Recent Patents on DNA & Gene Sequences 2008, 2, 111-132
111
Brazilian Genome Sequencing Projects: State of the Art
Eduardo Righi Capanema Xavier1,2,*, Beatriz Parreiral Xavier Capanema3, Jerônimo Conceição
Ruiz2, Guilherme Oliveira2, Roberto Meyer4, Vivian D’Afonseca1, Anderson Miyoshi1 and Vasco
Azevedo1
1
Departamento de Biologia Geral do Instituto de Ciências Biológicas da Universidade Federal de Minas Gerais.
Avenida Antônio Carlos, 6627. Campus Pampulha. Belo Horizonte, Minas Gerais. CEP 31.270-010, Brasil. 2Centro de
Pesquisas René Rachou. Fundação Oswaldo Cruz - FIOCRUZ. Ministério da Saúde. Avenida Augusto de Lima, 1715.
Barro Preto. Belo Horizonte, Minas Gerais. Brasil. CEP 30.190-002, 3Faculdade de Direito da Universidade Federal
de Minas Gerais. Avenida João Pinheiro, 100. Centro. Belo Horizonte, Minas Gerais. CEP 30.130-180, Brasil.
4
Laboratório de Imunologia, Instituto de Ciências da Saúde. Universidade, Federal da Bahia. Avenida Reitor Miguel
Calmon, S/N-Vale do Canela. Salvador, Bahia. CEP 40140-100, Brasil.
Received: February 2, 2008; Accepted: April 2, 2008; Revised: April 14, 2008
Abstract: This review covers all Brazilian Genome, EST and Metagenome Projects, Sequencing Networks’ history and
structure, and patents related to Brazilian Genome Projects, beginning with the first genome sequenced in this country, i.e.
the 9a5c strain of Xylella fastidiosa CVC, up till the recently sequenced 1002 strain of Corynebacterium
pseudotuberculosis, which was done with a mixed strategy that included both traditional Sanger methodology and Avant
Garde 454 Life Sciences pyrosequencing technology. Almost 90% of all genomic research that has been done in Latin
America is a product of Brazil’s effort to support and stimulate OMICs in our country. Consequently, we gave special
attention to patents registered by Brazilian genome networks and/or Brazilian scientists involved in genomics,
transcriptomics, proteomics, EST, and metagenome projects, as well as in the development of bioinformatics software and
techniques.
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Keywords: Genome, EST, metagenome, sequencing projects, Brazil, Xylella fastidiosa, Corynebacterium pseudotuberculosis,
sanger, pyrosequencing, 454, OMICs, bioinformatics, patents.
INTRODUCTION
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Those who potentially will benefit from DNA patenting
around the globe should keep their sights turned towards
Brazil. More than 85% of all sequencing projects in Latin
America have been conducted in our country [1]. Along with
coffee, soybean, banana, eucalyptus and sugar cane [2-4],
Brazil’s key crop for renewable energy, many other organisms have been and are being researched and sequenced
throughout the country [5, 6]. We have focused our attention
on genome projects executed in Brazil as well as EST and
metagenome sequencing projects, such as the Corynebacterium pseudotuberculosis Genome Project, Brazil’s first
genome sequencing project, carried out with 454 Life
Sciences pyrosequencing technology [J.C. Ruiz, G. Oliveira
- personal communication], along with the traditional Sanger
method [7-10], conducted by the Minas Gerais Genome
Network. We also made an effort to include in each section
all available information on patents directly or indirectly
related to these genome projects. It is likely that this type of
systems biology research (omics) will reach a vertex in the
next years due to the delivery of new sequencing techniques
[7, 8, 9, 11, 12] that both drastically reduce sequencing costs
and are able, in some specific cases, to provide up to a 100fold increase in throughput over current Sanger sequencing
*Address correspondence to this author at the Departamento de Biologia
Geral do Instituto de Ciências Biológicas da Universidade Federal de Minas
Gerais. Avenida Antônio Carlos, 6627. Campus Pampulha. Belo Horizonte,
Minas Gerais. CEP 31.270-010, Brasil; Tel/Fax: + 55 31 3409-2610;
E-mail: vasco@icb.ufmg.br
1872-2156/08 $100.00+.00
technology [7, 12, 13]. Moreover, sequencing will become
increasingly more viable for those interested in participating,
thereby widening access to the global benefits provided by
omics research.
A breakthrough for Brazilian molecular biologists and
the first bioinformaticians, the Xylella fastidiosa genome was
resolved in a coordinated effort involving various university
laboratories [14]. It was the first phytopathogen to have its
entire genome sequenced, and it provided a tremendous
stimulus for the development of sequencing technology in
Brazil [5, 6, 15]. It resulted in the creation of new genome
networks [6], as well as relevant know-how, software and
technical training and information. This first genome project
involved a tremendous coordinated effort; consequently,
some believed that Brazil could become a Panama Canal for
scientists interested in real science and not in corporate
profits. This is because science in Brazil was built and is
sustained by federal (mostly) and state universities and
research centers, all supported by public funds. Clearly,
while this cooperative effort avoids the costs of competitive
duplication, the possibility of profit is not ignored, since
patenting is necessarily done in cooperation with the
government whenever the research is government sponsored
in federal and state universities and government-supported
research centers [6]. That said; there is less incentive for
entities such as corporations, joint-ventures and foreign
parties to share intellectual property rights with these federal
and state universities. Consequently, the commercial side of
this process has not thrived and the patenting has not
progressed much. However, this non-commercial orientation
© 2008 Bentham Science Publishers Ltd.
112 Recent Patents on DNA & Gene Sequences 2008, Vol. 2, No. 2
has actually helped keep scientists interested in participating
and cooperating. This is a paradox that works in Brazil for
one specific reason: the strength and consistency of the
sequencing networks concentrated in the south-east region of
the country [5]. Fig. (1) illustrates this scenario. Brazil is a
strong participant globally in genome sequencing projects
Fig. (2).
BACKGROUND
The first organism to have its genome sequenced in
Brazil was Xylella fastidiosa (species name reflecting its
complex nutritional requirements condition); it is the cau-
Capanema Xavier et al.
sative agent of citrus variegated chlorosis (CVC), a disease
that affects orange trees, grapevine, citrus and coffee, and it
was the first phytopathogen worldwide to have its genomic
sequence fully read. This sequencing was done in a
cooperative effort by the Xylella fastidiosa consortium of the
Organization for Nucleotide Sequencing and Analysis
(ONSA) [16, 17]. This bacterium is a parasite of the host
xylem; pathogenicity is a consequence of the activity of
toxins, antibiotics and ion sequestration systems, as well as
bacterium-bacterium and bacterium-host interactions mediated by a range of proteins [18]. According to Doddapaneni et
al. [19], there are currently four sequenced strains (9a5c,
Dixon, Ann1 and Temecula-1). NCBI’s TaxBrowser 1 repor-
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*Brazilian states by regions: North Region: AC - Acre; AM - Amazonas; RR - Roraima; RO - Rondônia; PA - Pará; AP - Amapá; TO Tocantins; Northeast Region: MA - Maranhão; PI - Piauí; CE - Ceará; RN - Rio Grande do Norte; PB - Paraíba; PE - Pernambuco; AL Alagoas; SE - Sergipe; BA - Bahia; Center-West Region: GO - Goiás; MT - Mato Grosso; MS - Mato Grosso do Sul; DF - Distrito Federal;
Southeast Region: SP - São Paulo; RJ - Rio de Janeiro; MG - Minas Gerais; ES - Espírito Santo; South Region: PR - Paraná; SC - Santa
Catarina; RS - Rio Grande do Sul.
** Abbreviations: CNPq - Conselho Nacional de Desenvolvimento Científico e Tecnológico (National Council of Scientific and
Technological Development); FAPESP - Fundação de Amparo à Pesquisa do Estado de São Paulo (Foundation for Research Support of the
São Paulo State); FAPEMIG - Fundação de Amparo à Pesquisa do Estado de Minas Gerais (Foundation for Research Support of the Minas
Gerais State); FAPERJ - Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (Foundation for Research Support of the Rio de
Janeiro State);
Find figures at http://www.lgcm.icb.ufmg.br/publications.
Fig. (1). Map showing genome/EST/metagenome projects in Latin America with the working networks and the sequenced organisms.
