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CS177 Lecture 9 SNPs and Human Genetic Variation


Motivation to study human genetic variation. Intellectual interests: evolution of our species. ... Major source of genetic variation ' ... – PowerPoint PPT presentation

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Title: CS177 Lecture 9 SNPs and Human Genetic Variation

CS177 Lecture 9 SNPs and Human Genetic Variation
  • Tom Madej 11.07.05

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

  • We can use SNPs to study variants of proteins
    that occur in humans.
  • As an example, lets 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_000537.
  • View the GenPept report for the protein, and
    find the positions of the changes in the
  • 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
  • Click OK, this will highlight all residues on
    the molecules that have an atom within 5
    Angstroms of any atom on the highlighted (DNA)

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
  • Pharmaceutical genetics will determine an
    individuals 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
  • 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
  • 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
  • But this is too expensive!

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