Epidemiology 217 Molecular and Genetic Epidemiology I - PowerPoint PPT Presentation

Loading...

PPT – Epidemiology 217 Molecular and Genetic Epidemiology I PowerPoint presentation | free to download - id: 1b0adf-Zjc5N



Loading


The Adobe Flash plugin is needed to view this content

Get the plugin now

View by Category
About This Presentation
Title:

Epidemiology 217 Molecular and Genetic Epidemiology I

Description:

Now more complex genetic disorders and environment ... Each somatic cell is diploid (two copies of each autosome) Thus, 3 genotypes at locus 4 ... – PowerPoint PPT presentation

Number of Views:296
Avg rating:3.0/5.0
Slides: 41
Provided by: ValuedGate2134
Learn more at: http://rds.epi-ucsf.org
Category:

less

Write a Comment
User Comments (0)
Transcript and Presenter's Notes

Title: Epidemiology 217 Molecular and Genetic Epidemiology I


1
Epidemiology 217 Molecular and Genetic
Epidemiology I
  • Course Director
  • John Witte
  • Professor of Epidemiology Biostatistics

2
Genetic Epidemiology
  • Overview
  • Role of inherited factors in disease
  • Historical focus single gene disorders.
  • Now more complex genetic disorders and
    environment
  • Many designs same as epidemiology (e.g.,
    case-control)
  • Some specialized analysis methods.
  • Population genetics increasingly important
  • Goals
  • Understand biological process
  • Prevention strategies, lifestyle intervention,
  • Improved therapeutic strategies, personalized
    medicine

3
Course Goals
  • Develop a framework for interpreting, assessing,
    and incorporating molecular and genetic measures
    in your own research.
  • Learn about
  • Determining the genetic contribution to disease
  • Common molecular and genetic measures
  • Searching for disease-causing genes, and their
    interaction with environmental factors
  • Pharmacogenomics
  • Genetic testing, ethics.

4
Course Details
  • Class meets for 10 Tuesdays, 115-245 pm
  • Course Director John S. Witte, PhD Phone
    415-502-6882 email wittej_at_humgen.ucsf.edu
  • Office hours by appointment
  • Teaching Assistant Zian Tseng, MD
  • zhtseng_at_medicine.ucsf.edu
  • website
  • http//www.epibiostat.ucsf.edu/courses/schedule/mo
    l_methodsi.html

5
Syllabus
6
Homework Assignments
  • Count for 60 of grade (30 for final project,
    10 for class participation).
  • Brief problem sets.
  • Due at 5 pm on Mondays to
  • geneticepi08_at_yahoo.com
  • So we can discuss the following day.
  • Late assignments are not accepted.

7
Reading Assignments
  • Provide important background information
  • Must be completed before the start of the
    corresponding lecture.
  • Students may be called upon during class to
    answer questions about the readings.

8
Web Resources
  • Videos from UAB Short course on statistical
    genetics http//www.soph.uab.edu/ssg_content.asp?
    id1174
  • Doraks notes on genetics http//dorakmt.tripod.c
    om/genetics/
  • Strachan Reads Human Molecular Genetics
  • http//www.ncbi.nlm.nih.gov/books/bv.fcgi?ridhmg

9
DNA
10
Human Chromosomes
11
Human Chromosome 21
Telomeres Centromere p stands for petit q stands
for grand 21q22.1 is pronounced twenty-one q two
two point one
12
Single Nucleotide Polymorphism (SNPs)
  • Change a single DNA letter
  • Most frequent genetic variant
  • 1/1300 base pairs
  • 10 million common SNPs (gt 1- 5 MAF) - 1/300 bp

13
Genotypes
Each somatic cell is diploid (two copies of each
autosome) Thus, 3 genotypes at locus 4
14
Why are SNPs Important?
Person 1
Person 2
Gene A
Gene A
SNP may cause Gene A to make altered protein
SNP variations in DNA
National Cancer Institute
15
Potentially Functional Gene Regions
cis regulator
promoter
Amino acid coding RNA processing Transcription
regulation
16
Types of SNPs
  • Noncoding
  • Coding
  • Synonymous no change in amino acid
  • Nonsynonymous/nonsense change to stop codon
  • Nonsynonymous/missense change amino acid
  • Normal allele
  • Gene sequence …..GCG GGA GCC
    GAT………………
  • Protein Sequence ……Ala Gly Ala
    Asp………………
  • C677T allele
  • Gene Sequence …..GCG GGA GTC
    GAT……………….
  • Protein Sequence ……Ala Gly Val Asp
    ..……………

