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In silico analysis and biological
significance from genomic data
Edmundo GrisardMIP/CCB/UFSC
1
Universidade Federal de Santa Catarina Centro de Ciência BiológicasDepartamento de Microbiologia, Imunologia e Parasitologia
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Background:• Biologist• PhD in Parasitology• Professor of Cellular and Molecular Parasitology @ UFSC• CNPq research fellow
Research interests:• Hemoflagellate protozoan parasites:
• Trypanosoma spp. – Chagas Disease• Leishmania spp. – Cutaneous/Visceral leishmaniasis
• Host-Parasite interaction• Comparative Genomics and Proteomics• Phylogeny / Taxonomy• Diagnostics• Strain characterization
Lab webpages: www.proto.ufsc.br / www.bioinformatica.ufsc.br E-mail: [email protected]
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The complexity of life
Vitruvian Men (1490)Leonardo Da Vinci (1452-1519)
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Getting deeper, in detail...
De Humani Corporis Fabrica Libri Septem (1543)Andreas Vesalius (1514-1564)
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“Organisms evolve through adaptative processes in response to the environment “
Charles R. Darwin(1809-1882)
Darwin’s notebook “B”
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Hug et al., Nature Microbiology 16048 (2016)doi:10.1038/nmicrobiol.2016.48
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DNA structure (1953) James D. Watson and Francis Crick
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• Gilbert & Sanger (70’s):• ~10 bp / year
• Manual sequencing - slab gels (80-90’s):• Radioisotopes• 150-200 bp / week
• Automated sequencers (90’s onwards):• 1st generation: 300-400 bp+
• 2nd generation: 700 bp – 1.5 Kb• 3rd generation (output per run):
• PacBio: >10 Gb (50% > 50Kb)• Illumina: >2,000 Gb• Mini Ion: >30 Gb
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9GOLD Access: 11/11/2019
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Growth of the GenBank dataset
https://www.ncbi.nlm.nih.gov/genbank/statistics/ - 11/11/2019
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Genome size X Organism complexity
13ib.bioninja.com.au, 2019
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Genome size X Coding genes
NCBI, 2019
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Genome contents
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The biological dogma
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DNA / RNA
PROTEINDEGENERATE
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Post-translational modifications &
Structure
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HemoglobinFlexible quaternary structure
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Each cell within an organism have a unique:
Genome
Transcriptome
Proteome
Metabolome
Secretome
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Lamarck’s & Darwin’s & Wallace’s concerns…
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• Type of data:• Eukaryotic or Prokaryotic• DNA, RNA, Protein, Structure, …• Genes, Proteins, Families• Functional domains, Antigens, Signatures• Intra- and Inter-specific variability
• Concept of species ~ Phylogeny• Similarity:
• Measurable !• Phylogeny• Distance, molecular clock, barcoding,…
• Homology:• Non-Measurable ! Imply on ancestrality• Orthology and Paralogy
• Search for patterns:• In silico prediction• Benchwork validation
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http://tolweb.org/tree/
“DNA-based”
“RNA-based”
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What to compare? / What to look for?
• Sequence (Size/Composition)• Presence / Absence of a gene:
• Introns, Pseudogenes, Duplications, Transposons, ITS, …• Syntheny• Transcription / Expression levels• Post-Transcriptional / Post-Translational modifications• Protein structure• Function• Activity• Life cycle stages:
• Stage-specific expression• Homeostatic Versus Pathological stages:
• Mutations• Drug resistance
(Few) Biological questions
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Deepness
(Data type, number of markers and specimens, broadness of taxa, rooting, algorithm, …)
Str
ing
en
cy
(Su
bst
itu
tio
ns,
Tra
nsl
oc
atio
ns,
Ch
arg
e, S
yno
nim
, …) Biological questions
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Comparative pattern recognition
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A.thaliana
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Similarity & Homology
Common evolutive origin? Similar/shared characteristics?
Same / Distinct function ?
