Biosynthetic Gene Content of the ‘Perfume Lichens’ Evernia prunastri and Pseudevernia furfuracea
    journal, January 2019


    The aspergillic acid biosynthetic gene cluster predicts neoaspergillic acid production in Aspergillus section Circumdati
    journal, July 2019

    • Lebar, M. D.; Mack, B. M.; Carter-Wientjes, C. H.
    • World Mycotoxin Journal, Vol. 12, Issue 3
    • DOI: 10.3920/wmj2018.2397

      Figures/Tables have been extracted from DOE-funded journal article accepted manuscripts.