17
Human Genome Statistics
  • 3,253,037,807 basepairs
  • SNPs 11,772,162
  • 21,667 known genes
  • 1,040 pseudogenes (defunct genes)
  • 269,405 exons
  • Mutation rate 10-8 per bp per generation
  • In each person
  • 65 new mutations expected
  • 1 variant per 1,331 basepairs
  • 2,444,055 variants
  • Most variants are old

http//www.ensembl.org/Homo_sapiens
18
Variation in Genomes
  • 4.1 million variants detected
  • 12.3 million base pairs of DNA
  • 3.2 million SNPs, other variants (CNVs, etc.)
  • Old estimate of human-human variation 0.1
  • New estimate gt 0.5 total genetic variation (or
    we are 99.5 similar)

Levy S, et al. PLoS Biology Vol. 5, No. 10, e254
19
Process of Genetic Epidemiology
Defining the Phenotype
Migrant Studies
Familial Aggregation
Segregation
Association Studies
Linkage Analysis
Cloning
Fine Mapping
Characterization
20
First Define the Phenotype!
Gleason DF. In Urologic Pathology The Prostate.
1977 171-198.
21
Migrant Studies
Weeks, Population. 1999
22
Familial Aggregation
  • Does the phenotype tend to run in families?

23
Twin Studies Prostate Cancer
  • Twin registry (Sweden, Denmark, and Finland)
  • 7,231 MZ and 13,769 DZ Twins (male)

Heritability 0.42 (0.29-0.50) Non-shared
Environment 0.58 (0.50-0.67) Lichtenstein et al
NEJM 2000 1334378-85.
24
Segregation Harry Potters Pedigree
Muggle
Wizard / Witch
Lily Evans
James Potter
Vernon Dursley
Petunia Dursley
Harry Potter
Dudley Dursley
25
Process of Genetic Epidemiology
Defining the Phenotype
Migrant Studies
Familial Aggregation
Segregation
Association Studies
Linkage Analysis
Cloning
Fine Mapping
Characterization
26
Linkage Harry Potters Pedigree
Measure co-segregation in pedigree Based on
detection of recombination events (meiosis)
Muggle
Wizard / Witch
Lily Evans
James Potter
Vernon Dursley
Petunia Dursley
or
Harry Potter
Dudley Dursley
or
27
Affected sib-pair Linkage
D
M1
M2
D
D
M1
M1
M2
28
Association Studies
ROCHE Genetic Education (www)
29
Linkage Disequilibrium
Hirschhorn Daly, Nat Rev Genet 2005
30
Genome-wide Association Studies (GWAs)
Altshuler Clark, Science 2005 3071052-3.
31
Multi-stage Study Designs
Hirschhorn Daly, Nat Rev Genet 2005
32
Admixture Mapping
  • Potentially powerful approach to searching for
    disease-causing genes
  • Requires
  • Two populations with naturally occurring
    phenotypic and genetic differences.
  • Recent gene flow between the populations (e.g.,
    within 10 generations).
  • Markers in the vicinity of the trait locus will
    also show excess ancestry from the population
    with the higher allele frequency

33
Admixture Mapping
Nature Genetics 37, 118 - 119 (2005)
34
Cloning a Gene
  • Showing that it is clearly causal for disease.
  • Generally requires experiments beyond those
    undertaken by a genetic epidemiologist.

35
Characterization
  • Once genes are identified, molecular methods are
    used to determine the structure of the gene,
    identification of regulatory elements, etc.
  • Use epidemiologic studies to distinguish public
    health implications
  • Determine frequencies of causal alleles and
  • Characterize their effectsand interacting
    environmental factorson disease rates.

36
Testing SNPs in Candidate Genes
www.sciona.com
37
(No Transcript)
38
23andMe
  • …first personal genome service.
  • Genotype 580K SNPs (Illumina).
  • Provide risk estimates for phenotypes.
  • Ancestry information, similarity.
  • Genome Explorer compare genotypes to results
    from other research.
  • Referrals to genetic counselors (?)

39
Taste Test
40
Assignment 1
  • Due by 5 pm on Monday, January 14, 2007, email
    to geneticepi08_at_yahoo.com
  • Reading.
  • Select disease you are currently researching or
    are interested in.
  • Define the clinical characteristics of this
    disease.
  • Determine from pubmed whether theres evidence
    supporting a genetic basis for this disease.
  • Note the number of articles on medline. Briefly
    glancing at some of the abstracts available from
    PubMed, give a qualitative assessment of whether
    or not there is positive or negative support.
  • of Articles on Medline Positive
    Support Negative Support
  • Genetic Epidemiology
  • Migrant Study
  • Familial Aggregation
  • Twin Studies
  • Segregation Analysis
  • Based on the above table, do you feel there is a
    genetic basis for your disease?
  • Is this for all (homogeneous) groupings of the
    disease, or particular subtypes?
About PowerShow.com