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......ASVJSIRWQEKVNLSMDAFKOAPDSFLASDKFLASVASMRDSVKS’DALSKDFLASDFKDSMKLSMCKLAMSDKGFHAISVNJDSVANSNINZFNDSGNDSIOVNSANDIFNOINVDSNVSMDAFEASDVAMVDSNGFIOANEINWIOENVIANDIOSNVNSODVNSODNVUNPNRUNVUIDNVIUSNDUINAUINSDUNVRUNGUNERUVNDFPSUNVASDUNRUINVUNWINRUVANUIBVUIBRIUBVUIEBNRTUIBVUIBPUBAUIAWPIUEBRUABVIYBAIPBWQIPWIDVBWBNVODVINWIRHUVWNVUNUNRUNOUNVDUNUOQNEDNVEURNVUNEOVNQNUVDNQUBUOEBRUOVBERBVDOUBWEUOVBOUNDVODQVOSIVNDIONEROGNERUOVNROUVBWVUQBODUBVDOJBNVUGBERUBVNWJOEWNFINWVIFHYNEWNEROQHTHEDOUBLEPBWQIPWHELIXFDJAHDSHFHASDFHLASDFISABOOKASKDFKASJDFDSFKSDFFROMJSDHFJKADJFKASDHFLAHSDFJKHAJSDJAMESDWATSONIPBIUWBEIUBQPIUBWUEPIBCVYWVBDYIYBSBCVABSDPIUFBQWERUVBRQBWEJBWEJTBQWHTVYSGSVNASRNTIOWHFAJSBFSDFJAWBDFGUWRBQUDPIUVSJKDBVUIPWEGUQFADSUGHOSDHGJBQEPWIGUDUIABVSUAIGFDABWEFUIVBWUDFBGAUGEFUDNFGANDSVEUDJAJSBDVIUAUSBURBGUBWQPQJDCJPWICIRRYBQVIBWIUBVUIEBNRTUIBVUIBPUBAUIAWPIUEBRUABVIYBAIPBWQIPWIDVBWBNVODVINWIRHUVWNVUNUNRUNOUNVDUNUOQNEDNVEURNVUNEOVNQNUVDNQUBUOEBRUOVBERBVDOUBWEUOVBOUNDVODQVOSIVNDIONEROGNERUOVNROUVBWVUQBODUBVDOJBNVUGBERUBVNWJOEWNFINWVIFHYNEWNEROQHODVSBDPVASDVARNOFVSUODBVAUSBUVIPBIUWBEIUBQPIUBWUEPIBCVYWVBDYIVWDYBSBCVABSDPIUFIUBVUIEBNRTUIBVUIBPUBAUIAWPIUEBRUABVIYBAIPBWQIPWIDVBWBNVODVINWIRHUVWNVUNUNRUNOUNVDUNUOQNEDNVEURNVUNEOVNQNUVDNQUBUOEBRUOVBERBVDOUBWEUOVBOUNDVODQVOSIVNDIONEROGNERUOVNROUVBWVUQBODUBVDOJBNVUGBERUBVNWJOEWNFINWVIFHYNEWNEROQHODVSBDPVASDVARNOFVSUODBVAUSBUVIPBIUWBEIUBQPIUBWUEPIBCVYWV.....
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......ASVJSIRWQEKVNLSMDAFKOAPDSFLASDKFLASVASMRDSVKS’DALSKDFLASDFKDSMKLSMCKLAMSDKGFHAISVNJDSVANSNINZFNDSGNDSIOVNSANDIFNOINVDSNVSMDAFEASDVAMVDSNGFIOANEINWIOENVIANDIOSNVNSODVNSODNVUNPNRUNVUIDNVIUSNDUINAUINSDUNVRUNGUNERUVNDFPSUNVASDUNRUINVUNWINRUVANUIBVUIBRIUBVUIEBNRTUIBVUIBPUBAUIAWPIUEBRUABVIYBAIPBWQIPWIDVBWBNVODVINWIRHUVWNVUNUNRUNOUNVDUNUOQNEDNVEURNVUNEOVNQNUVDNQUBUOEBRUOVBERBVDOUBWEUOVBOUNDVODQVOSIVNDIONEROGNERUOVNROUVBWVUQBODUBVDOJBNVUGBERUBVNWJOEWNFINWVIFHYNEWNEROQHTHEDOUBLEPBWQIPWHELIXFDJAHDSHFHASDFHLASDFISABOOKASKDFKASJDFDSFKSDFFROMJSDHFJKADJFKASDHFLAHSDFJKHAJSDJAMESDWATSONIPBIUWBEIUBQPIUBWUEPIBCVYWVBDYIYBSBCVABSDPIUFBQWERUVBRQBWEJBWEJTBQWHTVYSGSVNASRNTIOWHFAJSBFSDFJAWBDFGUWRBQUDPIUVSJKDBVUIPWEGUQFADSUGHOSDHGJBQEPWIGUDUIABVSUAIGFDABWEFUIVBWUDFBGAUGEFUDNFGANDSVEUDJAJSBDVIUAUSBURBGUBWQPQJDCJPWICIRRYBQVIBWIUBVUIEBNRTUIBVUIBPUBAUIAWPIUEBRUABVIYBAIPBWQIPWIDVBWBNVODVINWIRHUVWNVUNUNRUNOUNVDUNUOQNEDNVEURNVUNEOVNQNUVDNQUBUOEBRUOVBERBVDOUBWEUOVBOUNDVODQVOSIVNDIONEROGNERUOVNROUVBWVUQBODUBVDOJBNVUGBERUBVNWJOEWNFINWVIFHYNEWNEROQHODVSBDPVASDVARNOFVSUODBVAUSBUVIPBIUWBEIUBQPIUBWUEPIBCVYWVBDYIVWDYBSBCVABSDPIUFIUBVUIEBNRTUIBVUIBPUBAUIAWPIUEBRUABVIYBAIPBWQIPWIDVBWBNVODVINWIRHUVWNVUNUNRUNOUNVDUNUOQNEDNVEURNVUNEOVNQNUVDNQUBUOEBRUOVBERBVDOUBWEUOVBOUNDVODQVOSIVNDIONEROGNERUOVNROUVBWVUQBODUBVDOJBNVUGBERUBVNWJOEWNFINWVIFHYNEWNEROQHODVSBDPVASDVARNOFVSUODBVAUSBUVIPBIUWBEIUBQPIUBWUEPIBCVYWV.....