1
http://www.ncbi.nlm.nih.gov/sites/entrez?db=taxonomy
Brazilian Genome Projects
Recent Patents on DNA & Gene Sequences 2008, Vol. 2, No. 2
113
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Source: GOLD - Genomes OnLine Database [1].
http://www.lgcu.icb.ufung.br/publications.
Fig. (2). Percentage of genome sequencing projects by country from January 2005 until September 2007, including complete, draft
assemblies and ongoing efforts, according to the GOLD Server in December 2007.
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ted in November 2007 that two strains, 9a5c and Temecula1,
both sequenced by the São Paulo State Consortium, had
complete sequence status, whereas the Dixon and Ann1
strains were in the draft assembly stage [20]. Sequencing of
Xyllela fastidiosa strains M12 and M23 is in progress and is
being done by the DOE Joint Genome Institute. The State of
São Paulo Research Foundation - FAPESP et al. has issued a
patent [21] concerning the isolation and characterization of
an operon of Xylella fastidiosa; this was published November 15, 2001. It “relates to the isolation and characterization
of an operon (…) referred to as the XfGUM operon, which
contains nine genes and is involved in the production of a
compound with xanthan-gum-like properties. The expression
products of the operon and genes are also a part of the
invention, as are various uses of these”. Moreover, the entire
genome of X. fastidiosa was patented, with various uses
described. This patent number WO02082432 [22], claims a
“computer readable medium having recorded thereon a
nucleic acid molecule from X. fastidiosa genome” that bears
the X. fastidiosa genome sequence and allows therefore a
determination as to whether a plant, a plant part, or a
collection of plants are infested with X. fastidiosa or if any
given organism is potentially pathogenic to plants by
measuring homology against the X. fastidiosa genome,
which is an interesting bioinformatics-generated offshoot of
this patent. Another patent related to the X. fastidiosa
genome was issued for Kirkpatrick and Guilhabert (2006)
[23], who demonstrated an engineering resistance to Pierce’s
Disease. A protein called HecA-like hemagglutinin and its
gene are described; according to the inventors, this protein
constitutes a “molecular glue” that attaches to the bacteria
surface, causing cells to aggregate. This mechanism is
involved in bacteria-plant pathogenicity and invasion processes and could be used as a factor to slow down infection
if transgenic plants expressing HecA-like hemagglutinin
were to be engineered with this technology. It involves gene
sequences, i. e. the HecA-like hemagglutinin sequence
corresponding to the active bacterial gene, the physiological
traits of this gene’s expression and orthologous-induced
expression. The latest patent related to X. fastidiosa that we
could find is entitled “Biocontrol of X. fastidiosa” [24]. It
does not claim any sequences; rather it concerns specific
strains, providing possible mechanisms or strategies for
preventing disease in affected plants. The proposed biocontrol could be attained by inoculating plants with the patented
X. fastidiosa “benign” strain, so that bacteria populations can
reach equilibrium, preventing harmful strains from causing
damage.
Since the classic Xylella publication in Nature [14] in
1997, new genome, EST and metagenome projects (“soil
microbial communities from contaminated sediments”
developed by the Federal University of Santa Catarina UFSC) have grown, and a number of genome networks have
emerged following the ONSA example. Among these, the
ONSA consortium along with the Minas Gerais Genome
Network, a network managed by the René Rachou Research
Center of the Oswaldo Cruz Foundation (FIOCRUZ), have
conducted the Schistosoma mansoni Genome/EST Project,
which was initiated in April 2001 [25-27]. Almost 180,000
EST clones were sequenced, providing 68,664,542
114 Recent Patents on DNA & Gene Sequences 2008, Vol. 2, No. 2
nucleotide sequences, of which 17,998,756 are nonredundant, according to the ONSA WebSite2 [28-30]. This
flatworm, which belongs to the Trematoda class [31], along
with two other Schistosoma species, Schistosoma japonicum
and Schistosoma haematobium, infects more than 200
million people in over 70 countries [29, 32-35]. VerjovskyAlmeida [36] states in the Schistosoma Genome Project web
site3 of the University of São Paulo (USP) that “no patent
will be sought for sequence or clone information. It is
expected that patents might result from future work with the
clones, possibly for the protection of inventions and uses of
such clones or sequences for diagnostic procedures, vaccines, etc.” [37, 38]. Nevertheless, a patent with publication
number WO05023979, registered in 2005, bearing the
project title “Patente para o uso de genes encontrados no
Projeto Genoma do Schistosoma como diagnóstico, alvo de
desenvolvimento de vacina ou de drogas”4 was deposited in
the WIPO database with the title “Isolated S. mansoni
Nucleic Acid Molecules and Uses thereof” [39]; it was
registered, with FAPESP as first applicant and Sérgio
Verjovski-Almeida as first inventor. This patent claims “an
isolated nucleic acid molecule which encodes an S. mansoni
protein, or a portion thereof which is at least 20 amino acids
in length”. Also, the Oswaldo Cruz Foundation (FIOCRUZ)
developed a kit for schistosomiasis diagnosis through PCR.
This invention was patented [40], with publication number
WO01075148. Also related to the Schistosoma mansoni
research developed in Brazil, the Federal University of
Minas Gerais, along with Dr. Sérgio Costa Oliveira has a
patent (WO07118292) that involves the production of
recombinant proteins by means of genetic engineering
techniques (recombinant DNA) - ad hoc membrane protein
Sm29 - and an immunoenzymatic assay to detect IgG
antibodies against the Sm29 protein [41]. Similarly, many
other S. mansoni patents involve proteins and their encoding
regions for vaccination uses [42-47] and for antibody
production [48]. Glutathione-s-transferase Sm26 of S.
mansoni, the DNA encoding 28 kDa glutathione-s-transferase of Schistosoma mansoni and the protein product are
described. There are also patents for antibody-producing
clones that react with antigens produced by S. mansoni for
diagnostic purposes and for pharmaceutical preparations
[48]. An especially interesting patent involving Schistosoma
describes a method of transgene expression and secretion in
this trematode via viral or non-viral vectors in order to turn
the parasite into a drug delivery organism [49]. It is a method
to produce Schistosoma worms that would serve as
intermediate vectors that could express gene products into
the patient’s bloodstream and could also be used for mass
production, quality control, termination of therapy and dose
titration [50]. It is a gene therapy method that would
substitute the patient's own cells to produce the desired gene
product, e. g. insulin for diabetic patients or erythropoietin
for patients with anemia caused, for instance, by chronic
kidney disease [51] or by solid organ transplantation [52,
53].
Capanema Xavier et al.
Considerable effort was made to put together a large
national genome network. This resulted in the creation of the
Brazilian National Genome Project Consortium, which
brought together 25 laboratories, a bioinformatics center and
three coordination laboratories. The first project carried out
by the Brazilian National Genome Project Consortium,
published in 2003, was the Chromobacterium violaceum
Genome Project [54-56]. Chromobacterium violaceum is a
Gram-negative free-living bacteria that inhabits soil and
water in tropical areas [57, 37]; it infects mammals, including human beings, [58] often causing death by septicemia
[59]. The Brazilian National Council for Scientific and
Technological Development (CNPq) et al. issued in 2004 a
patent [60] entitled “Gene-Coding Polynucleotides of the
Chromosome of the Bacterium Chromobacterium violaceum,
Expression and Activity of these Polynucleotides and their
Applications”, which constitutes more than a whole-genome
patent in its claiming extensions. It claims for polynucleotides or groups that are identical or have a similarity of at
least 70% to those identified with SEQ ID numbers 1-29,
along with fragments thereof coding for the oxidationreduction of arsenic, cyanide, cyanate and other heavy metals, synthesis of hydrocyanic acid and biocide compounds,
chitinases and chitin dextrinases, hemolysins, polyhydroxyalkanoates, violacein, and polypeptides inducible by
herbicides and that can be preferentially isolated from the
chromosome of the ATCC 12472 strain of C. violaceum. The
patent also claims complementary polynucleotides of those
cited or that include at least 15 successive nucleotide bases
of the polynucleotide sequences from those cited. It
constitutes a massive patent effort to obtain control of the
sequenced polynucleotides and forthcoming sequences of
any C. violaceum strain or other organisms bearing such
sequences that could eventually be sequenced. A German
organization has patented a method for biosynthesis of the
natural blue-violet colorants violacein and desoxyviolacein
that is based on the use of C. violaceum pigments [61].
