CS177 Lecture 9 SNPs and Human Genetic Variation

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CS177 Lecture 9 SNPs and Human Genetic Variation

• Tom Madej 11.07.05

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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.

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Exercise!

• 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.

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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.

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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.

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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.

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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
  individuals response to a drug.

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Sources of genetic variation (during meiosis)

• Chromosomal reassortment
• Mutation errors in DNA copying
• Recombination

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

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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

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LD and recombination hotspots
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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!

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