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...HYNEWNEROQHTHEDOUBLEPBWQIPWHELIXFDJAHDSHFHASDFHLASDFISABOOKASKDFKASJDFDSFKSDFFROMJSDHFJKADJFKASDHFLAHSDFJKHAJSDJAMESDWATSONIPBIUWBEIUBQPI...
THE DOUBLE HELIX IS A BOOK FROM JAMES WATSON
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Patterns might be evolutionary conserved
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Patterns might be evolutionary conserved
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34Sharing of geographical distribution, hosts, vectors, genes, proteins, epitopes, …
Trypanosoma rangeliTrypanosoma rangeli
Trypanosoma cruzi
Study models
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Multicopy gene families
Gene Family T. rangeli
SC-58
T. cruzi
CL Brener
MASP 50 1465
GP63 444 449
Trans-sialidases 120 1481
Amastins 72 27
DGF 422 569
KMP-11 148 40
Tuzin 34 83
RHS 689 777
Mucin 15 992
MSH6 2 2
MSH2 2 2
GPI8 2 2
!
Trypanosoma spp.
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SintenyNo DGFNo TS< Transposable elements (Tc, Tb, Lm)
Trypanosoma spp.
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Frame shiftsStop codons
Full ORF
SC-58 and Choachí strains
RIF4 / RIF5
(Adapted from Kolev et al., 2011)
Trypanosoma spp.
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Trypanosoma spp.
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Start Project
Nucleic AcidAmino Acid
Load Local / Genbank sequences
Load Local Reads / Chormats
Like non-redudant sequences
Quality and VectorScreening
Clusterization
Load Local / Genbank sequences
Non-redundatsequences
Gene Prediction
Gimmer GimmerHMM ORF by COG
Predicted Genes / ORF Sequences
Similarity Features
BLAST InterProScan HMMER
Other Features
OrthoMCL tRNA-Scan AFP
Analyses Features
Curation
Phyip
Phyml Ancescon
Alignment
WebLogo
Results
Psort
Automatic Annotation Codon Usage
Finish
Modelgenerator
Manual Annotation
SignalP
Microarray
Sequences like reads
Export
RPS-BLAST PSI-BLAST
Exclusive Workflowsee figure 3
Base Calling
Tools development
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40https://tree.opentreeoflife.org/opentree/argus/opentree11.4@ott93302
~2.7 million species~1.4 million synonyms~0,5 million unknowns
Tree of Life
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Conflicts / Lack of resolution
Tree of Life
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Trypanosoma spp.