Another patent related to this organism makes use of C.
violaceum as well as Chlorella vulgaris to recover and
concentrate gold utilizing the microorganism’s capa-bility of
producing cyanide ion, forming a cyanide ion-con-taining
culture with gold ore. It is therefore a methodological patent
[62].
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2
http://verjo18.iq.usp.br/schisto/
http://verjo18.iq.usp.br/schisto/About/info.html
A translation to the patent’s project title: “Patent to the use of genes found in the
Schistosoma Genome Project as diagnostic, development of vaccine targets or drugs”.
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The second project that the Brazilian National Genome
Project Consortium worked on was a Mycoplasma sequence
project, which comprised: (i) Mycoplasma hyopneumoniae
pathogenic 7448 strain; (ii) non-pathogenic Mycoplasma
hyopneumoniae strain J; and (iii) Mycoplasma synoviae, an
avian pathogen. According to Vasconcelos et al. (2005) [63],
Mycoplasmas are a group of more than 180 species with no
cell wall that parasitize various organisms, including plants,
humans and other animals. Due to their nutritional
requirements, they typically exhibit host tissue specificities.
This is a feature that is likely related to the fact that this
group has undergone considerable genome reduction during
its evolution, probably as a consequence of taking advantage
of complementary host metabolism mechanisms. However,
according to the authors [63], bottlenecks and asexual
reproduction have been responsible for the accumulation of
deleterious mutations in these organisms, resulting in
Brazilian Genome Projects
Table 1.
Recent Patents on DNA & Gene Sequences 2008, Vol. 2, No. 2
115
Brazilian Genome, EST and Metagenome Projects, with All Related Patents
Organism or Subject
Genome Network or
Responsible Center
Status
Type of Project
Related Patent Numbers
Anopheles darlingi
CNPqa, LNCC a
Incomplete
Genome and EST
WO07073591*
WO06029605
WO04075912
WO05103243
WO04034783
WO04029088
WO03087322
WO03079796
WO03020913
WO03013238
WO01000667
WO94006295
Bos indicus
ESALQ a/ USPa
Incomplete
EST
Incomplete
Genome
Bradyrhizobium japonicum
EMBRAPA
a
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SEMIA 5079
Cancer Genome Project
Ludwig Institute for Cancer Research
- SP
Incomplete
Chromobacterium violaceum
Brazilian National Genome Project
Consortium, CNPq, MCTa
Complete
UNICAMPa, FAPESPa
EMBRAPA/Café, EMBRAPA/Café,
Brazilian Consorcium for the
Research and Development of Coffee
Complete
FIOCRUZa/CPqRRa/ UFMGa /
FAPEMIG a
Incomplete
ATCC 12472
Coffea arabica
F
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N
Corynebacterium pseudotuberculosis
1002
D
or
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s
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EST
Genome
WO98050401
WO07094885
WO02008386
WO01038492
WO00004778
WO87007910
WO04031229
WO04056960
WO02050299
WO91008316
Genome
-
Genome
WO90011351
WO07074991
WO06008098
WO06008097
WO04050694
WO03046123
WO02051231
WO02022799
WO01066573
WO01049854
WO01049854
WO01002583
WO01002583
WO95019442
WO03040290
WO03040180
WO02100530
WO01085967
WO01000843
WO01000843
WO01000844
WO01000842
WO01000805
WO01000804
WO01000802
WO03040181
116 Recent Patents on DNA & Gene Sequences 2008, Vol. 2, No. 2
Capanema Xavier et al.
(Table 1) Contd....
Genome Network or
Organism or Subject
Status
Type of Project
Related Patent Numbers
Incomplete
EST
WO06113594
Responsible Center
Eimeria acervulina
USP
WO04052393
WO04002527
WO03004684
WO03004683
WO99050387
Eimeria maxima
USP
Incomplete
EST
WO06113594
WO04052393
WO04002527
WO03054157
WO03004684
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WO03004683
WO99050387
Eimeria tenella
Eucalyptus grandis
USP
Incomplete
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F
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N
FAPESP
Gluconacetobacter diazotrophicus
UFRJa, LNCC/MCT, EMBRAPA,
PAL5
UENFa , UERJa, FAPERJa , CNPq,
MCT
Herbaspirillum seropedicae
GenoPar Consortiuma
Incomplete
EST
EST
WO05070180
WO05010040
WO05005472
WO04052393
WO04002527
WO03004684
WO99050387
WO06052554
WO05032241
WO04048595
WO98013503
WO97030162
Incomplete
Genome
WO02045513
Incomplete
Genome
WO02045513
WO07100162
Z67
Leifsonia xyli xyli
WO06113594
FAPESP/ UNICAMP
Complete
Genome
WO07026860
Leishmania chagasi
ProGeNea, MCT, BNB a, CNPq
Incomplete
EST
WO96033414
Leptospira interrogans Copenhageni
FAPESP, CNPq, USP, UNICAMP
Complete
Genome
WO06002631
Litopenaeus Vannamei
UFSCar a, CNPq
Incomplete
EST
WO00034476
Moniliophthora (Crinipellis)
perniciosa
UNICAMP, SEAGRIa
Incomplete
Genome
-
CTCB07
Fiocruz L1-130
Singer
Brazilian Genome Projects
Recent Patents on DNA & Gene Sequences 2008, Vol. 2, No. 2
117
(Table 1) Contd....
Genome Network or
Organism or Subject
Status
Type of Project
Related Patent Numbers
Incomplete
Genome
WO07130846
WO07091881
WO07014885
WO07010413
WO06128390
WO06102767
WO06060663
WO05111205
WO05077411
WO05005639
WO05004911
WO04083459
WO04055214
WO04011436
WO03093307
WO03089462
WO03070981
WO03053459
WO03053459
WO03038402
WO03011336
WO02050262
WO99045119
WO99002670
WO98032862
Responsible Center
FAPa , FENAMa
Mycobacterium bovis BCG
Moreau RDJ
o
F
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N
Complete
Mycoplasma hyopneumoniae J
LNCC, UFRGS
Complete
7448
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LNCC, UFRGSa
Mycoplasma hyopneumoniae
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Genome
WO07116032
WO07103042
WO06056841
WO05112995
WO05060328
WO05009462
WO04058142
WO04003161
WO03004051
WO03003941
WO02049666
WO02010343
WO00031115
WO99026664
WO96028472
WO95009870
WO93016726
WO92018161
WO92003157
WO91018627
WO86000019
Genome
WO07116032
WO07103042
WO06056841
WO05112995
WO05060328
WO05009462
WO04058142
WO04003161
118 Recent Patents on DNA & Gene Sequences 2008, Vol. 2, No. 2
Capanema Xavier et al.
(Table 1) Contd....
Genome Network or
Organism or Subject
Status
Type of Project
Related Patent Numbers
Responsible Center
WO03004051
WO03003941
WO02049666
WO02010343
WO00031115
WO99026664
WO96028472
WO95009870
WO93016726
WO92018161
WO92003157
WO91018627
WO86000019
Mycoplasma synoviae
LNCC, UFRGS
Complete
UnBa, UFGa, MCT, CNPq
Incomplete
53
Paracoccidioides brasiliensis
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Pb01 ATCC-MYA-826
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Pichia (Hansenula) angusta
(polymorpha)
Rhizobium tropici
PRF 81
UNICAMP
Incomplete
EMBRAPA
Incomplete
UNICAMP, FAPESP
Incomplete
o
F
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N
Saccharum sp.
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Genome
Differential Gene
Expression
Genome
Genome
EST
-
WO98055649
WO03052063
WO07137075
WO07107000
WO07058086
WO07006318
WO06134623
WO06090913
WO05115412
WO05054462
WO05019439
WO04005517
WO03089640
WO03020014
WO02015703
WO02015702
WO02013614
WO01060159
WO00044221
WO99033966
WO99013855
WO98012206
WO98002560
WO95023156
WO95017806
WO94025568
WO94019924
WO07106966
WO98043631
Brazilian Genome Projects
Recent Patents on DNA & Gene Sequences 2008, Vol. 2, No. 2
119
(Table 1) Contd....
