1. In dogs, certain alleles of the MITF gene are associated with extreme white spotting, although this is a bit of a misnomer as many of the dogs don’t have white “spots” so much as they are just mostly white. The allele is also linked with deafness: Dogs with white coloration caused by the mutant MITF alleles are frequently, but not always, deaf. Deafness can affect one or both ears^[1]. Based on these descriptions, how many ways could you classify this allele of MITF?  Explain your reasoning.

2. A yellow-fur phenotype in mice is caused by a mutant allele of the agouti gene. Wild-type mice have a grey-brown fur color. In 1905, Lucien Cuénot observed that a cross between a yellow mouse and a true-breeding wild type mouse always gave a 1:1 ratio of yellow:wild-type offspring.  But when he crossed two yellow mice, he observed a 2:1 ratio of yellow:wild-type. What does this tell you about the mutant allele? Explain your reasoning.

3. Familial hypercholesterolemia (FH) is caused by a loss of function allele of the LDLR gene: the protein product encoded by the loss of function allele cannot take uptake cholesterol from the blood, resulting in higher levels of LDL (“bad” cholesterol) in the bloodstream. Although loss of function alleles are usually recessive, FH is a dominant disorder. Explain why this loss of function allele confers a dominant phenotype.

4. A “dominant negative” allele produces a nonfunctional protein, but in a heterozygote, the nonfunctional protein gets in the way of the normal, healthy protein’s function and confers a dominant phenotype.  An example of this is the p53 tumor suppressor. Some p53 mutations act as dominant negative alleles because p53 normally functions as a tetramer (a protein made up of four subunits). The nonfunctional mutant protein binds to the healthy protein and prevents it from doing its job.  Explain how a dominant negative allele is different from a loss of function allele in a haploinsufficient gene.

5. Some cat breeders specifically advertise themselves as Manx cat breeders. Is it possible for all of their kittens to be Manx?

Science and Society

6. Dominant lethal alleles are maintained in a population only if they are lethal after reproductive maturity. For example, someone with Huntington’s Disease would not know they had the disease until after they had children, and their children have a 50% chance of inheriting the lethal allele. Huntington’s Disease is a progressive neurological disorder associated with disorders in movement, cognitive impairment, and depression and other psychiatric complications. At the end of life, most HD patients are bedridden and unable to speak. Symptoms usually appear in middle age, although this is variable with juvenile and late-onset forms possible as well. Most patients die within 10-25 years of the onset of symptoms.

Modern genetic testing makes it possible to test whether someone has the allele. If one of your parents were diagnosed with HD, would you want to be tested? How would knowing you carried a lethal allele affect the way you approach your life?