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Trypanosoma spp.
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Trypanosoma spp.
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~65% hypothetical (5,043)
Trypanosoma spp.
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T. rangeli
T. grayiT. evansiT. vivaxT. brucei
Extracellular
IntracellularIntra orextracellular ?
T. cruziT. cruzi marinkellei
Trypanosoma spp.
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SHAW, 1994
“Leishmaniasis is a group of heterogeneousclinical manifestations caused by distinctspecies of protozoan parasites of the GenusLeishmania”
Adapted from Antinori, Schifanella & Corbellino, 2011
Study models
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Leishmania spp.
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49Lainson & Shaw, 1987
Leishmania spp.
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12 3 4 CN1234CN1234CN1234CN12 34CN12 3 4CN
12 3 4 CN1234CN1234CN1234CN12 34CN12 34CN
MPI RSP MTF SF3B1 FAD A2P i
UBE1 ASAT ICD G6PDH STK ALAT .
Leishmaniose
Caracterização dos isolados de LV de Florianópolis
Tatiane Catecati et al. (Unpublished results)
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5’ A2rel
• Amastigote-specific• Visceralization• Virulence
Leishmaniose
Caracterização dos isolados de LV de Florianópolis
Tatiane Catecati et al. (Unpublished results)
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Genomes of L. infantum from Florianópolis
ISOLATES IDTOTAL NUMBER OF
READS
READS MAPPED ON THE REFERENCE
GENOME (ABSOLUTE)
READS MAPPED ON THE REFERENCE
GENOME(%)
SC1006(DOG, 2015)
20972393 20550871 97.99%
SC1007(DOG, 2016)
32328874 31682098 98.00%
SC1008(DOG, 2010)
21575573 20959774 97.15%
SC1009(HUMAN, 2017)
24426247 23365451 95.66%
Leishmaniose
+ 4 isolates
Jennifer Ottino et al. (Unpublished results)
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L-Cysteine Glutathione (GSH)
Ornithine
Putrescin
SpermidinTrypanothion
e (TS[H]2)
L-CystathionineL-Homocystein
L-Methionin
CβS
L-Serine
O-Acetil-L-Serine
CS
Romero et al., P&V, 2014
Romero et al., AAC, 2015
Cysteine / Cysthationine biosynthesis
Leishmania spp.
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T. rangeli:• Lacks de novo cysteine biosynthesis• Single route for cysteine biosynthesis – homocysteine• Uses the transulfuration pathway (as Tb)
!
MW
Tc
EP
I
Tr
EP
I
Lb
PR
O
rCB
S
CBS
STOP CODON
CS
Romero et al., P&V, 2014
Romero et al., AAC, 2015
Leishmnia spp.
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Challenges for MASTER/PrInt/CAPES:
Improve the genome assembling strategies:• Long, repetitive sequences• Non-coding regions• Hypothetical / Conserved Hypothetical proteins
Improve genome annotation:• Algorithm development & training
• Multiple biological variables • Time consuming manual curation
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Professor Mário Steindel
Dra. Patricia Stoco
Dr. Glauber WagnerDra. Milene de Moraes
Dra. Débora LückemeyerDra. Ibeth Romero
Dra. Elisa PrestesDr. Abadio Costa Jr.
Caibe Alves, MSc
Laís Yamanaka, MScCarime Pontes, MSc
Adriana Silva, MScFábio Indá, MSc
Tatiana Catecati, MSc
Laryssa de LizViviane Flores
Amábilli RosarNatalia Gutierrez
Dr Ana Teresa Vasconcellos
Professora Santuza Teixeira
Dr Daniela BartholomeuDr Ricardo Fujiwara
Dr João Cunha
Jennifer Ottino MSc
Professor Arnaldo Zaha
Professor Henrique Ferreira
Dr Hercules Moura
Professor Björn Andersson
Dr Hamid Darban
Dr Samuel GoldenbergDr Silvane Murta
Dr Elisa Cupolillo
Professor José Franco da Silveira
Professora Nobuko Yoshida
Professor Sergio Schenkman
Professor John Kelly
Dr Michael Lewis
Dr Kevin Tyler
Dr Gustavo Vallejo
Dr Luiz Felipe OliveiraDr Aline Sereia