CS177 Lecture 9 SNPs and Human Genetic Variation Tom Madej

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.

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.

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_ 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.

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.

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.

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.

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

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

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.

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

LD and recombination hotspots

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!