Download Genomics Bioinformatics Medicine. Institute of Medicine, October 15, 2002, Washington DC

Genomics, Bioinformatics & Medicine
(http://brutlag.stanford.edu/)
Institute of Medicine
October 15, 2001
Doug Brutlag
Professor of Biochemistry & Medicine (by courtesy)
Stanford University School of Medicine
© Doug Brutlag, 2001
Leveraging Genomic Information
• Novel Diagnostics
• Microchips & Microarrays - DNA
• Gene Expression - mRNA -cDNA
• Proteomics - protein modification
• Novel Therapeutics
• Drug Target Discovery
• Rational Drug Design
• Molecular Docking
• Gene Therapy
• Understanding Disease
• Inherited Diseases - OMIM
• Infectious Diseases
• Pathogenic Bacteria
© Doug Brutlag, 2001• Viruses
Central Paradigm of Molecular Biology
DNA
© Doug Brutlag, 2001
Central Paradigm of Molecular Biology
DNA
© Doug Brutlag, 2001
Central Paradigm of Molecular Biology
DNA
© Doug Brutlag, 2001
RNA
Central Paradigm of Molecular Biology
DNA
© Doug Brutlag, 2001
RNA
Protein
Central Paradigm of Molecular Biology
DNA
© Doug Brutlag, 2001
RNA
Protein
Symptoms
(Phenotype)
Central Paradigm of Molecular Biology
DNA
© Doug Brutlag, 2001
RNA
Protein
Symptoms
(Phenotype)
Opinions
Information
(http://www.ncbi.nlm.nih.gov)
© Doug Brutlag, 2001
NCBI Genes & Diseases
(http://www.ncbi.nlm.nih.gov/disease/)
© Doug Brutlag, 2001
NCBI: Online Mendelian Inheritance in Man
(http://www.ncbi.nlm.nih.gov/omim/)
© Doug Brutlag, 2001
Diagnosis Using DNA Arrays
© Doug Brutlag, 2001
Diagnosis of Cystic Fibrosis
© Doug Brutlag, 2001
Affymetrix M. tuberculosis Chip
(courtesy Tom Gingeras, Affymetrix)
M. tuberculosis
(H37Rv) Array
M.
tuberculosis
Interrogates 4706
genome loci
(H37Rv)
- 3983 Genes
4,411,529
bp
S.T. Cole, etal
(1998) Nature 393 :
537
© Doug Brutlag, 2001
Single Nucleotide Polymorphisms (SNPs)
GCTGTATGACTAGAAGATCGAT
GCTGTATGACGAGAAGATCGAT
• Individual’s genomes differ from each other by 0.1%
• There are 3 million polymorphic sites in the human
genome
• SNPs an be used for identification
• SNPs can be used for diagnosis of disease
© Doug Brutlag, 2001
Single Nucleotide Polymorphisms (SNPs)
• Most SNPs are genetically neutral
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Used in DNA fingerprints
Forensic medicine
Paternity
Immigration in the United Kingdom
• Some SNPs reflect distinguishing characteristics
• Often the basis for discrimination or other stigma
• Some SNPs cause disease (very rare)
• SNPs can serve as genetic markers for other traits
• SNPs can be correlated with a predisposition to
disease
• Clinical trials correlate SNPs with drug efficacy
• Clinical trials correlate SNPs adverse drug reactions
© Doug Brutlag, 2001
Microarrayer in Pat Brown’s Lab
(http://cmgm.stanford.edu/pbrown/)
© Doug Brutlag, 2001
DNA Microarrays Measure
Gene Expression (mRNA)
© Doug Brutlag, 2001
Breast Cancers Classified by
451 Gene Expression Assays
(Sørlie et al., PNAS 98, 10869-10874 (2001))
© Doug Brutlag, 2001
Breast Cancers Classified by
451 Gene Expression Assays
(Sørlie et al., PNAS 98, 10869-10874 (2001))
© Doug Brutlag, 2001
Diagnostics Using Protein Gel Electrophoresis
(http://www.expasy.ch/ch2d/)
(Prof. Denis Hochstrasser)
© Doug Brutlag, 2001
Renal Cell Carcinoma
(Sarto C. et al, Electrophoresis 1997, 18, 599-604)
Normal
RCC
Normal
RCC
© Doug Brutlag, 2001
Protease Mutations in Multidrug-Resistant
HIV-1 Isolates from Heavily Treated Patients
(Bob Shafer & Tom Merigan)
54
48
82
10
63
71
Red: Mutations in Substrate Cleft
Purple: “Accessory changes”
© Doug Brutlag, 2001
Diagnosis of Drug Resistance in
HIV Protease and Reverse Transcriptase
© Doug Brutlag, 2001
Genomic & Bioinformatics Resources
• DNA
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Genome Sequences
On Line Mendelian Inheritance in Man
Inherited Disease
Single-Nucleotide Polymorphisms (SNPs)
• RNA
• mRNA Expression Level
• Gene Expression Microarrays
• Disease Correlations
• Proteins
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Proteomics
Structural Genomics
Protein Ligand Docking
© Doug Brutlag, 2001
Current Technical Challenges Using
Genomic Information in Medicine
• Genome is not complete; all genes are not yet identified
• There are 160,000 gaps in public and private genomes
• We do not have mRNA libraries from all tissues and
developmental stages
• Proteins, their locations and their modifications must be
cataloged
• Disease genes are not identified and characterized
• Most OMIM traits are not located precisely or cloned
• Genetic differences between normal and disease state are not
known
• Gene expression differences between normal/disease state is not
yet characterized.
• Structures of proteins difficult to obtain
• Determining structures by NMR & X-ray diffraction is labor
intensive
• Structure prediction is not yet reliable
© Doug Brutlag, 2001
Current Policy Challenges Using
Genomic Information in Medicine
• Deficit of genomics and bioinformatics expertise
• Few M.S. and Ph.D. programs in genomics & bioinformatics
• Very few schools offer computational biology undergraduate
majors
• Genomics & bioinformatics are not taught in medical school
curricula
• Genomics & bioinformatics should be taught in basic science years
• Methods and interpretations of genomic data should be integrated
into clinical curricula
• Dearth of physicians trained in medical genetics
• Physicians to carry out academic research
• Physicians knowledgeable in genetic counseling
• Privacy and information policies are not in place
• Access to information should be regulated
• Use of information must be specified
© Doug Brutlag, 2001
Acknowledgements
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Institute of Medicine for the opportunity to speak
Pat Brown, Professor of Biochemistry, Stanford
Ron Davis Professor of Biochemistry, Stanford
Tom Gingeras, VP Biological Science Affymetrix
Denis Hochstrasser Professor of Clinical Medicine,
Cantonal Hospital of Geneva
Tom Quertermous, Professor of Cardiovascular Medicine
David Relman, Professor of Medicine (Infectious
Disease), Stanford
Peter Small & Gary Schoolnik, Professors of Medicine
(Infectious Disease), Stanford
Bob Shafer & Tom Merigan, Department of Medicine
(Infectious Disease), Stanford
© Doug Brutlag, 2001