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Research Article

Evolution of Invasion in a Diverse Set of Fusobacterium Species

Abigail Manson McGuire, Kyla Cochrane, Allison D. Griggs, Brian J. Haas, Thomas Abeel, Qiandong Zeng, Justin B. Nice, Hanlon MacDonald, Bruce W. Birren, Bryan W. Berger, Emma Allen-Vercoe, Ashlee M. Earl
Michael S. Gilmore, Editor
Abigail Manson McGuire
aBroad Institute, Cambridge, Massachusetts, USA
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Kyla Cochrane
bDepartment of Molecular and Cellular Biology, University of Guelph, Guelph, Ontario, Canada
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Allison D. Griggs
aBroad Institute, Cambridge, Massachusetts, USA
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Brian J. Haas
aBroad Institute, Cambridge, Massachusetts, USA
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Thomas Abeel
aBroad Institute, Cambridge, Massachusetts, USA
dVIB Department of Plant Systems Biology, Ghent University, Ghent, Belgium
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Qiandong Zeng
aBroad Institute, Cambridge, Massachusetts, USA
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Justin B. Nice
eProgram in Bioengineering, Lehigh University, Bethlehem, Pennsylvania, USA
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Hanlon MacDonald
eProgram in Bioengineering, Lehigh University, Bethlehem, Pennsylvania, USA
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Bruce W. Birren
aBroad Institute, Cambridge, Massachusetts, USA
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Bryan W. Berger
cDepartment of Chemical Engineering, Lehigh University, Bethlehem, Pennsylvania, USA
eProgram in Bioengineering, Lehigh University, Bethlehem, Pennsylvania, USA
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Emma Allen-Vercoe
bDepartment of Molecular and Cellular Biology, University of Guelph, Guelph, Ontario, Canada
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Ashlee M. Earl
aBroad Institute, Cambridge, Massachusetts, USA
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Michael S. Gilmore
Harvard Medical School
Roles: Editor
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DOI: 10.1128/mBio.01864-14
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  • FIG 1 
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    FIG 1 

    Phylogenetic tree based on nucleotide sequences of 498 core orthogroups, or orthogroups containing exactly one copy from each of the 26 Fusobacterium strains plus the outgroup, Leptotrichia buccalis. Bootstrap values are indicated for each node. The node indicated with an arrow illustrates a 3-way trifurcation (based on bootstrap values and individual orthogroup trees [see Text S1 in the supplemental material]), representing an adaptive radiation. The five clades are outlined with boxes. The clades containing species believed to actively or passively invade host cells are indicated with dark and light gray shading, respectively. The mechanism by which F. mortiferum (in white) can invade cells is unknown.

  • FIG 2 
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    FIG 2 

    Gene categories expanded in active and passive invaders (Q < 0.0005). (A) The top 12 GO terms expanded in the active invaders were largely membrane related. (B) Pfam domains expanded in the active invaders include the known virulence-related adhesins FadA and RadD, as well as a massive expansion of MORN2 domains of unknown function. (C) A different set of adhesins, including the trimeric autotransporter adhesion protein YadA, is expanded in the passive invaders. (See Table S5 in the supplemental material for a full listing of categories expanded in both active and passive invaders for Q < 0.05.) (D) Clade-specific summary of expanded Pfam domains. The number of dots represents the average number of domains present in a genome from each of the five clades. For MORN2, there can be multiple domains per gene.

  • FIG 3 
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    FIG 3 

    Gene families expanded in active invaders clustered in the genome. This multiple alignment of our set of seven finished F. nucleatum genomes shows an example of a region with close physical association among FadA, RadD, and MORN2 family proteins. The gray-shaded connectors represent orthologous protein pairs. This genomic region also contains an ompA gene shown to be involved in biofilm formation in Fusobacterium (69), as well as numerous strain-specific genes, transposases, IS elements, and genes previously identified as being differentially expressed under aggregation conditions (11). In two genomes (F. nucleatum subsp. nucleatum ATCC 25586 and F. nucleatum subsp. polymorphum ATCC 10953), a synteny break (indicated with a black line) placed the canonical fadA gene (FN0264) in this region rather than a second radD gene. Several regions similar to this are located in the genome.

  • FIG 4 
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    FIG 4 

    Species distribution of MORN2 orthogroups. Each column represents an orthogroup. The boxes are colored according to the average number of MORN2 domains per protein, and for each orthogroup containing two or more paralogs, the numbers indicate the number of paralogs. There is tremendous variation in the number and structure of proteins containing MORN2 domains across genomes. Active invaders (species names shaded in dark gray) contain longer, more complex MORN2-containing proteins than passive invaders (species names shaded in light gray). Passive invaders contain only a small complement of short, “ancestral” orthogroups, which are present across all species. Expansions of active invader orthogroups, especially in F. periodonticum, can be seen by the presence of paralogs.

