GENOMICS AND HUMAN GENETICS IN MEDICINE

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GENOMICS AND HUMAN GENETICS IN MEDICINE

• Vivian G. Cheung, MD
• University of Pennsylvania
• The Childrens Hospital of Philadelphia
• Department of Pediatrics

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MEDICINE IN THE 21st CENTURY

• MARRIAGE OF GENETICS AND GENOMICS

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GENETICS

• The study of heredity (variation)
• Progress
• Mendels Law
• Discovery of chromosome, DNA
• Discovery of disease genes (CF,
  Huntington)

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GENOMICS

• The study of genomes - a global approach to
  cells, organs and organisms at the DNA, RNA and
  protein levels.
• Progress
• High-throughput technologies
• Sequences of 24 complete genomes and soon
  the human genome

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GENETICS AND GENOMICSTODAY

• Genetic variants disease and drug metabolism
• Human genome sequence gene content
• Gene expression profiles catalogue of genes
  expressed in each tissue type and in different
  cellular functions.

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GENETICS AND GENOMICSTOMORROW

• Diagnosis
• Treatment
• Prevention

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MODEL ATAXIA TELANGIECTASIA

• Work in progress
• Illustrates how combining genetics and genomics
  can improve diagnostic tools, therapies, and
  preventive measures.

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ATAXIA TELANGIECTASIA

• Autosomal recessive disorder mutations in ATM,
  chromosome 11q22-23.
• Progressive neuromotor dysfunction, immune
  deficiency, telangiectasia, and predisposition to
  cancer.
• Cellular level hypersensitivity to ionizing
  radiation and chromosomal instability.

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ATM Gene

• A large gene 150 kb, 66 exons, 13 kb
  transcript.
• More than 200 mutations have been defined.
• ATM protein C-terminus is highly similar to PI-3
  kinase - plays a role in cell cycle progression
  and DNA damage response.

IR
ATM
Stops cell cycle for DNA repair.
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AT

• Incidence 1 in 40,000
• No treatment / cure
• Carriers 1 in 100
• No diagnosis for carrier status
• Increased risk for cancers, breast cancers

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CURRENT STATUS

• Diagnosis very inadequate
• Treatment none
• Prevention none (of progression and
  development of malignancies)
• We know the disease causing gene!!

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TOOLS DNA MICROARRAYS

• Survey thousands ( 30,000) of genes for their
  relative abundance.
• Technology and reagents are readily available.

RNA AT pts RNA normal
..
..
..
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METHODS
AT/-
NL
RNA RNA RNA
scan and analyze data
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DX by Molecular Fingerprint

• Find genes that allow us to identify AT carriers
  use microarrays to screen for genes
  differentially expressed between carriers and
  normal controls.
• Results AT carrier compared to normal,
• 10 genes increased 2 fold
• 3 genes decreased 2 fold

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Differentially expressed genes between AT
carriers and normal controls
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TREATMENT

• First, identify all the cellular pathways
  involved with the disease.
• Then, select the ones that are potential targets
  for intervention.

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Identification of the IR-response pathway
IR
Identify the genes that are differentially expres
sed explain why AT cells are so susceptible to
IR.
Expression profile at 2, 6, 12, 24 hours post
irradiation.
AT
IR
NL
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Principal Components Analysis of the Gene
Expression Data
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Normal
AT
12 Hr
2 Hr
2 Hr
6 Hr
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Differentially expressed genes that are most
correlated with the first component.
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PREVENTION

• Disease, progression, and complications
• Map susceptibility genes
• Positional cloning
• Direct IBD Mapping
• others

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CONCLUSION

• Shape medical research by combining genetics and
  genomics to improve the care of patients through
  development of tools that will improve
• diagnosis
• treatment
• prevention
• of diseases.

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Cheung lab Kuang-Yu Jen Jason Watts Josh
Burdick Statistical analysis Richard Spielman