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Incorporating Physiological Genomics into the Medical Student Curriculum

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Teaching both introductory genetics AND how it fits with basic physiology ... Short Tandem Repeat Polymorphism (STRP) Simple Sequence Length Polymorphism (SSLP) ... – PowerPoint PPT presentation

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Title: Incorporating Physiological Genomics into the Medical Student Curriculum


1
Incorporating Physiological Genomics into the
Medical Student Curriculum
  • IUPS Refresher Course
  • Integrating Genomics into Physiology Courses A
    New Paradigm or Just More Information?
  • Anne Kwitek, Ph.D.
  • Human and Molecular Genetics Center
  • Medical College of Wisconsin

2
Integration of Physiological Genomics
  • Separate Course
  • Incorporate within Medical Physiology Course
  • Independent genetics series
  • Information integrated throughout the Course

3
Challenges
  • Teaching both introductory genetics AND how it
    fits with basic physiology
  • Seemingly disparate information how to make
    physiological genomics fit a basic physiology
    course

4
What to Cover
  • Introduction to genomics and genetics
  • Basic tools and technology
  • Linkage
  • Monogenic disease
  • Complex disease
  • Expression
  • Examples using topics covered in class

5
Goals of Genetics Lectures
  • Introduction
  • Become familiar with the concepts and
    technologies behind genomics and genetics
  • Applications
  • Applications of genetics and genomics toward the
    understanding of human monogenic disease
  • Applications of genetics and genomics toward the
    understanding of human complex disease

6
Introduction to Genomic Tools and Technology
7
Genomics vs. Genetics
  • Genomics Structural aspects of the genome
  • Genetics The use of transmission of genetic
    material

8
Genetic Markers to Locate Disease
  • Simple Sequence Repeat (SSR) microsatellite
  • CA repeat
  • Short Tandem Repeat Polymorphism (STRP)
  • Simple Sequence Length Polymorphism (SSLP)
  • Single Nucleotide Polymorphism (SNP)

9
Simple Sequence Repeat (SSR)
Mom tctttgggactg cacacacacaca
tcagaatccggag tctttgggactg cacacacacacaca
tcagaatccggag
Dad tctttgggactg cacacacacacacaca
tcagaatccggag tctttgggactg cacacacacacacacaca
tcagaatccggag
Child
Child
Child
Child
1 2 3 4
10
Single Nucleotide Polymorphisms (SNPs)
  • We are 99.9 identical at the genome level
  • (1/1000 bp differences)
  • Will use sequence variants (SNPs) as a form of
    diagnosis
  • Different outcomes of variation
  • Coding
  • Synonymous changes
  • Non-synonymous changes
  • Non-coding
  • Changes in gene expression/protein levels

11
Expression Profiling
  • Compare expression in tissues between disease and
    normal states
  • Compare expression in tissues before/after drug
    treatment
  • Evaluate many thousands of genes at the same time
  • Genes turned up or down in disease state may lead
    to understanding of mechanism
  • Lead to a diagnostic fingerprint

12
See Figure 3.9 from A Primer of Genome Science,
Second Edition Greg Gibson and Spencer V.
Muse Sunderland, MA Sinauer Associates, 2004
13
Linkage and Association
14
Disease Traits
  • Qualitative
  • Trait that is either present or absent
  • e.g. Cystic fibrosis
  • Quantitative
  • Trait with a continuous distribution of
    measurement
  • e.g. height, weight
  • Clinical definition of disease
  • E.g. Hypertension

15
Monogenic (Mendelian) Disease
  • Simple inheritance patterns within families
  • Autosomal Dominant
  • Autosomal Recessive
  • X-linked
  • Caused by a mutation in a single gene
  • Relatively rare
  • Powerful for identifying genes by linkage
    analysis and positional cloning

16
Complex (Common) Disease
  • No clear pattern of Mendelian inheritance
  • A mix of genetic and environmental factors
  • Incomplete penetrance
  • Phenocopies
  • Heterogeneity
  • High frequency of disease-causing allele

17
Gene Mapping Strategies
  • Linkage Analysis within Pedigrees
  • Allele Sharing within Relative (Sib) Pairs
  • Association Study

18
Linkage Analysis Within Pedigrees
  • Tests for the likelihood of recombination between
    assumed disease and marker alleles.
  • Great for single gene disorders
  • Limitation for common/multifactorial diseases
  • frequency of disease
  • locus heterogeneity
  • penetrance of the disease

19
Example of Linked Marker
12
34
23
24
12
34
1
2
2
3
2
2
2
2
23
2
2
23
12
2
2
13
20
Association Study
  • Correlation of different SNPs in this region with
    disease.
  • Family-based and case-control based