Genome Network or
Organism or Subject
Status
Type of Project
Related Patent Numbers
WO05023979
WO01075148
WO07118292
WO06088951
WO04043998
WO03002597
WO02085930
WO00017654
WO97033613
WO97033610
WO91012327
WO91009621
WO90002563
WO83001837
Responsible Center
Schistosoma mansoni
ONSAa, FAPESP
Complete
EST
Soil
UFSCa, CNPq
Incomplete
Metagenome
UFSC, CNPq
Incomplete
FAPESP, USP
Incomplete
FAPESP, USP
Incomplete
FAPESP, USP, UNICAMP
FAPESP, USP
from contaminated sediments
Trypanosoma rangeli
t
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r
SC-58, Choachi
Xanthomonas axonopodis pv.
aurantifolii B
11122
o
F
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N
Xanthomonas axonopodis pv.
aurantifolii C
10535
Xanthomonas axonopodis pv. citri
XV101, 306
Xanthomonas campestris campestris
ATCC 33913
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microbial communities
EST
Genome
WO05090595
WO04018673
WO03054177
-
WO03001911
Genome
WO03001911
Complete
Genome
WO03001911
Complete
Genome
WO06003989
WO05054470
WO02072795
WO02044352
WO02012293
WO01007635
WO00078967
WO00020616
WO98041612
WO98012301
WO98002545
WO96036765
WO93021307
WO93017096
WO93017096
WO90015143
WO88001172
WO87005937
WO87000006
WO86001830
120 Recent Patents on DNA & Gene Sequences 2008, Vol. 2, No. 2
Capanema Xavier et al.
(Table 1) Contd....
Genome Network or
Organism or Subject
Status
Type of Project
Related Patent Numbers
Responsible Center
Xanthomonas smithii citri
FAPESP, USP, UNICAMP
Incomplete
Genome
-
Xylella fastidiosa
UNICAMP, FAPESP, USDA a
Incomplete
Genome
WO06069160
WO05023005
Pierce's Disease Strain
WO05023005
WO02082432
WO01085905
Xylella fastidiosa CVC
ONSA, FAPESP
Complete
Genome
WO02082432
WO01085905
8.1.b clone 9.a.5.c
Xylella fastidiosa-grape
FAPESP, USDA, AEGa , Brazilian
Temecula1
National Genome Project Consortium
Zea mays
FAPEMIG, UFMG
Complete
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WO02082432
WO01085905
Incomplete
Differential Gene
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WO06084868
WO04063379
WO02006322
WO01083790
WO00053732
* Brazilian Group or Researcher’s patents set in boldface; a Abbreviations used herein: ESALQ - Escola Superior de Agricultura “Luiz de Queiroz”; USP - Universidade de São Paulo;
EMBRAPA - Empresa Brasileira de Pesquisa Agropecuária; CNPq - Conselho Nacional de Desenvolvimento Científico e Tecnológico; MCT - Ministério da Ciência e Tecnologia;
UNICAMP - Universidade de Campinas; FAPESP - Fundação de Amparo à Pesquisa do Estado de São Paulo; FIOCRUZ - Fundação Oswaldo Cruz; CPqRR - Centro de Pesquisas
René Rachou; UFMG - Universidade Federal de Minas Gerais; FAPEMIG - Fundação de Amparo à Pesquisa do Estado de Minas Gerais; UFRJ - Universidade Federal do Rio de
Janeiro; LNCC - Laboratório Nacional de Computação Científica; UENF - Universidade Estadual do Norte Fluminense; UERJ - Universidade do Estado do Rio de Janeiro; FAPERJ Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro; ONSA - Organization for Nucleotide Sequencing and Analysis; GenoPar - Programa Genoma do Estado do Paraná;
ProGeNe - Programa de Genética e Farmacogenética do Instituto de Psiquiatria do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo; UFSCar Universidade Federal de São Carlos; SEAGRI - Secretaria da Agricultura, Irrigação e Reforma Agrária do Estado da Bahia; FAP - Fundação Ataulpho de Paiva; FENAM - Fundação
Nacional dos Médicos; UFRGS - Universidade Federal do Rio Grande do Sul; UnB - Universidade de Brasília; UFG - Universidade Federal de Goiás; UFSC - Universidade Federal
de Santa Catarina; USDA - United States Department of Agriculture; AEG - Agronomical and Environmental Genomes.
Source: GOLD - Genomes OnLine Database. http://www.genomesonline.org [1].
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minimal genomes that maintain basic core functions and
adaptations required for their survival through specific
hosting and intrinsic parasitism. Mycoplasma hyopneumoniae is the causative agent of enzootic pneumonia in pigs,
whereas M. synoviae is responsible for respiratory tract
disease and synovitis in chickens and turkeys. Gene sequences of M. hyopneumoniae have been patented by the
National Council for Scientific and Technological Development (CNPq) et al., referring to the polypeptides encoded by
these genes and the uses thereof, including the protection
induced by the immune response animals produce against
these polypeptides [64]. Antigenic potential is therefore one
of the aims of these patents. They also specify intellectual
property of similar polynucleotides that have at least 70%
identity, along with nucleotide sequences coding for
polypeptides by amino acid sequences and fragments. These
correspond to pathogenic strain 7448 of M. hyopneumoniae.
Methods for serological diagnosis of M. hyopneumoniae
infection in mammals and a cultivation process that is
preferential for this organism were also included. A SEQ ID
Nr. 1 was sought, together with the DNA coding sequence
for the protein described, its regulator sequence, the vector
used to express the claimed protein, the host cell (E. coli)
that was used to express the protein, the immunogenic
composition that the claimed protein bears as well as the
immunogenic composition of a fragment of the claimed
protein, the method used to induce the immune response in
the animal with the claimed protein, a method to detect
antibodies produced by the administration of the protein
(diagnostic method) and the amount of protein that should be
used. A large number of patents related to M. hyopneumoniae describe vaccination methods, including a
vaccination kit with an immunogenic dose of live attenuated
Porcine Reproductive Respiratory Syndrome (PRRS) virus,
which involves a novel method of vaccination of a pig by
administering a whole or partial cell, a modified live
preparation, a subunit, a nucleic acid or DNA vaccine of M.
hyopneumoniae to a weaned piglet; a M. hyopneumoniae
multi-strain vaccine in the form of whole or partial cell
bacteria or in the form of a subunit vaccine; a mixed vaccine
for preventing porcine respiratory disease, comprising inactivated Haemophilus parasuis S4 and S5, M. hyopneumoniae
and PRRS virus to prevent swine enzootic pneumonia,
PRRS, porcine respiratory disease complex (PRDC) and
post-weaning multisystemic wasting syndrome (PMWS); an
oil-in-water emulsion of bacterial or viral suspensions that
acts as a vehicle for the delivery of a pharmaceutical composition, ad hoc inactivated M. hyopneumoniae bacterium,
Brazilian Genome Projects
Recent Patents on DNA & Gene Sequences 2008, Vol. 2, No. 2
an inactivated d porcine circovirus type 2 (PCV-2) virus or
combinations thereof; another combined vaccine with M.
hyopneumoniae with at least one viral antigen comprising an
adjuvant mixture of acrylic acid polymer, a mixture of a
metabolizable oil, such as one or more unsaturated terpene
hydrocarbons, and a polyoxyethylene-polyoxypropylene
block copolymer; M. hyopneumoniae polypeptides and nucleic acids, as well as nucleic acid expression vectors containing nucleic acids for treating swine to prevent enzootic
pneumonia; another vaccine with whole or partial cell
inactivated or modified live preparations, a subunit vaccine,
or a nucleic acid or DNA vaccine that is synthesized or
recombinantly produced; a M. hyopneumoniae bacterin
vaccine composition that provides immunity against infection after a single administration; a temperature-sensitive
vaccine; methods of identifying gene sequences of potential
vaccine antigens and polypeptides encoded by the gene
sequences as well as the use of such sequences to induce a
protective immune response in animals with the use of a
marker (preferably polyHis tag) co-expressed with a protein
translated from the nucleotide sequence; a M. hyopneumoniae protein prepared by recombinant DNA or synthetic
means, its DNA coding sequence, the expression vector and
methods of treating swine to prevent enzootic pneumonia
using vaccines as well as diagnostic tests based on the
protein or antibodies produced against the protein [65]; a
putative protective antigen against Mycoplasma spp.