  • FIG 5 
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    FIG 5 

    Expansion of an “ancestral” MORN2 orthogroup in F. periodonticum. This orthogroup is present in all species, including the passive invaders, but it is greatly expanded in F. periodonticum. In F. periodonticum, this expanded cluster is also located near other known virulence-related adhesins, including RadD and YadA family members. All members of this orthogroup are present in this small region of the genome. Arrows represent syntenic orthogroup members. The orthogroup identification no. for this expanded group is 844916212 (see Table S2 in the supplemental material).

Supplemental Material

  • Figures
  • Additional Files
  • Table S1

    Summary of genomes used in this analysis. Table S1, PDF file, 0.2 MB.

    Copyright © 2014 Manson McGuire et al.

    This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-ShareAlike 3.0 Unported license, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited.

  • Text S1

    The supplemental text contains additional discussion concerning the adaptive radiation of fusobacterial lineages, ANI-based species definition, species-specific orthogroups, species-specific gene family expansions, protein families expanded in active invaders that cluster in the genome, active invader-specific features present in F. nucleatum from cancerous tumors, MORN2 domains in other organisms, and chromosomal rearrangements in Fusobacterium, as well as supplemental Materials and Methods. Download Text S1, DOCX file, 0.1 MB.

    Copyright © 2014 Manson McGuire et al.

    This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-ShareAlike 3.0 Unported license, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited.

  • Figure S1

    (a) Phylogenetic tree used to rename strains. Shown is the unrooted tree based on single-copy core orthogroups across all 26 Fusobacterium strains (excluding the outgroup). F. nucleatum F0401 clustered closely with F. nucleatum subsp. polymorphum, so we have renamed this strain F. nucleatum subsp. polymorphum F0401. Fusobacterium sp. strains 2_1_31 and 1_1_41FAA clustered closely with the two F. periodonticum strains, so we have renamed these strains F. periodonticum. Fusobacterium sp. strain D12 clustered closely with F. necrophorum, 3_1_5R clustered closely with F. gonidiaformans, and 12_1B clustered closely with F. ulcerans, so we have renamed these accordingly. (b) Unrooted tree based on 994 uniform OrthoMCL orthogroups shared between 15 strains of F. nucleatum (including the additional genome F. nucleatum subsp. animalis ATCC 51191). We found that six of our strains clustered closely with the F. nucleatum subsp. animalis strain. Therefore, we are renaming 21_1A, D11, 4_8, 3_1_33, 11_3_2, and 7_1 as strains of F. nucleatum subsp. animalis. It is also clear that 3_1_36A2, 3_1_27, and 4_1_13 are strains of F. nucleatum subsp. vincentii. (c) Tree of only F. nucleatum based on 16S rRNA gene sequences, including both the 16S rRNA gene sequences from the sequenced strain of F. nucleatum subsp. fusiforme. We observed the same phylogenetic pattern in the 16S rRNA gene-based calculations as we did with the whole-genome orthogroup-based calculations. Our observation that F. nucleatum subsp. fusiforme clusters most closely with F. nucleatum subsp. vincentii is in agreement with the Living Tree Project [2]. In the 16S rRNA gene sequence analysis, we observe that none of our strains cluster closely with F. nucleatum subsp. fusiforme. (d) ANI plot for F. nucleatum. Each point represents a pairwise comparison of two F. nucleatum genomes. The red-circled area shows pairwise comparisons between members of the same subspecies. The blue-circled area shows pairwise comparisons between members of different subspecies. A species threshold of 94 to 95% ANI is indicated by the green-shaded area. (d) Intraspecies ANI plot for species other than F. nucleatum. Each point represents a pairwise comparison of two F. periodonticum genomes. The red-circled area shows pairwise comparisons between members of the same subspecies (F. periodonticum 2_1_31 and F. periodonticum D10). The blue-circled area shows pairwise comparisons between members of different subspecies. A species threshold of 94 to 95% ANI is indicated by the green-shaded area. Download Figure S1, PDF file, 0.5 MB.

    Copyright © 2014 Manson McGuire et al.

    This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-ShareAlike 3.0 Unported license, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited.

