Transcript MedicalAspectsVariations

The medical relevance of
genome variability
Gabor T. Marth, D.Sc.
Department of Biology, Boston College
[email protected]
Medical Genomics Course – Debrecen, Hungary, May 2006
Lecture overview
1. Phenotypic effects caused by known
genetic variants
2. Genetic mapping to find genetic variants that
cause diseases – linkage analysis and association
studies
3. Genome-wide association mapping resources –
the HapMap
4. Structural and epigenetic variations in disease
1. Phenotypic effects caused by
known genetic variants
Many SNPs do have phenotypic effects
some notable genetic diseases:
cystic fibrosis
cycle-cell anemia
Badano and Katsanis, NRG 2002
Genetic variants in Pharmacogenetics
Evans and Rellig, Science 1999
Genetic variants in Pharmacogenetics
Evans and Rellig, Science 1999
Using genotype information in the
drug development pipeline
Roses. NRG 2004
Are all genetic variants functional?
~ 10 million known SNPs
SNPs, on the scale of the genome,
can be described well with the
“neutral theory” of sequence
variations the vast majority of
SNPs likely to have no functional
effects
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How do we find the few functional variants in the background of
millions of non-functional SNPs?
2. Genetic mapping to find genetic
variants that cause diseases – linkage
analysis and association studies
Genetic mapping
Allelic association (linkage)
• allelic association is the nonrandom assortment between
alleles i.e. it measures how well
knowledge of the allele state at
one site permits prediction at
another
marker site
functional site
• significant allelic association between a marker and a
functional site permits localization (mapping) even without
having the functional site in our collection
• allelic association, and the use of genetic markers is the
basis for mapping functional alleles
Mendelian diseases have simple inheritance
genotype inheritance
genotype + phenotype inheritance
Linkage analysis compares the transmission of
marker genotype and phenotype in families
Complex disease – complex inheritance
Badano and Katsanis, NRG 2002
Allele frequency and relative risk
Brinkman et al. Nature Reviews Genetics advance online publication;
published online 14 March 2006 | doi:10.1038/nrg1828
Association study strategies
• region(s) interrogated: single gene, list of candidate genes (“candidate gene study”),
or entire genome (“genome scan”)
• direct or indirect:
causative variant
• single-SNP marker or multiSNP haplotype marker
• single-stage or multi-stage
marker that is co-inherited
with causative variant
causative variant
Association study strategies
for economy, one cannot genotype every SNP in thousands of clinical samples:
marker selection is the process where a subset of all available SNPs is chosen
1. hypothesis driven (i.e. based on gene function)
2. LD-driven – based entirely on the reduction of redundancy presented by the
linkage disequilibrium (LD) between SNPs; tags represent other SNPs they are
correlated with
causative variant
Case-control association testing
• genotyping cases and controls at various polymorphisms
clinical cases
• searching for markers with
“significant” marker allele frequency
differences between cases and controls;
these marker signify regions of possible
causative alleles
AF(controls)
clinical controls
AF(cases)
Marker selection depends on genome LD
Daly et al. NG 2001
3. Genome-wide association mapping
resources – the HapMap
The HapMap resource
• goal: to map out human allele and association structure
of at the kilobase scale
• deliverables: a set of physical and informational reagents
LD structure in four human populations
International HapMap Consortium, Nature 2005
Genome-wide scans for human diseases
SNPs in Complement Factor H (CFH)
gene are associated with Age-related
Macular Degeneration (AMD)
Klein et al, Science 2005
4. Structural and epigenetic variants
in disease
Structural variants in disease
Feuk et al. Nature Reviews Genetics 7, 85–97 (February 2006) | doi:10.1038/nrg1767
Structural variations and phenotype
Feuk et al. Nature Reviews Genetics 7, 85–97 (February 2006) | doi:10.1038/nrg1767
Epigenetics and cancer
Baylin at al. NRC 2006.