21
Association Studies
  • Advantages
  • Ease of collecting subjects to study, i.e. cases
    and controls
  • More powerful to detect genes
  • Analysis methodology similar to standard
    case-control methods
  • Disadvantages
  • Most assumption-laden
  • Spurious Associations far exceed true
    associations
  • Ascertainment Bias/Allele frequencies

22
Applications of Physiological Genomics
23
Why Study Monogenic Disease
  • Advantages
  • Clear genetic inheritance
  • Single gene mutation
  • Hopefully lead to better understanding of
    mechanism of more common forms of disease
  • Disadvantages
  • Rare
  • Not causing most common disease

24
Linkage Studies of Hypertrophic Cardiomyopathy
(HCM)
  • One of the most common inherited cardiac
    disorders
  • Prevalence in young adults of 1 in 500
  • Autosomal dominant
  • Variable expressivity
  • Etiological heterogeneity
  • Environmental and genetic modifiers

25
Linkage Studies on Monogenic HCM
1/2
3/4
1/4
1/3
1/4
1/4
2/3
1/1
1/2
1/3
1/3
26
Linkage Results to Gene Mutation
  • Linkage of a marker to a disease does not mean a
    gene is found!
  • Fine-mapping
  • Positional Candidate Genes
  • Look for obvious biological candidates within the
    region of linkage
  • Screen for mutations in this gene in disease
    families SEQUENCING
  • Successful for HCM!

27
Mutations in Monogenic Disease
  • Mutations are often causal
  • Mutations are often severe, i.e. destroy
    protein function
  • Non-sense mutations
  • Missense mutations
  • Insertions/deletions

28
Understanding Pathways through Monogenic Disease
  • Other mutations related to common disease?
  • Not complete loss of function mutations
  • Interactions with other genes/environment
  • May not be gene involved in common forms, but
    part of the pathway

29
Hypertension and the Kidney
  • Linkage in monogenic forms of severe hypertension
    and hypotension
  • Gitelman Syndrome
  • GRA
  • Aldosterone Synthase Deficiency
  • Liddle Syndrome
  • PHA1
  • Bartter syndrome
  • AME
  • Hydroxylase deficiency
  • Hypertension exacerbated by pregnancy

30
Hypertension and the Kidney
  • 17 genes cloned
  • 8 for hypertension
  • 9 for hypotension
  • All genes involving sodium handling in the
    nephron
  • All Monogenic forms of hypertension/hypotension

31
See Figure 1 from Lifton et al. Cell 104545-556,
2001 http//www.cell.com/content/issue?volume104
issue4 Free access
32
Genes in Complex Disease
  • Multiple genes, each with additive effect
  • Genes interacting with one another
  • Genes interacting with environment

33
Hypertension
  • Complex
  • Many different subtypes
  • Animal models offer advantages for finding genes
    for complex disease
  • Inbred
  • Controlled breeding
  • Controlled environment

34
Comparative Genomics
  • Tying Phenotype and Genotype Across Species

35
(No Transcript)
36
Comparative Genomics and Gene Identification
37
Human and Rat ARPKDWard, et al, Nature Genetics,
30259-269 http//www.nature.com/ng/journal/v30/n
3/full/ng833.html (free access)
PKD
Linkage Human 6
Linkage Rat 9
38
PKDH1 Gene in Human and Rat
PKD
Gene Mutation
Gene Mutation
39
Subdividing Cancer through Gene Expression
Profiling
  • Classify cancers based on their gene expression
    profiles
  • Compare different cancer types to identify
    fingerprint gene expression
  • Provide diagnostic tool

40
See Figure on gene expression profiles of
mesenchymal, leukemia, epithelial, and melanoma
cells along with 3 probability graphs comparing
overall survival of patients with GC B-like vs.
activated B-like from A Primer of Genome
Science, Second Edition by Greg Gibson and
Spencer V. Muse. Sunderland, MA Sinauer
Associates, 2004
41
Genomics to Proteomics
42
Finding Genes for Disease
  • We know the blueprint
  • Technology makes possible large-scale testing
    that will likely become the norm in your practice
  • Diagnostics
  • Therapy

43
The Basics About Genetic Testing
  • To find out if a person is a carrier for a
    certain disease
  • To learn if a person has an inherited
    predisposition to a certain disease, like breast
    or ovarian cancer (also known as susceptibility
    testing)
  • To help expecting parents know whether their
    unborn child will have a genetic disease or
    disorder (prenatal testing)
  • To confirm diagnosis of certain diseases or
    disorders (for example, Alzheimer's disease)

44
Goals of Personalized Medicine
  • Match the right drug/treatment with the right
    patient
  • Predisposition testing
  • Preventative medicine
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