  • Table S2

    (a) All SYNERGY orthogroups for the 27 genomes in our data set. (b) Orthogroups specific to active invaders. (c) Orthogroups containing MORN2 proteins. Table S2, XLSX file, 0.8 MB.

    Copyright © 2014 Manson McGuire et al.

    This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-ShareAlike 3.0 Unported license, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited.

  • Figure S2

    Gene content variability within species and subspecies, using our SYNERGY orthogroup data. We grouped each species separately for this analysis, except for F. nucleatum, where we grouped each subspecies separately. (Groupings are shaded alternately.) Download Figure S2, PDF file, 0.8 MB.

    Copyright © 2014 Manson McGuire et al.

    This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-ShareAlike 3.0 Unported license, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited.

  • Table S3

    Species- and subspecies-specific orthogroups. Table S3, XLSX file, 0.1 MB.

    Copyright © 2014 Manson McGuire et al.

    This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-ShareAlike 3.0 Unported license, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited.

  • Table S4

    Protein families and orthogroups overrepresented in individual species and subspecies. Table S4, DOCX file, 0.2 MB.

    Copyright © 2014 Manson McGuire et al.

    This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-ShareAlike 3.0 Unported license, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited.

  • Table S5

    (a to f) Full list of GO, Pfam, and KEGG groupings overrepresented in the active and passive invaders. (g) Orthogroups unique to active invader genomes. (h) Orthogroups unique to passive invader genomes. Table S5, XLSX file, 0.1 MB.

    Copyright © 2014 Manson McGuire et al.

    This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-ShareAlike 3.0 Unported license, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited.

  • Table S6

    Neighborhood analysis. (a) Proteins found near MORN2 proteins in the 7 finished F. nucleatum genomes. (b) Proteins found near FadA proteins in the 7 finished F. nucleatum genomes. (c) Proteins found near RadD proteins in the 7 finished F. nucleatum genomes. Table S6, XLSX file, 0.1 MB.

    Copyright © 2014 Manson McGuire et al.

    This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-ShareAlike 3.0 Unported license, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited.

  • Figure S3

    Whole-genome multiple alignments of fusobacterial genomes. (A) Genes encoding MORN2-containing proteins associate with synteny breaks in a whole-genome alignment of finished F. nucleatum genomes. The color gradient indicates location within the reference genome (F. nucleatum animalis 7_1). Syntenic regions are also indicated with light gray connecting lines. MORN2-containing proteins are indicated with small vertical lines and black triangles within each genome. (B) Mauve alignments for each active invader species with >1 representative. For F. nucleatum, the alignment is of one finished F. nucleatum genome from each of four different subspecies. (C) Mauve alignments for passive invader species. Active invader genomes have more genomic rearrangements than passive invader genomes. Download Figure S3, JPG file, 2.5 MB.

    Copyright © 2014 Manson McGuire et al.

    This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-ShareAlike 3.0 Unported license, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited.

Additional Files

  • Figures
  • Supplemental Material
  • Supplementary Data

    Supplementary Data

    Files in this Data Supplement:

    • Figure sf1, PDF - Figure sf1, PDF
    • Figure sf2, PDF - Figure sf2, PDF
    • Table st1, PDF - Table st1, PDF
    • Text s1, DOCX - Text s1, DOCX
    • Figure sf3, JPG - Figure sf3, JPG
    • Table st2, XLSX - Table st2, XLSX
    • Table st3, XLSX - Table st3, XLSX
    • Table st4, DOCX - Table st4, DOCX
    • Table st5, XLSX - Table st5, XLSX
    • Table st6, XLSX - Table st6, XLSX
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Evolution of Invasion in a Diverse Set of Fusobacterium Species
Abigail Manson McGuire, Kyla Cochrane, Allison D. Griggs, Brian J. Haas, Thomas Abeel, Qiandong Zeng, Justin B. Nice, Hanlon MacDonald, Bruce W. Birren, Bryan W. Berger, Emma Allen-Vercoe, Ashlee M. Earl
mBio Nov 2014, 5 (6) e01864-14; DOI: 10.1128/mBio.01864-14

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Evolution of Invasion in a Diverse Set of Fusobacterium Species
Abigail Manson McGuire, Kyla Cochrane, Allison D. Griggs, Brian J. Haas, Thomas Abeel, Qiandong Zeng, Justin B. Nice, Hanlon MacDonald, Bruce W. Birren, Bryan W. Berger, Emma Allen-Vercoe, Ashlee M. Earl
mBio Nov 2014, 5 (6) e01864-14; DOI: 10.1128/mBio.01864-14
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