Page 108 - Genetics_From_Genes_to_Genomes_6th_FULL_Part3

402 Chapter 11 Analyzing Genomic Variation

mutant chromosomes, while all wild-type chromo- within one of the CFTR gene’s introns. The following
somes have a T base at this SNP. You would like to results are obtained:
think that you have discovered the disease locus and
the causative mutation but realize you need to con-
sider other possibilities. First
Dad Mom child Fetus
a. What is another possible interpretation of the results?
b. How would you go about obtaining additional ge-
netic information that could support or eliminate
your hypothesis that the base-pair difference is re-
sponsible for the disease?

a. What is the probability that the child who will de-
Problems 33 and 34 show that you can make predictions velop from this fetus will exhibit the disease?
about a child’s genotype by genotyping linked markers
even if you don’t directly examine the disease-causing b. When this child grows up, what is the probability
mutation. This method can be valuable for diseases that any one of her own children will be afflicted
showing high allelic heterogeneity if the linkage is ex- with the disease?
tremely tight. c. The cystic fibrosis gene displays extensive allelic het-
33. The pedigrees indicated here were obtained with erogeneity: More than 1500 different mutations of the
three unrelated families whose members express CFTR gene have been shown to be associated with
the same disease caused by a completely penetrant cystic fibrosis worldwide. With this fact in mind, why
dominant allele. The disease allele is linked at a might human geneticists choose to test the fetus in the
distance of 10 cM from an SSR marker locus with indirect manner described in this problem rather than
three alleles numbered 1, 2, and 3. The SSR alleles focusing directly on the mutations that actually
present within each living person’s genotype are caused the disease in the first child?
indicated below the pedigree symbol. The phenotypes 35. The drug ivacaftor has recently been developed to
of the newly born labeled individuals—A, B, C, treat cystic fibrosis in children with the rare G551D
and D—are unknown. mutant allele of CFTR.
a. Do you think that ivacaftor would be effective only
in patients homozygous for the G551D mutation,
or might it work as well in compound heterozy-
13 22 13 22 gotes in which one copy of chromosome 7 had
G551D and the other copy a different allele of
12 32 12 32 12 32 CFTR, such as the more prevalent allele ΔF508?
(The protein encoded by G551D folds up properly
? ? ? ?
12 32 12 32 12 32 and inserts into the cell membrane, but is ineffi-
A B C D cient in chloride ion transport. Ivacaftor increases
the efficiency of G551D’s ion transport. The
ΔF508 protein does not fold up properly and there-
a. What is the probability of disease expression in fore does not get inserted into the cell membrane.)
each of these newborn babies? b. Why do you think ivacaftor would be more effective
b. Why would a human geneticist be unlikely to use in children than in older cystic fibrosis patients?
this SSR marker for diagnosis of the genetic disease? c. The scientists who developed ivacaftor had a model
34 Approximately 3% of the population carries a mutant for cystic fibrosis: a line of cells that grow in cul-
allele at the CFTR gene responsible for the recessive ture and that are homozygous for G551D. These
disease cystic fibrosis. A genetic counselor is examin- cells accumulate mucus at their surfaces that pre-
ing a family in which both parents are known to be vent cilia (tiny hairs on the outside of cells) from
carriers for a CFTR mutation. Their first child was beating. Explain how the scientists could use this
born with the disease, and the parents have come to disease model to screen for drugs that would be ef-
the counselor to assess whether the new fetus inside fective against G551D-associated cystic fibrosis.
the mother’s womb is also diseased, is a carrier, or is d. Ivacaftor is used in combination with an even
homozygous wild type at the CF locus. DNA samples newer drug called lumacaftor to treat individuals
from each family member and the fetus are tested by homozygous for the most common CF allele,
PCR and gel electrophoresis for an SSR marker ΔF508. Lumacaftor helps the ΔF508 mutant