Lecture Objectives!1) Understand the extent of population variation in the human genome 2) Distinguish simple Mendelian inheritance and polygenic traits 3) Identify the role of SNP genotyping in gene mapping 4) Explain the HapMap Project and its role in establishing genetic linkage to disease 5) Understand some of the technical and statistical approaches in studying genetic association w/disease risk and outcomes as it impacts clinical practice 6) Distinguish clinical utility of diagnostic tests from cause and effect! - Source of genetic variation!- Genetic inheritance (SNPs), Envi exposures, replication errors!- Genetic variation in population: SNPS= single nucleotide polymorphisms, CNVs= copy # variations --> associated w/disease risk, outcome, and response!- genetic determinants of a trait: single gene, envi, polygenic (many causes/things)!- Many international genomic projects that are trying to map critical regions of genes that are related to traits!- Ex. International HapNap Project= a consortium dedicated to catalog variations (SNPs) in the human genome to accelerate mapping of human disease genes!- Picked people from diff regions of the world and looked at their genetic variations!- Annotate boundaries of genetic variations because closely linked genes tend to segregate together in pedigrees!- trying to look at SNPs that were linked= genetic variations that when they're close togeher on the genome, tend to travel together!- SNPs associated w/disease!- used for gene mapping using DNA chips!- inherited in blocks called haplotypes = recombination events occur at pretty regular locations and blocks can be followed!- haplotypes can be followed thru generations and may be more characteristic of one ethnic group vs. another!- variants may or may not be disease causing, but may have association!- may be found in different frequencies in diff. ethnic populations!- Genetic Mapping!- Use genetic markers to map segregation of traits (disease or clinical outcomes) in family lineages!- Assume: genes inherited Mendelianally, enough genetic varition to find assoc. w/disease, have tech, genetic markers segregate w/disease, can account for genetic recomb. and develop linkage!- LOD Score= a statistical test of linkage!- logarithm of the odds of linkage compared to non-linkage, the liklihood that 2 genetic markers will segregate together!- measures the likelihood of 2 genetic markers to cosegregate in a pedigree and is affected by recombination!- the closer they are on the chrom, the more tightly they are linked!- Score of 3= high linkage association, Score of -2= loci aren't linked!- Nonrandom association of alleles at linked loci when searching for a causal gene!- find a relationship of genotype to disease trait!- if 2 unrelated individs with a common disease share an ancestral disease allele, they may also share loci closely linked (markers will segregate together)!- linkage disequilibrium= combinations of closely linked loci can occur more frequently thanexpected from independent segregation!- SNP linkage disequilibrium is the basis for the HapMap project!- Recombination that unlinks genetic markers is dep on:!- distance between markers, time, recombination hot spots !- recomb unlinks markers/loci!- To map a disease using SNPs: 1) Find statistical evidence of association of a given haplotype block w/a disease!2) Study candidate SNPs or gene seqs w/in that block to find a gene that contributes to disease!- Haplotype block structure - Wherever there is a cosegregation of markers, it's red.!- Red triangle= 1 haplotype block, DNA seqs that segregate together!- Note: there are far more haplotype blocks in Africans than Europeans because the African popn is oder --> more opportunities for recombination --> haplotypes get separated into smaller and smaller blocks !- Genetic association to find disease gene impacted/complicated by:!- Penetrancce, polygenic traits, modifier genes, envi, time of onset, geographical diffs in SNP freqs, epigenetics!- Can deal w/limitations via Association studies= degress of co-occurence of an allele w/a trait providing Relative Risk = Odds Ratio - Odds Ratio: relative risk of a group w/test allele having the disease compared to the risk in the control group of the test population !- Not everyone who has the allele gets the disease and not everyone who gets the disease has the allele !- Relative Risk vs. Absolute Risk - 50% increase in relative risk (relative to pop'n) for a certain disease that's normally 1/100,000 people!- Absolute risk is 1.5/100,000 = 1/66,666 = 0.0015% absolute risk!- Popn Genetics- Not nec. random or = assortments of genetic variations - Envi influences - Founder effects - Geographic (ethnic origins) - SNP clustering by race --> common clustering of genotype in ethnic groups, but variation does occur w/in the clustering!- For many diseases, single SNPS may not show association--complex (multiple SNP) interactions!- Clinical validity!- of a SNP assoc. is measured by how well it predicts a clinical condition!- Sensitivity= genotype catches all cases - Specifity= avoid misdiagnosing unaffected!- decisions on clinical utility!- How do physicians assess clinical utility of SNPs?!1) Are reports of association validated?!2) Biologic correlation that can explain the association?!3) Penetrant at levels worth reporting?!4) Recommended by professional societies?!5) Recommended by FDA?!6) Testing covered by
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