prepared by a method that involves applying a Mycoplasma
with an antibody probe, producing a biological sample taken
a short time after an immune animal has been challenged
with Mycoplasma; a method for making an inactivated
vaccine of M. hyopneumoniae by inactivating the bacteria
with thimerosal and mixing it with aluminum hydroxide
adjuvant and DEAE dextran; a process of inactivation of
organisms of the genera Mycoplasma and Acholeplasma,
comprised of treating them with ethyleneimine or a suitable
derivative thereof that is particularly applicable to the
production of a vaccine against M. hyopneumoniae; a bacterin comprised of a sufficient amount of a virulent M.
hyopneumoniae isolate that has been inactivated with binary
ethyleneimine to immunize a pig, along with a suitable
physiologically acceptable carrier; vaccine components and
compositions useful for vaccinating pigs against M.
hyopneumoniae and secondary pathogenic infections; and a
vaccine intended to protect against diseases caused by microorganisms that have a membrane as the most external
envelope, such as M. hyopneumoniae, which contains, as the
active principle, plasmic membranes of the microorganisms
that cause these diseases [66-84, respectively]. Finally, a
patent was applied for that involves adhesins, a feature that
Mycoplasma exhibit [85]. This patent describes the invention
as the identification, purification and characterization of M.
hyopneumoniae adhesins with an affinity chromatography
procedure, which incorporates a novel M. hyopneumoniae
receptor analogue for the attachment and/or removal of the
adhesins from a mycoplasmal preparation. It also describes
an in vitro microtiter plate adherence assay for the characterization of M. hyopneumoniae and adhesins from that
microorganism. Monoclonal antibodies against the adhesins
are also included.
The Brazilian National Genome Project Consortium,
through its management of the National Laboratory for
Scientific Computing (LNCC), has started to sequence the
Anopheles darlingi genome and has undertaken the challenge
to develop the corresponding EST project simultaneously
[86-88]. Anopheles darlingi is a mosquito vector of malaria,
a disease affecting more than 300 million people yearly
according to the WHO and other sources [89-94]. This
disease is caused by the protozoan Plasmodium. In Brazil,
especially in Amazonia, this disease has increased because of
uncoordinated land settlement [95-98]. According to the
LNCC Anopheles darlingi Genome/EST Project Web Site5,
studies performed in the Rio Negro region have shown that
about 95% of the anophelines in contact with man are A.
darlingi species; it also states that the project’s main goal is
to compare the A. darlingi genome with that of A. gambiae
[99-101]. Malaria causes the individual to experience fever
and chills at differing regular time intervals, depending on
the type of Plasmodium the individual is infected with [89,
102, 103]. If not treated appropriately, malaria can cause
severe complications and death. Prophylaxis can be achieved
by the use of bed netting and insecticides to avoid
mosquitoes, along with antimalarial drugs [89-91,104].
There are also preventive drugs that can be taken, for
instance, by travelers who go to malaria-risk areas [90, 91].
Plasmodium falciparum is the agent of the most severe form
of malaria in humans [91,96,105]. It has a complex life
cycle; during asexual stages, the protozoan multiplies within
red blood cells, causing them to literally explode or break
apart at the end of the schizogony manifestation. This phenomenon occurs cyclically and is responsible for the intermittent pathognomonic characteristic of Plasmodium infection [106-108]. While in the invertebrate host, Plasmodium
can also produce via asexual reproduction infective stages
known as sporozoites that accumulate in the mosquito’s
salivary glands and can initiate vertebrate infection [91,92,
109]. Patents related to Anopheles have been concentrated on
drugs able to control the spread of Plasmodium within the
mosquito population and on techniques to map and diminish
mosquito population growth. Molecules have also been
registered, such as proteins, with their coding DNA sequences and organic compounds that could trigger immune
responses in the anophelines in order to make them refractory to the Plasmodium invasion [110, 111]. A patent applied
for by the European Molecular Biology Laboratory (EMBL)
describes a procedure that attempts to prevent the transmission of malaria through the mosquito by modulating the
vector’s innate immune responses to the Plasmodium
parasite by focusing on gene families that encode
pedtidoglycan recognition proteins (PGRPs), leucine-rich
repeat proteins (LRRPs) and C type lectins (CTLs) using
pattern recognition receptors (PRRS) [112]. Similarly,
another patent focuses on the use of thioester-containing
proteins that are part of the immune system of the mosquito
A. gambiae, using them in mosquitoes of the genus Anopheles in order to make them refractory towards the malaria
parasite [112]. Two carboxy-peptidase B enzymes from A.
gambiae and homologs thereof have been patented by the
Pasteur Institute in France. The carboxypeptidases would be
used in the production of vaccines; the patent includes the
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http://www.darlingi.lncc.br/index.htm
122 Recent Patents on DNA & Gene Sequences 2008, Vol. 2, No. 2
antibodies produced in this manner along with the methods
of using them. They are aimed at blocking Plasmodium
development in the inver-tebrate host. Another patent
developed by the Pasteur Institute isolates nucleic acid
molecules that encode multiple drug resistance proteins from
Drosophila melanogaster or A. gambiae (dMRP or gMRP
vectors - as cited in the patent registry) and describes how
host cells can be transformed with vectors containing these
nucleic acids [113]. Patent WO03087322 specifies
equipment and methods for the production of strains of
haematophagous insects with desired properties, such as
hypoallergenicity or hyperinfectivity, along with methods of
producing a parasite strain able to withstand
cryopreservation at temperatures close to freezing,
equipment and methods for the injection of an attenuated
parasite vaccine and for the production of parasites and
haematophagous insects that are free from contamination by
unwanted biological agents, as well as equipment and
procedures for the aseptic rearing of parasites with complex
life cycles to avoid contamination [114]. Patent
WO03020913 describes an invention related to A. gambiae
odor receptor genes as well as methods for identifying odor
receptor genes; it describes nucleotide sequences of A.
gambiae odor receptor genes and amino acid sequences of
their encoded proteins (including peptides or polypeptides),
with their related products and methods. The inventors state
that these sequences may be operatively linked to promoter
sequences and transformed into host cells. They describe
methods of production, i.e. recombination methods, for
antibodies to an odor receptor protein, along with derivatives
and analogs. Methods for identifying molecules to bind or
modulate the activity of these odor receptor genes are also
provided [115]. The government of the United States of
America, represented by the Secretary of the Department of
Health and Human Services is an applicant for a patent
claiming the DNA and amino acid sequences of a novel antithrombin peptide, named anophelin, which was isolated from
the salivary glands of the mosquito Anopheles albimanus.
Capanema Xavier et al.
Anti-thrombotic therapeutic applications of anophelin are
also disclosed [116]. A patent presented by A.E. Eiras [117]
along with the Federal University of Minas Gerais describes
a trap and methods to capture mosquitoes of the species
Aedes aegypti, Aedes albopictus, Anopheles sp. and Culex
sp. in order to monitor, detect and control them. The trap is a
dark container with at least one opening, with a totally or
partially sticky inner surface [118-120].
NETWORK STRUCTURE
Brazil is currently the Latin American leader of the
genomics field Fig. (1); the nearly 40 genome/EST/
metagenome projects around the country follow the
operational design that is typical of our multi-institution
government funded omics projects [121]. Since 1997, with
the foundation of the ONSA Network [16], most of the
sequencing projects that have been carried out in the various
states that support these programs (São Paulo, Minas Gerais,
Rio de Janeiro, Santa Catarina, Rio Grande do Sul, Bahia
and Santa Catarina) have followed this design [122]. As
A.J.G. Simpson [5] states, these “contributions have been
achieved exclusively through the use of large networks, a
strategy that has proved to be particularly appropriate for our
own, relatively small scientific community in a developing
country”.
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A genome network is an association of university
laboratories, federal and state research centers and collaborators willing to share both time and resources on a given
sequencing project. These groups include laboratory leaders
and co-workers who divide the sequencing work, with
overall financing by government research and development
funding agencies. These research support agencies finance
such projects (i) directly, by granting funds to keep the
sequencing process running, buying reagents, dyes and
cloning kits and (ii) indirectly, by maintenance of the lab
facilities, including sequencing machines, staff payrolls and
general lab equipment. Consequently, these funding agencies
Abbreviations: JGI - Joint Genome Institute (DOE/USA); TIGR - The Institute for Genomic Research; JCVI - J. Craig Venter Institute;
WashU - Washington University; Sanger - Wellcome Trust Sanger Institute; BROAD - Broad Institute (MIT/Harvard); GEN
(GENOSCOPE) - Centre National de Séquençage (France); FAPESP - Fundação de Amparo à Pesquisa do Estado de São Paulo; CNPq Conselho Nacional de Desenvolvimento Científico e Tecnológico; FAPEMIG - Fundação de Amparo à Pesquisa do Estado de Minas Gerais;
FAPERJ - Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro. Source: GOLD - Genomes OnLine Database [1].
