The medical relevance of genome variability Gabor T. Marth, D.Sc. Department of Biology, Boston College 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 Badano and Katsanis, NRG 2002 some notable genetic diseases: cystic fibrosis cycle-cell anemia

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 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 non- random 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: /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 marker that is co-inherited with causative variant single-SNP marker or multi- SNP haplotype marker single-stage or multi-stage

Association study strategies 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 1. hypothesis driven (i.e. based on gene function) causative variant 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

Case-control association testing searching for markers with “significant” marker allele frequency differences between cases and controls; these marker signify regions of possible causative alleles AF(cases) AF(controls) clinical cases clinical controls genotyping cases and controls at various polymorphisms

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 Klein et al, Science 2005 SNPs in Complement Factor H (CFH) gene are associated with Age-related Macular Degeneration (AMD)

4. Structural and epigenetic variants in disease

Structural variants in disease Feuk et al. Nature Reviews Genetics 7, 85–97 (February 2006) | doi: /nrg1767

Structural variations and phenotype Feuk et al. Nature Reviews Genetics 7, 85–97 (February 2006) | doi: /nrg1767

Epigenetics and cancer Baylin at al. NRC 2006.