Structural Genomics and Human Health

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Structural Genomics and Human Health

• Lei Xie, PhD
• lxie_at_sdsc.edu

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Enter the Genome IT Era
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Background
Proteins are the worker molecules that make
possible every activity in your body
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Background Generic Codes
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Background From DNA to Protein

• DNA carries the genetic information of a cell and
  consists of thousands of genes
• genes are transcribed into RNA (transcription)
• proteins are built based upon the code in the RNA
  (translation).

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Background -
3D shape enables proteins to accomplish their
function in your body
Proteins are made of amino acids like beads on a
necklace.
To become active, proteins must fold into their
final shape
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Genes and Disease
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The Human Genome Project has a Broad Impact
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Personalized Medicine
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Background - SNPs

• Definition must occur in gt 1 of population
• Accounts for gt 90 of all genetic variation
• Est. 1.4M in initial map of the genome
• 60,000 in coding regions
• A synonymous SNP does not change the protein
  non-synonymous does
• Synonymous still important in regulation eg
  transcription factor binding etc.
• See http//www.ornl.gov/TechResources/Human_Genome
  /faq/snps.html

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Genetic Variation and its Relationship to Disease
has Been Known for Some Time..
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Example Sickle cell anemia

• Sickle cell anemia (SCA) is an autosomal
  recessive disease caused by a point mutation
  (SNP) in the hemoglobin beta gene (HBB) found in
  region 15.5 on the short arm (p) of chromosome 11
• The hemoglobin protein (HBB) is 146 aa long and
  has a molecular weight of 15,867 Da

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Example Sickle cell anemia

• Hemoglobin (HBB), found in red blood cells, is
  responsible for carrying oxygen around the body
• It is made up of two different types of protein
  chains alpha and beta
• Normal adult HBB is a tetrameric protein
  consisting of two alpha chains and two beta
  chains (see PDB structure)
• The hemoglobin beta gene (HBB) codes for the beta
  chain found in hemoglobin (often called beta
  globin)
• A point mutation (SNP) in beta globin is
  responsible for the sickling of red blood cells
  seen in SCA

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Example Sickle cell anemia

• In SCA the hydrophobic aa valine takes the place
  of hydrophilic glutamic acid at the 6th aa
  position of the HBB beta polypeptide chain
• This is caused by a SNP in which a T is
  substituted for an A in the middle position of
  codon 6
• The SNP converts the GAG codon (encoding Glu) to
  a GTG codon (encoding Val)

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Example Sickle cell anemia

• Normal deoxy hemoglobin
• 4 grey clusters are non-covalently bonded heme
  groups which bind oxygen
• Gold spheres are phosphate groups
• Green and blue chains are alpha, gold and
  turquoise chains are beta.
• Red box highlights the region in which the sixth
  glutamic acid residue is located (i.e. where the
  SNPs lies)

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Example Sickle cell anemia

• The SNP substitution creates a hydrophobic region
  on the outside of the proteins structure
• This region then sticks to the hydrophobic
  region on adjacent hemoglobin molecules beta
  chain
• This polymerization of mutant hemoglobin
  molecules results in the formation of rigid fibers

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Example Sickle cell anemia

• Polymerization of mutant hemoglobin only occurs
  after red blood cells have released their oxygen
  molecules
• As these red blood cells re-bind oxygen, the long
  fibers of mutant hemoglobin depolymerize and
  break apart into single molecules
• Cycling between polymerization and
  depolymerization causes red blood cell membranes
  to become rigid

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Example Sickle cell anemia

• The rigidity of the red blood cells, and their
  distorted shape when not carrying oxygen, can
  block small blood vessels
• This blocking can produce micro vascular
  occlusions which can cause necrosis (death) of
  the tissue

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Example Sickle cell anemia

• SCA is an autosomal recessive genetic disorder.
  For it to be expressed, a person must inherit two
  copies of the mutant (Hb S) variant or one copy
  of the mutant (Hb S) and one copy of another
  genetic variant
• Carriers who have the normal HBB gene (Hb A) and
  one copy of the mutant (Hb S) are described as
  having sickle cell trait, but do not express the
  disease symptoms.

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SNP profiles

• There is now a concentrated effort to identify
  all the different SNPs in the human genome -
  hapmap
• This will be used to generate a single map of the
  entire human genome and where each all the SNPs
  lie
• The genomes of individuals will therefore contain
  a unique map of SNPs, thus providing individual
  SNP profiles

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SNP profiles

• These SNP profiles will be important for
  analyzing responses to disease treatments
• SNP profiles are also thought to be important in
  explaining patients differential responses to
  drug treatment
• Since SNPs are also good gene markers, SNP
  profiles will also be important in identifying
  the collection of genes that contribute to the
  development of complex diseases states

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Conclusions

• Many SNPs have no effect on cell function, but
  others could pre-dispose people to disease states
  or influence drug treatment responses
• SNPs can either effect a proteins
  structure/function or they can effect regulatory
  aspects of gene expression
• Mapping SNPs to the genome will produce useful
  individual SNP profiles and identify multiple
  genes associated with diseases
• This makes SNPs extremely important for
  biomedical research and for developing
  pharmaceutical products or medical diagnostics

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Useful Links

• http//www.ornl.gov/TechResources/Human_Genome/med
  icine/pharma.html
• PDB ( http//www.rcsb.org )

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The Big Picturehttp//www3.ncbi.nlm.nih.gov/Entre
z/
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Navigation By Data Sourcehttp//www.ncbi.nlm.nih.
gov/About/glance/story_discovery.html
LocusLink Chromosome location
Genbank All public DNA sequences
RefSeq Non-redundant Sequences for major
organisms
Click on the computers to go to the resources
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Navigation By Data Sourcehttp//www.ncbi.nlm.nih.
gov/About/glance/story_discovery.html
Omim Relate gene to phenotype with emphasis on
disease
PubMed The literature reference to all databases
PDB 3D Structure
Click on the computers to go to the resources