Find figures at http://www.lgcm.icb.ufmg.br/publications.
Fig. (3). Foundations that fund genome projects in Brazil and in the world showing main institutes and groups responsible for these genome
projects.
Brazilian Genome Projects
Table 2.
Recent Patents on DNA & Gene Sequences 2008, Vol. 2, No. 2
123
Funding Agencies and Managers
Group
Location (City, State)
Genome/EST/Metagenome Projects
Web Sources
Funding Agency
CNPq/MCT
Brasília, Distrito
Federal (DF)
Anopheles darlingi, Chromobacterium violaceum, Mycoplasma
hyopneumoniae, Mycoplasma synoviae, Rhizobium tropici,
Paracoccidioides brasiliensis, Crinipellis perniciosa, Leishmania
chagasi, Gluconacetobacter diazotrophicus, Leptospira interrogans,
Litopenaeus vannamei, Herbaspirillum seropedicae, Soil microbial
communities from contamined sediments
http://www.cnpq.br
FAPESP
São Paulo, São Paulo
(SP)
Bos indicus, Coffea arabica, Mycobacterium bovis, Human Cancer
Genome, Leifsonia xyli xyli, Saccharum sp., Schistosoma mansoni,
Xanthomonas axonopodis, Xanthomonas campestris, Xanthomonas
smithii, Xylella fastidiosa
http://www.fapesp.org
FAPEMIG
Belo Horizonte, Minas
Gerais (MG)
Schistosoma mansoni, Corynebacterium pseudotuberculosis, Zea mays
http://www.fapemig.br
FAPERJ
Rio de Janeiro, Rio de
Janeiro (RJ)
Gluconacetobacter diazotrophicus
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Manager Group
LNCC
Petrópolis, Rio de
Janeiro (RJ)
CPqRR/FIOCRUZ
Belo Horizonte, Minas
Gerais
EMBRAPA
Brasília, Distrito
Federal (DF)
São Paulo, São Paulo
(SP)
UNICAMP
Campinas, São Paulo
(SP)
UFMG
Belo Horizonte, Minas
Gerais (MG)
UnB
Brasília, Distrito
Federal (DF)
UFBA
Salvador, Bahia (BA)
Anopheles darlingi, Bradyrhizobium japonicum, Chromobacterium
violaceum, Mycoplasma hyopneumoniae, Mycoplasma synoviae
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http://www.faperj.br/
Schistosoma mansoni, Corynebacterium pseudotuberculosis, Zea mays
Bradyrhizobium japonicum, Coffea arabica, Zea mays
Xylella fastidiosa, Xanthomonas axonopodis, Xanthomonas
campestris,Xanthomonas smithii
http://www.lncc.br/frame.html
http://www.cpqrr.fiocruz.br
http://www.embrapa.br/
http://www2.usp.br/portugues
/index.usp
Xylella fastidiosa, Xanthomonas axonopodis, Xanthomonas campestris,
Xanthomonas smithii
http://www.unicamp.br/
Corynebacterium pseudotuberculosis, Schistosoma mansoni, Zea mays
http://www.ufmg.br
Paracoccidioides brasiliensis
http://www.unb.br/
Crinipellis perniciosa
http://www.portal.ufba.br/
Abbreviations: CNPq - Conselho Nacional de Desenvolvimento Científico e Tecnológico; MCT - Ministério da Ciência e Tecnologia; FAPESP - Fundação de Amparo à Pesquisa do
Estado de São Paulo; FAPEMIG - Fundação de Amparo à Pesquisa do Estado de Minas Gerais; FAPERJ - Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro; LNCC Laboratório Nacional de Computação Científica; CPqRR - Centro de Pesquisas René Rachou; FIOCRUZ - Fundação Oswaldo Cruz; EMBRAPA - Empresa Brasileira de Pesquisa
Agropecuária; USP - Universidade de São Paulo; UNICAMP - Universidade Estadual de Campinas; UnB - Universidade de Brasília; UFBA - Universidade Federal da Bahia.
are applicants for all the patents that are products of this
genome research see Table (2).
ORGANIZATION FOR NUCLEOTIDE SEQUENCING
AND ANALYSIS (ONSA)
Financed by the Foundation for the Support of Research
in the State of São Paulo 6 (FAPESP), the Organization for
6
A “Fundação de Amparo” could be translated as “Foundation for Research Support”.
For instance, the “Fundação de Amparo à Pesquisa do Estado de São Paulo” could be
translated as “The São Paulo State Foundation for Research Support” or simply “The
São Paulo State Research Foundation”. Thus, the Foundations for Research Support are
organized by state but are sustained by federal funds.
Nucleotide Sequencing and Analysis (ONSA) is a pioneer
sequencing network in Brazil [134]. It was responsible for
carrying out the full sequencing of the phytopathogen Xylella
fastidiosa CVC 9a5c. It basically involves two major universities in Brazil, the University of São Paulo (Universidade de
São Paulo - USP) and the University of Campinas (Universidade de Campinas - UNICAMP). Other major genome
projects, including Saccharum sp. (sugar cane), Coffea
arabica (tetraploid coffee species) and Schistosoma mansoni,
are being conducted by ONSA through partnerships with
other networks and collaborators.
124 Recent Patents on DNA & Gene Sequences 2008, Vol. 2, No. 2
BRAZILIAN NATIONAL
CONSORTIUM
GENOME
PROJECT
The Brazilian National Genome Project Consortium
includes 25 laboratories, a bioinfomatics center and three
coordinating laboratories distributed throughout much of the
country. It is likely the largest genome network currently
active in Brazil and was responsible for the Chromobacterium violaceum Genome Project, which started in 2001
and was published in 2003 [54]; it also has taken on the
Mycoplasma Genome Project, which comprises Mycoplasma
hyopneumoniae strains 7448 and J and Mycoplasma synoviae
[63], and runs the Anopheles darlingi Genome/EST Project.
MINAS GERAIS GENOME NETWORK (RGMG)
Supported by the State of Minas Gerais Research
Foundation (FAPEMIG), the RGMG includes collaborating
laboratories of the Federal University of Ouro Preto (UFOP),
EMBRAPA (Empresa Brasileira de Pesquisa Agropecuária
- Brazilian Agricultural Research Corporation) Milho e
Sorgo (Maize and Sorghum), the Federal University of
Minas Gerais (UFMG), the Federal University of Viçosa
(UFV), the Federal University of Lavras (UFLA) and the
Federal University of Uberlândia (UFU). This network is
managed by the Oswaldo Cruz Foundation (FIOCRUZ),
through one of its research centers in Belo Horizonte, the
capital of Minas Gerais state, the René Rachou Research
Center (CPqRR).
Capanema Xavier et al.
Coryneform bacteria. It describes a system for inducible
expression of a foreign gene in Corynebacteria, which is
triggered by a temperature increase; an operator is sequentially introduced into a promoter system derived from
Corynebacterium ammoniagenes, effectively expressing
GFP in the bacteria. Two patents [135, 136], describe these
methods: “nucleic acid sequences for regulating gene
transcription and expression, said novel promoters and
expression units, methods for modifying or inducing the
transcription rate and/or expression rate of genes, expression
cassettes containing said expression units, genetically
modified microorganisms with a modified or induced
transcription rate and/or expression rate and methods” for
producing biosynthetic products by cultivating the genetically modified microorganisms to produce two different
products, P1-34 expression units and PEF-TS expression
units. Given the biotechnological expression members that
the actinobacteria group has been known for, some patents
relate specifically to the biotechnological products from this
group, such as patent WO04050694 [137, 138], which specifies methods for the biosynthesis of methionine, including
nucleic acid molecules from C. glutamicum that are involved
in this process. Also, following this biotechnological line in
genome projects, Basf Aktiengesellschaft et al. (2003) [139]
filed a patent involving novel nucleic acid molecules for the
construction of genetically improved microorganisms and
methods for the production of fine chemicals, in particular
amino acids. This line of research is also responsible for a
number of patents [140-157]. An interesting feature that
Actinobacteria exhibit as a group is their capacity to produce
regulatory proteins that act epigenetically along the bacteria’s genome, as claimed by patent number WO03040181
[158], entitled “Genes from Corynebacterium glutamicum
Coding for Regulatory Proteins”.
