Single nucleotide polymorphisms

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Single nucleotide polymorphisms

• Usman Roshan

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SNPs

• DNA sequence variations that occur when a single
  nucleotide is altered.
• Must be present in at least 1 of the population
  to be a SNP.
• Occur every 100 to 300 bases along the 3
  billion-base human genome.
• Many have no effect on cell function but some
  could affect disease risk and drug response.

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Toy example
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SNPs on the chromosome
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Perl exercise

• Determining SNPs from a pairwise genome
  alignment
• Can we solve this problem with a Perl script?

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Bi-allelic SNPs

• Most SNPs have one of two nucleotides at a given
  position
• For example
• A/G denotes the varying nucleotide as either A or
  G. We call each of these an allele
• Most SNPs have two alleles (bi-allelic)

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Perl exercise

• Determining SNP type from a multiple genome
  alignment.

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SNP genotype

• We inherit two copies of each chromosome (one
  from each parent)
• For a given SNP the genotype defines the type of
  alleles we carry
• Example for the SNP A/G ones genotype may be
• AA if both copies of the chromosome have A
• GG if both copies of the chromosome have G
• AG or GA if one copy has A and the other has G
• The first two cases are called homozygous and
  latter two are heterozygous

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SNP genotyping
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Perl exercise

• SNP encoding
• Convert SNP genotype from a character sequence to
  numeric one

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Real SNPs

• SNP consortium snp.cshl.org
• SNPedia www.snpedia.com

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Application of SNPs association with disease

• Experimental design to detect cancer associated
  SNPs
• Pick random humans with and without cancer (say
  breast cancer)
• Perform SNP genotyping
• Look for associated SNPs
• Also called genome-wide association study

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Case-control example

• Study of 100 people
• Case 50 subjects with cancer
• Control 50 subjects without cancer
• Count number of dominant and recessive alleles
  and form a contingency table

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Perl exercise

• Contingency table
• Compute contingency table given case and control
  SNP genotype data

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Odds ratio

• Odds of recessive in cancer a/b e
• Odds of recessive in no-cancer c/d f
• Odds ratio of recessive in cancer vs no-cancer
  e/f

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Risk ratio (Relative risk)

• Probability of recessive in cancer a/(ab) e
• Probability of recessive in no-cancer c/(cd)
  f
• Risk ratio of recessive in cancer vs no-cancer
  e/f

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Odds ratio vs Risk ratio

• Risk ratio has a natural interpretation since it
  is based on probabilities
• In a case-control model we cannot calculate the
  probability of cancer given recessive allele.
  Subjects are chosen based disease status and not
  allele type
• Odds ratio shows up in logistic regression models

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Example

• Odds of recessive in case 15/35
• Odds of recessive in control 2/48
• Odds ratio of recessive in case vs control
  (15/35)/(2/48) 10.3
• Risk of recessive in case 15/50
• Risk of recessive in control 2/50
• Risk ratio of recessive in case vs control 15/2
  7.5

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Odds ratios in genome-wide association studies

• Higher odds ratio means stronger association
• Therefore SNPs with highest odds ratios should be
  used as predictors or risk estimators of disease
• Odds ratio generally higher than risk ratio
• Both are similar when small

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Statistical test of association (P-values)

• P-value probability of the observed data (or
  worse) under the null hypothesis
• Example
• Suppose we are given a series of coin-tosses
• We feel that a biased coin produced the tosses
• We can ask the following question what is the
  probability that a fair coin produced the tosses?
• If this probability is very small then we can say
  there is a small chance that a fair coin produced
  the observed tosses.
• In this example the null hypothesis is the fair
  coin and the alternative hypothesis is the biased
  coin