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Epidemiology 217
Omics, Bioinformatics, & Resources at UCSF
John Witte
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.
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
Harry Potter’s Pedigree
Harry Potter
Lily Potter James PotterAunt PetuniaUncle Vernon
Dudley Dursley
What happened to Filch ?
Argus Filch
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?
Moving Beyond Germline DNA
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
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
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.
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.
• 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
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.
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.
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.
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.
http://www.lecb.ncifcrf.gov/phosphoDB/2d-description.gif
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.
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.
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.
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.
HMDB
• http://www.hmdb.ca
• Brings together: – chemical, – physical, – clinical and – biological data
• on thousands of endogenous human metabolites.
Lots of Data!
“The study of genetic and other biological information using computer and statistical techniques.”
A Genome Glossary, Science, Feb 16, 2001
Bioinformatics in Genetic Epi
Some key aspects:• Data management• Candidate regions / genes (selection and
SNP mining)• Genetic Analyses (e.g., genotyping)• Statistical Analyses
Data Management
5/20
Demogr. Database
Laboratory Database Clinical
Database
Health and Habits
DatabaseNutritional Database
Genomic Database
CaP Genes Databases
Hub
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
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
Genetic Testing: Sciona
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.
“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.
Concerns with Testing ?
1. Misleading statements about value of results.
2. No genetic counseling.
3. Use of confidential genetic (and dietary) information
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.
