epidemiology 217 omics, bioinformatics, & resources at ucsf john witte
TRANSCRIPT
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Epidemiology 217
Omics, Bioinformatics, & Resources at UCSF
John Witte
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Follow-up from HW’s
• Assignment #3
• For linkage looking for sharing departing from 50%
• Genotypes 677TT and 1298CC never observed together.– Lethal– T and C rare (T=6%)– Recent SNP, insufficient meiosis to separate.
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Questions on Assignment #4?Coding CC CT TT
Co-dominant 0 1 0
0 0 1
Dominant 0 1 1
Recessive 0 0 1
Log Additive 0 1 2
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Harry Potter’s Pedigree
Harry Potter
Lily Potter James PotterAunt PetuniaUncle Vernon
Dudley Dursley
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What happened to Filch ?
Argus Filch
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Genomics
• Not looking at a single candidate gene or SNP.
• Genome: complete DNA sequence
• Raises issues of multiple comparisons.• In HW, when looking at MTHFR we used
P < 0.05 for a single comparison.• What happens when looking for linkage or
association on a genome-wide scale?
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Moving Beyond Germline DNA
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omics no of occurrencesgenomics 7522
proteomics 4420
pharmacogenomics 533
toxicogenomics 141
metabolomics 74
bionomics 73
metabonomics 63
transcriptomics 63
glycomics 23
chemogenomics 22
ionomics 19
nutrigenomics 19
Phenomics 17
http://biocomp.dfci.harvard.edu/tgi/omics_count.html
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Moving Beyond Genome
Transcriptome: All messenger RNA molecules (‘transcripts’)
Proteome:All proteins in cell or organism
Metabolome:all metabolites in a biological organism (end products of its gene expression).
Sys
tem
s B
iolo
gy
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Transcriptome
• mRNA: takes information from DNA during transcription to sites of protein synthesis.
• Undergoes translation to yield gene product.
• Can vary with external environmental conditions.
• Reflects the genes that are being actively expressed at any given time.
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Example: Expression Microarrays
• Compare tumor vs normal mRNA expression levels.
• Tells the relative amounts of different mRNAs.
• But not directly proportional
to the expression level of
the proteins they code for.
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• Characterize proteins.• Each protein has a
particular shape and function that determine its role in the body.
• Compare variations in their expression levels under different conditions.
• Study their interactions.• Identify their functional
role.
Proteomics
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Proteome Complexity
• Recall that genome is relatively static.• In contrast, many cellular proteins are
continually moving and undergoing changes such as:
1. binding to a cell membrane,2. partnering with another protein,3. gaining or losing a chemical group such as a
sugar, fat, or phosphate, or 4. breaking into two or more pieces.
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Size of Proteome?
• > 1 Million Proteins >>> 21,000 genes in humans.
• Large number due to complexity (a given gene can make many different proteins)
• Features such as folds and motifs, allow them to be categorized into groups and families.
• This should help make it easier to undertake proteomic research.
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How to Analyze Proteomes
• Broad range of technologies• Central paradigm:
– 2-D gel electrophoresis (2D-GE), and mass spectrometry (MS).
– 2D-GE is used to separate the proteins by isoelectric point and then by size.
– MS determines their identity and characteristics.
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2-D gel electrophoresis
• Large mixtures of proteins separated by electrical charge and size.
• The proteins first migrate through a gel-like substance until they are separated by their charge.
• They are then transferred to a second semi-solid gel and are separated by size.
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http://www.lecb.ncifcrf.gov/phosphoDB/2d-description.gif
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Mass spectrometry
• MS measures two properties:1. the mass-to-charge ratio (m/z) of a mixture of
ions (particles with an electric charge) in the gas phase under vacuum; and
2. the number of ions present at each m/z value.
• The end product is a mass spectra (chart) with a series of spiked peaks, each representing the ion or charged protein fragment present in a given sample.
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Mass spectrometry
• The height of the peak is related to the abundance of the protein fragment.
• The size of the peaks and the distance between them are a fingerprint of the sample and provide a clue to its identity.
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Metabolome
• All small molecule (<1500 Da) metabolites found in a cell, organ or organism.
• E.g., metabolic intermediates, hormones and other signalling molecules, and secondary metabolites.
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Copyright restrictions may apply.
Wishart, D. S. et al. Nucl. Acids Res. 2007 35:D521-D526; doi:10.1093/nar/gkl923
">Human Metabolome Database
http://www.hmdb.ca
Brings together: chemical, physical, clinical and biological data
Thousands of metabolites.
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HMDB
• http://www.hmdb.ca
• Brings together: – chemical, – physical, – clinical and – biological data
• on thousands of endogenous human metabolites.
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Lots of Data!
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“The study of genetic and other biological information using computer and statistical techniques.”
A Genome Glossary, Science, Feb 16, 2001
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Bioinformatics in Genetic Epi
Some key aspects:• Data management• Candidate regions / genes (selection and
SNP mining)• Genetic Analyses (e.g., genotyping)• Statistical Analyses
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Data Management
5/20
Demogr. Database
Laboratory Database Clinical
Database
Health and Habits
DatabaseNutritional Database
Genomic Database
CaP Genes Databases
Hub
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Bioinformatics in Proteomics
• Creation and maintenance of databases of protein info.
• Development of methods to predict the structure and/or function of newly discovered proteins and structural RNA sequences.
• Clustering protein sequences into families of related sequences and the development of protein models.
• Aligning similar proteins and generating phylogenetic trees to examine evolutionary relationships
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Resources at UCSF• Study Design & Biostatistics (Dept & Cancer Center)www.biostat.ucsf.edu/services.html
• Genomics Core Facilitygenomics.ucsf.edu/
• Gladstone Genomics Core Laboratorywww.gladstone.ucsf.edu/gladstone/site/genomicscore/
• Genomics and Proteomics Corehttp://derisilab.ucsf.edu/core
• Mass Spectrometryhttp://www.ucsf.edu/brc
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Genetic Testing: Sciona
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Test for SNPs in 7 Genes• GSTM1, CYP1A1, GSTT1 and GSTP1
– Phase I and II detoxification genes.
• MnSOD– Codes for enzyme that may defend against free radical
damage.
• MTHFR– Encodes enzyme that helps the body to use folate so that
cells can grow and repair, or maintain their DNA.
• ALDH2– Codes for aldehyde dehydrogenase 2 enzyme, which
converts acetaldehyde (metabolized from ETOH) into acetic acid and water.
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“Preventive Health Profile”
• Antioxidants - Your Personal Advice– Diet questionnaire shows low consumption of antioxidants.– Gene test shows that you have a beneficial SNP that helps fight
oxidative stress.– But you still need to increase your daily intake of antioxidants to
support your body's antioxidant abilities.
• Antioxidants - Putting Advice Into Action– Increase your consumption of foods rich in the most important
antioxidants: vitamins C, A and E, beta carotene and selenium.– Eat plenty of fruits and vegetables, major sources of
antioxidants. Make sure to include at least one portion of citrus fruit.
– Common foods particularly rich in various antioxidants are soy products, tea and garlic, as well as red wine.
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Concerns with Testing ?
1. Misleading statements about value of results.
2. No genetic counseling.
3. Use of confidential genetic (and dietary) information
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Final Project
• Based on the current state of the literature (from your reviews):– Describe a molecular / genetic project that
you can justify undertaking.
• One page description, due March 4th by email to Nerissa.