Apply What You’ve Learned

Review

17.4 Comparisons of haplotypes of individuals with and without a particular genetic disease can identify loci associated with the disease.

17.4 Pharmacogenomics is the study of how an individual’s genome affects responses to drugs or other outside agents.

17.5 Chemical methods are used to identify components of the proteome.

Different people metabolize the (hypothetical) antianxiety drug Calm at different rates. This variation is potentially a problem because too-high concentrations of the drug can have harmful side effects, while too-low concentrations may not give the desired therapeutic effect. Knowledge about how genotypes affect the metabolism of Calm would be very useful.

In a study, people who had been genotyped at various single nucleotide polymorphisms (SNPs) across the genome were given Calm. Twelve hours later, they had their blood drawn to assess the concentration of the drug. Individual concentrations were normalized by dividing by the global mean concentration and multiplying by 100. The results for the three SNPs with the greatest effects are shown in the figure below. Note that the double letters correspond to the nucleotides on homologous chromosomes (e. g., “AC” means there is A on one chromosome and C on its homolog).

image

Questions

Question 1

Describe the relationship between genotype and Calm concentration and between genotype and Calm metabolism for each of the three SNPs.

For SNP 5689, individuals with genotype AA have the highest concentrations (and thus the slowest metabolism) of Calm. Individuals with GG have the lowest concentrations (fastest metabolism) of Calm. Heterozygotes are intermediate. For SNP 8835, AA homozygotes have the lowest concentrations (fastest metabolism), CC homozygotes have the highest concentrations (slowest metabolism), and heterozygotes are intermediate. For SNP 11286, the heterozygotes have the highest concentrations (slowest metabolism). The two homozygotes have roughly similar concentrations and thus similar metabolisms.

Question 2

Based on the data, would you recommend a higher dose or a lower dose of the drug for individuals with the AA genotype than for those with the GG genotype at SNP 5689? Explain your answer.

Because AA individuals at this SNP have a slower metabolism of the drug than do GG individuals, the AA individuals should receive a lower dose.

Question 3

Suppose SNP 5689 were at a gene that encoded an enzyme that broke down the drug. Would you expect the enzyme encoded by the A allele of the gene to be more or less active than the enzyme encoded by the G allele? Explain your answer.

AA homozygotes have the slowest metabolism and GG homozygotes have the fastest. Thus one would expect that the enzyme encoded by the A allele of the gene would be less active than the enzyme encoded by the G allele.

Question 4

Suppose SNP 8835 were at a gene that encoded an inhibitor for the enzyme in Question 3. Would you expect the enzyme encoded by the A allele of the gene to be more or less active than the enzyme encoded by the C allele? Explain your answer.

AA homozygotes have the fastest metabolism and CC homozygotes have the slowest. Thus one would expect that the inhibitor encoded by the A allele of the gene would be less active than the inhibitor encoded by the C allele.

Question 5

The drug Calm appears to affect protein synthesis at several genes in liver tissue. Briefly describe how a medical researcher could examine which proteins have altered expression in a mouse model, highlighting the technique that would be used.

Give the treatment mice the drug and leave others as the control. Prepare liver tissue from the treatment and the control mice. Use two-dimensional gel electrophoresis and mass spectrometry to identify differences in the proteins from the livers of treatment and control mice.