Similarity Search in Databanks

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Similarity Search in Databanks
Pair wise alignment
Find similar sequences to a working draft. As
databanks grow, homologies get harder, and
quality is reduced. Alignment Tools BLAST
FASTA (time saving heuristics- approximations).
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The Globin Family Multiple Sequence Alignment
(MSA)
Multiple alignment find protein families and
functional domains.
All globin molecules have a similar 3D structure,
despite large sequence differences. Globins amino
acid sequence identities range from 99 (very
similar) to 16 (very different).
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The Structural Prediction Problem
Given a protein sequence, compute its structure.

• Possible in principle.
• Astronomical, highly under-constrained search
  space.
• Biophysics complex and incomplete.
• Next to impossible in practice.

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Structure - Function Relationships
structure
sequence
function
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3D Structure of Globins
Yellow Lupine Leghemoglobin
Human a??Globin
Whale Myoglobin
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Phylogeny
Evolution - a process in which small changes
occur within species over time. These changes
could be monitored today using molecular
techniques.

• The Tree of Life
• A classical, basic
• science problem,
• since Darwins 1859
• Origin of Species.

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Searching Protein Sequence Databases - How far
can we see back ?
Tree of Life
Mammalian radiation
Invertebrates/ vertebrates
Plant/ animals
Prokaryotes/ eukaryotes
First self replicating systems
Formation of the solar system
Origin of the universe ?
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Sickle Cell Anemia
A genetic disease causing changes in the shape
and function of red blood cells (112 carriers in
African Americans). Anemia poor oxygen
delivery. Cause abnormal hemoglobin - a
mutation in the b-globin gene.
Normal
Sickle Cell
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Why had the Mutation Survived the Natural
Selection ?
Mutation (anemia) provides resistance to
malaria. Malaria Disease caused by
mosquito-borne parasite Plasmodium, which needs
high oxygen levels in blood.
Mechanisms to Fight Malaria Parasites

• Kill mosquitoes (e.g. DDT).
• Interrupt parasite lifecycle (anti-malarial
  drugs).
• Change the oxygen micro-environment of the
  parasite
• in the body (sickle cell anemia carriers).