Gene Hunting

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Gene Hunting

• Natália F. Martins

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Resumo

• Motivação
• Estratégia
• Automatização (?)
• Exemplos
• Referências

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Motivação

• A Busca de genes pode ser motivada pela
  necessidade de desenvolvimento de drogas
  inibidoras,
• Por aplicações biotecnológicas, biofábricas
• Ciência básica.

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Traditional Organization of Gene Hunting
Physicians - working with families, gather
medical information
Families - cooperating thru an interest in their
own families
Biomedical scientists -- analyzing DNA, disease
biochemistry
Coordination -- informal, based on the medical
scientific norms of the professions, with complex
patterns of cooperation.
Generating public knowledge on the disease --
publication key
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Methodology

• A qualitative phase
• Selection of words, therms and related literature
• A quantitative phase
• Expression levels, microarray data, experimental
  data.
• Combinatorial chemistry, drug design

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Whole genomes
Key words interactions
References
Arrays data
Top10 list
Experimental phase
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Automatização é Possível
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Exemplos

• Cell signaling
• Zebra fish
• Virulence

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Cell signaling pathways in Paracoccidioides
brasiliensis - inferred from comparisons with
other fungi

• The identification of putative genes involved in
  the cellular signaling pathways was performed by
  the search by key word service provided by the
  bioinformatics group of the PbGenome project
  (Felipe et al., 2003). The classification of
  candidates according to the signaling category
  families was performed by a BLASTx (Zhang, 2003)
  comparison of sequences against a database with
  all the signaling protein sequences from Genbank
  (Benson et al., 2004). The analyzed clusters were
  assembled by CAP3 software in the
  sequence-processing pipeline from the PbGenome
  project. The multiple sequence alignment of the
  candidates was performed using CLUSTAL W software
  (Aiyar, 2000).

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Transcriptome Analysis of Zebrafish Embryogenesis
Using Microarrays

• PLoS Genet. 2005 August 1(2) e29. Published
  online 2005 August 26. doi 10.1371/journal.pgen.0
  010029.
• Methods
• Embryo collection
• RNA isolation and reference RNA
• Zebrafish oligonucleotide probe design and
  microarray construction
• Data acquisition and statistical analysis

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Vibrio cholerae recovered directly from patient
specimens

• Methodology
• Collection of clinical samples
• RNA and genomic DNA extraction.
• Microarrays and hybridization
• Statistical analysis

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Differential expression of genes in the TCP
island during early compared with late human
infection, represented as log10 fold change.
Expression of the transposase sequence (tnp) of
the TCP island is shown at the left, and that of
the integrase gene
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Gene Hunting and Drug Design
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Genetic basis of disease

• Phenotype
• Disease state
• Complex, often contested definitions diagnoses,
  arising at different ages etc.

• Genotype
• Genetic mutations (polymorphisms)
• Located over 50,000-80,000 genes, subject to high
  levels of natural variation or noise

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Added Statistical complexity

• Two types of disease
• Monogenic -- mutation in one gene leads to
  disease follows Mendelian inheritance
• Polygenic -- mutations in several genes lead to
  disease follows complex inheritance patterns
• Susceptibility -- genes may confer susceptibility
  rather than necessarily the disease itself
  (penetrance)
• Very high levels of background noise making the
  search for mutations difficult
• Population genetics projects very complex and
  difficult access to desirable population a key

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Key Types of Knowledge for Population Genetics
Medical Records Provides information on
phenotypes, but this can be complex, difficult to
define, not available to the patient in full
detail.
Genetic Records Also known as genetic maps.
Developed from tissue samples, blood etc. using a
range of different techniques including search
for genetic markers.
Genealogical Records Given the complexity of
finding statistical correlation, family records
provide improved roadmaps by reducing the
background noise, using inheritance information
common markers.
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Summary and Implications

• A market exists for genetics exists, but is
  constrained
• Very little buying and selling of property rights
  to populations
• The borrowing strategy has, along with fears of
  group revolts, necessitated the imposition of
  medical research norms that limit the degree to
  which information can be exploited
• A moral economy surrounds this market
• Competition between public and commercial
  projects may be increasing

Fonte www.genomeprairie.ca/gels/news/crsgovrdocs
/Casper.ppt 2005
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Future
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• What the bleep do we know?