CS177 Lecture 9 SNPs and Human Genetic Variation

1. CS177 Lecture 9SNPs and Human Genetic Variation Tom Madej 11.07.05

2. Lecture overview • Very brief and fast overview of on-line databases. • Formulating queries in Entrez. • Molecular biology of diseases, including an extensive example involving a lot of linking between a number of Entrez databases.

3. Exercise! • We can use SNPs to study variants of proteins that occur in humans. • As an example, let’s use P53, find a P53 structure with a DNA molecule (query Structure). • Under “Links” for structure 1TUP, notice there is a SNP link, follow it. • Record the rs# for the first SNP (and others), then click on “GeneView”. • Click on the rs# in the table if you actually want to see the SNP.

4. P53 exercise (cont.) • Scroll down to the table, you will notice that the first SNP is missing (for some reason?) but the other two are there. • For each SNP note the a.a. position of the change, then go back up and follow the protein link for NP_000537. • View the “GenPept” report for the protein, and find the positions of the changes in the sequence. • Record a subsequence of the residues around the changes; the reason for this is the numbering with the structure may be different.

5. P53 exercise (cont.) • Now there are various ways to proceed. There is not a curated CD available for P53 so we can just use Cn3D. • From the MMDB Structure Summary page bring up Cn3D to view the molecule. • Highlight the DNA molecule, then from “Show/Hide” pick “Select by distance”, and then “Residues only”. • Click “OK”, this will highlight all residues on the molecules that have an atom within 5 Angstroms of any atom on the highlighted (DNA) molecule.

6. P53 exercise (cont.) • You have to “map” your SNP positions to the residues in the structure (some or all may or may not be there). • Check to see if any of the SNPs is one of the highlighted residues, and thus (quite possibly) involved in DNA binding. • If a curated CD is available, you can view the structure from CDD and check if any of the SNP positions are annotated.

7. Motivation to study human genetic variation • Intellectual interests: evolution of our species. • Medical importance: there is a genetic component to many diseases, esp. the complex ones such as diabetes, cancer, cardiovascular, and neurodegenerative. • Pharmaceutical: genetics will determine an individual’s response to a drug.

8. Sources of genetic variation (during meiosis) • Chromosomal reassortment • Mutation; errors in DNA copying • Recombination

9. Reassortment of genetic material during meiosis Molecular Biology of the Cell, Alberts et al. Garland Publishing 2002 (Fig. 20-8)

10. Single Nucleotide Polymorphisms (SNPs) • Major source of genetic variation • “Single nucleotide” means a single DNA nucleotide (base) is affected. • “Polymorphism” means the change appears with some minimal frequency in the population. The opposite would be “monomorphic”, meaning a single isolated occurrence.

11. HapMap project • Haplotype – set of alleles on a chromosome that tend to inherited as a block • Guide design and analysis of medical genetic studies • Provide a collection of SNPs spanning the genome, and serving as genetic markers • Study correlations (linkage disequilibrium, LD) between the SNPs

12. LD and recombination hotspots

13. Genetic association study • Given a sample of people, some with and some without a certain phenotype (e.g. a certain disease). • Call the two sets D and not-D. • Investigate the genetic factors shared by the people in D, but absent from the people in not-D. • The most straightforward way: genotype all the individuals. • But this is too expensive!