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The Minas Gerais Genome Network has organized two
genome projects to date; these are the Schistosoma mansoni
Genome Project7 and the Corynebacterium pseudotuberculosis Genome Project [123-125]. The latter is the first
genome project in Brazil that has used both Sanger
traditional sequencing technology and a pyrosequencing
technology developed by Roche Applied Sciences, 454 Life
Sciences pyrosequencer [7,126,127]. Corynebacterium
pseudotuberculosis is a gram-positive actinobacteria that
causes a disease that affects small ruminants, which is commonly known as caseous lymphadenitis (CLA) [128]. This
disease is hard to eradicate due to the limited effectiveness of
available drug therapy [123]. Actinobacteria is a group that
includes many organisms that have already been sequenced
[129, 130]. Genera of considerable medical, veterinary and
biotechnological interest, such as Mycobacterium, Nocardia
and Rhodococcus, are also part of this suprageneric taxon
[131, 132]. One of the most important toxins of C. pseudotuberculosis involved in caseous lymphadenitis infection is
phospholipase D (PLD) toxin, which was patented in 1990
by the Commonwealth Serum Laboratories Commission
[133]. A vaccine composed of a toxoided pure PLD toxin
was developed for use against CLA in sheep, based on
nucleotide and amino acid sequences of the toxin; these are
disclosed in the patent, together with the cloning and
expression of the PLD toxin gene in E. coli and coryneform
bacteria. Another patent registered in 2007 [134] describes
an inducible expression vector that can be used against
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The Schistosoma mansoni Genome Project carried out by the Minas Gerais Genome
Network is working along with the EST Project managed by the ONSA Network. The
results have been delivered together and most of the work has been done as a form of
partnership, including microarray analysis carried out at the Federal University of
Minas Gerais - UFMG.
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The RGMG network is also involved with a project to
detect genes expressed in corn under drought conditions, in a
partnership with the EMBRAPA Maize & Sorghum center.
This project seeks to understand the molecular basis of water
stress tolerance in plants by identifying differentially
expressed genes in roots of maize lines that have different
levels of drought tolerance [159]. Corn is a very important
agricultural product; therefore many patents have been
deposited claiming a number of Zea mays gene regions,
DNA sequences and genetic engineering methods [160]. For
instance, patent WO06084868 presents an invention for the
expression of cassettes comprising at least one transcription
regulating nucleotide sequence obtained from the group of
genes of monocotyledonous plants consisting of coffeoylCoA-O-methyltransferase genes, C8,7-sterol isomerase
genes and chloroplast protein genes, which are mainly
transcription regulating sequences obtained from Z. mays
and Oryza sativa; these sequences are mainly involved in
root/kernel-preferential,
leaf/endosperm-preferential,
root/silk/kernel-preferential and constitutive expression.
Another patent includes methods for modulating development and/or developmental pathways that comprise nucleotide sequences (SEQ ID Nr. 1, 3 and 5) and amino acid
sequences (SEQ ID Nr. 2, 4 and 6) for maize REVOLUTA.
These sequences are involved in controlling or modulating
cell division, differentiation and development of the plant’s
meristem. Similarly, polycomb genes MEZ1 and MEZ2 from
Brazilian Genome Projects
Recent Patents on DNA & Gene Sequences 2008, Vol. 2, No. 2
125
maize have been patented by the Wisconsin Alumni
Research Foundation et al. [161] and Monsanto Technology
Llc. [162], describing promoters from male reproductive
tissues isolated from Z. mays that can be used “in plants to
regulate transcription of target genes including genes for
control of fertility, insect or pathogen tolerance, herbicide
tolerance or any gene of interest”. There is also a patent
involving transgenic features from Z. mays [163], providing
nucleic acids encoding polypeptides of DNA methyltransferase that can be used to stabilize transgene expression in
transgenic plants, to alter the yield or biochemical qualities
of plants by silencing targeted genes in plants in vivo.
proposed in the project include sequencing of ESTs from the
mycelium and yeast forms and identification of stagespecific differential cDNAs (ESTs) from one of the two
cellular forms of P. brasiliensis by using (i) electronic
subtraction, (ii) DDRT-PCR and (iii) microarray chips.
Bayer Corporation et al. has issued a patent describing
nucleic acid probes and primers from hybridization assays
for detecting two fungi (P. brasiliensis and Pneumocystis
carinii) that cause disease in humans and animals [84].
These probes can detect rRNA, rDNA or polymerase chain
reaction products from most fungi in clinical, environmental
or food samples.
THE NATIONAL LABORATORY FOR SCIENTIFIC
COMPUTING - LABORATÓRIO NACIONAL DE
COMPUTAÇÃO CIENTÍFICA (LNCC)
GENOME PROGRAM FROM THE PARANÁ STATE GENOPAR
The National Laboratory for Scientific Computing
(LNCC) is a major reference laboratory for both sequencing
projects and bioinformatics. It is located in the city of
Petrópolis, in the state of Rio de Janeiro; among other activities, the LNCC coordinates a number of sequencing
projects. It is responsible for the delivery of Chromobacterium violaceum, Mycoplasma hyopneumoniae strains
7448 and J, and Mycoplasma synoviae complete genome
sequences [63, 164]. The LNCC also runs the Anopheles
darlingi Genome/EST Project, which is currently active,
managing the Brazilian National Genome Project Consortium’s projects and delivering the genomes [165].
This network is responsible for the sequencing of a
nitrogen-fixing bacterium that associates with gramineae,
called Herbaspirillum seropedicae [175, 176]. It regulates
nitrogen fixation by a transcriptional activator named NifA
protein, which has not yet been patented [177]. Nevertheless,
two patents were found in the WIPO database [178]
concerning this organism, both claiming the whole organism
as the patent’s main issue or invention. These include patent
number WO07100162 which discloses a bacterium belonging to the genus Azospirillum or Herbaspirillum that can live
symbiotically in a plant to impart resistance against disease
caused by pathogenic molds, bacteria or viruses;
WO02045513 describes biological inoculants for enhancing
the growth of plants, including bacterial strains of
Herbaspirillum seropedicae 2A, Pantoea agglomerans
P101, Pantoea agglomerans P102, Klebsiella pneumoniae
342, Klebsiella pneumoniae zmvsy, Herbaspirillum seropedicae Z152 and Gluconacetobacter diazotrophicus PA15.
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The LNCC has made a great effort to develop and improve software that has been used to assemble and annotate
genome projects throughout Brazil. The software, baptized
SABIA [166], which stands for “System for Automated
Bacterial Integrated Annotation”, consists of a web-based
platform used for scaffolding and clustering sequences as
well as performing general assemblies and running annotations. Most of the work delivered so far by the networks
has been done using SABIA technology. Although initially
designed for the processing of prokaryote data, the SABIA
software now also distributes a module for eukaryotic
genomes [167-169].
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THE BRAZILIAN CENTRAL REGION CONSORTIUM
The Brazilian Central Region Consortium has started to
map the funcional and differential genomes of the yeast and
mycelium forms of Paracoccidioides brasiliensis [170- 173].
This dimorphic fungus causes paracoccidioido-mycosis
(PCM), which is especially severe for children. This
infection can be acquired by humans who inhale spores or
propagules from mycelium form found in natural habitats; it
reaches the lungs and then becomes infective [174]. The P.
brasiliensis Genome Project is integrated with the Brazilian
National Genome Project Consortium; it includes 13
university institutions and is managed by the Universidade
de Brasília (UnB). Mapping is based on ESTs for detecting
genes in the yeast and mycelium forms, as well as genes that
are differentially expressed during fungus cell transition.
According to the genome network’s website8, the strategies
8
https://dna.biomol.unb.br/Pb-eng/
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GENOMICS IN A NEW ERA
The genome projects are reaching a new level of
technology [179-182]. This is a consequence of new
sequencing technologies, including the 454 Life Sciences
pyrosequencing method, Solexa-Lynx, Helicos Bioscience
Corp. [7,126,127,183-186], and others. The first successful
whole-genome shotgun sequencing project performed without using Sanger-based sequencing was completed in 2005
[126,127,187] using the 454 Life Sciences platform. Sanger
technology is costly, time consuming and labor intensive
[186,188]. Methods and equipment for rapid, efficient and
inexpensive delivery of DNA sequence information are
knocking at the scientific community’s door. A great deal of
work has been done during the past 12 years since the
complete sequencing of Haemophilus influenzae [189-193]
by the Institute for Genomic Research (TIGR) in the United
States. Currently, strategies for genotyping and resequencing are changing, permitting a broader overview into
DNA’s most important features; costs are also being
drastically reduced by novel detection methods, miniaturization of instrumentation, microfluidic separation and by
an increase in the number of assays per run [7,183,185,
186,194-196].
126 Recent Patents on DNA & Gene Sequences 2008, Vol. 2, No. 2
Table 3.
Capanema Xavier et al.
Patents Claimed by Brazilian Groups and/or Brazilian Researchers Related to Genome/EST/Metagenome Projects
Publication
Date
Support or
Financial
Group(s)/Applicant
De Vasconcelos,
A.T.R., Simpson,
A.J.G., Abreu,
H.N.S., et al.
08/07/2004
CNPq/ Yes
[64] Encoding Nucleotides of
Genes from the Chromosome of the
Bacterium Mycoplasma
hyopneumoniae, Expression and
Activity of the Polynucleotides and
their Applications
De Vasconcelos,
A.T.R., Camargo,
A.A., Carraro, D.M.,
et al.
07/07/2005
CNPq/ Yes
WO05023979
PCT/BR2004/000170
[39] Isolated S. mansoni Nucleic
Acid Molecules and Uses thereof
Verjovski-Almeida,
S., Leite, L.C.C.,
Farias, L.P., et al.
17/03/2005
Schistosoma sp.
WO01075148
PCT/BR2001/000035
[40] Method and Kit for the
Detection of Schistosomiasis
through the Polymerase Chain
Reaction
Teles Rabello, A.L.,
Dias Neto, E.,
Pontes, L.A.
11/10/2001
Xylella fastidiosa
WO01085905
PCT/IB2001/001004
[21] Isolated Gum Operon from
Xyllela fastidiosa, isolated Nucleic
Acid Molecules therefrom, and uses
thereof
Arruda, P., Da Silva,
F.R., Kemper, E.L.,
et al.
15/11/2001
[22] Isolated Genome of Xyllela
fastidiosa and uses thereof
Simpson, A.,
Reinach, F., Setubal,
J., et al.
17/10/2002
Related
Organism
Publication Number and
International Application
Number
Chromobacterium
violaceum
Mycoplasma
hyopneumoniae
Schistosoma
mansoni
Ref. No. and Title
Inventors
WO04056960
PCT/BR2003/000207
[60] Gene-Coding Polynucleotides
of the Chromosome of the
Bacterium Chromobacterium
violaceum, Expression and Activity
of these Polynucleotides and their
Applications
WO05060328
PCT/BR2004/000257
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Xylella fastidiosa
WO02082432
PCT/IB2001/001618
Source: WIPO - World Intellectual Property Organization.
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YET, THERE IS STILL A LACK OF FUNCTIONAL
GENOME PROJECTS
Although many sequencing projects are being delivered
and large collections of expressed sequences have been
obtained, there is an important gap in functional genome
projects since many genes have been annotated so far as
hypothetical, possible and putative genes. “Functional genomics, defined as applying global experimental approaches to
assess gene function, by using the information and reagents
provided by structural genomics (i.e. mapping and sequencing)” seems therefore to be the challenge for omics groups
nowadays [197]. Given the current explosion of computer
tools for comparative analysis of genomic sequences,
comparisons of genomic sequences from different organisms
being a central focus of contemporary genome analysis,
functional genomics has become imperative for relevant
progress [198, 199]. Consequently, structural approaches
need to be targeted; genome projects produce an enormous
amount of sequence data that needs to be annotated in terms
of molecular structure and biological function. The objective
therefore would be to determine protein structures efficiently
and to “exploit the solved structures for the assignment of
biological function to hypothetical proteins” [200-204].
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FAPESP/ Yes
FIOCRUZ/ Yes
FAPESP/ Yes
FAPESP/ Yes
CURRENT & FUTURE DEVELOPMENTS
It is amazing how far genomics has gone. However, some
estimates of the number of species on planet Earth reach up
to a number of 50 million species. That means that only 420% of species have been described (rounding to an estimate
of about 10 million species) [201]. Based on these projections, we have completely sequenced only 0.001360.00684% of the organisms inhabiting this planet [205].
By the time the Human Genome Project was completed,
numerous respected scientists and philosophers had agreed
that an antique and somewhat old fashioned branch of
biology called taxonomy would inexorably suffer a rebirth
process, which would be stimulated by the flood of molecular data that genome projects would soon deliver. That
actually did not happen; at least, it has not till now.
However, ask any colleague if they know an official taxonomist, PhD in taxonomy or really dedicated specialist, that
is, someone whose job it is to analyze, deploy and curate
databases who has no specific interest in a given organism
orgroup that he might be working on. Taxonomists have not
been reborn as prophesized; but they actually do exist and
the field itself has suffered a rebirth process to some extent.
These putative professionals have mingled with molecular
Brazilian Genome Projects
Recent Patents on DNA & Gene Sequences 2008, Vol. 2, No. 2
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127
* European Patent Office comprising France, Germany and the European Consortium as well as all other European countries. International
genomes could not be plotted for obvious reasons. Data for China’s 2006, 1990 and 1998 production was not retrievable at the source.
Source: WIPO - World Intellectual Property Organization.
Find figures at http://www.lgcm.icb.ufmg.br/publications.
Fig. (4). Total number of patents registered for the top 10 sequencing countries from 1985 to 2006.
biologists and computer scientists working directly with
sequencing and bioinformatics. Every single molecular
biologist and computer scientist working in the bioinformatics field has become a taxonomist by definition.
PATENTS AND THE WTO
Another phantom that the international community faces,
and shall increasingly keep on facing, relates to the Brazilian
patent-breaking policy [206, 207] based on WTO dispatches,
which somehow are discrepant with the national health
assistance program’s capacity to maintain drugs or drug
combinations accessible. The Brazilian government
compulsory licences the the drugs that it supplies gratis to
most of the affected population during epidemic/pandemic
threats, e. g. the anti-HIV cocktail sold by Merck Sharp &
Dohme and currently utilized by the Brazilian National
AIDS Program [207, 208]. Therefore, it is reasonable to
expect the same attitude when it comes to genomic
discoveries, gene and/or techniques patents [209]. Brazilian
legislation allows compulsory licensing, which is often
misunderstood as patent infringement, in cases that involve
public interest, health issues, nutrition, environmental
defense and national technological or sociological development [210]. The authorization can be found in the “Brazilian
Patent Law” (Lei de Patentes do Brasil - 9279/96. Artigo
71), by decrees 3201/99 and 4830/03; moreover, it is
128 Recent Patents on DNA & Gene Sequences 2008, Vol. 2, No. 2
Capanema Xavier et al.
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Sources: Eukaryotes based on C-value from websources [List of Websites] and genome project’s managers publicly available information.
Find figures at http://www.lgcm.icb.ufmg.br/publications.
Fig. (5). Genome sizes for Eukaryotes and Prokaryotes with available ESTs or deposited proteins from organisms researched in Brazil.
sustained by the TRIPS Agreement and by the Doha
Declaration [206]. Compulsory licensing allows the country
to obtain drugs or other products from another supplier
without being obliged to pay the fees charged by the original
developers after quality standards are met by the new
producers. For instance, Brazil buys some AIDS medicines
from India at a much lower cost than charged by an English
company (Merck Sharp & Dohme Efavirenz, which patented
a non-nucleoside reverse transcriptase inhibitor used in the
treatment of HIV infections).
ACKNOWLEDGEMENTS
It is our pleasure to thank all research centers, bioinformatics groups, financing foundations and laboratories
directly involved in the sequencing projects carried out in
Brazil. Special acknowledgements go to all of the sequencing staff at the Universidade Federal de Minas Gerais UFMG and the Centro de Pesquisas René Rachou - CPqRR,
which constitute the core with which our group (Laboratório
de Genética Celular e Molecular - LGCM, from the Instituto
de Ciências Biológicas of the Universidade Federal de
Minas Gerais) has done their work so far.
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