Page 103 - Genetics_From_Genes_to_Genomes_6th_FULL_Part2

262 Chapter 7 Anatomy and Function of a Gene: Dissection Through Mutation

mutations. Based on Fig. 7.14, which of the follow- Consult the Fast Forward Box Trinucleotide Repeat
ing mutagens can be classified as one-way and Disease: Huntington Disease and Fragile X Syndrome in
which as two-way? considering the following two problems.
a. 5-bromouracil 20. The mutant FMR-1 allele that causes fragile X syn-
b. hydroxylamine drome is considered to be X-linked dominant with
c. ethylmethane sulfonate incomplete penetrance and variable expressivity.
Why do most females heterozygous for one mutant
d. nitrous acid and one normal allele have at least some symptoms
e. proflavin of the disease?
16. In 1967, J. B. Jenkins treated wild-type male 21. The physicist Stephen Hawking, famous for his theo-
Drosophila with the mutagen ethylmethane sulfonate ries about black holes, has lived past the age of 70 with
(EMS) and mated them with females homozygous for amyotrophic lateral sclerosis (ALS), a paralyzing neu-
a recessive mutation called dumpy that causes short- rodegenerative disease that is usually fatal at a much
ened wings. He found some F 1 progeny with two younger age. Recently, geneticists discovered that a
wild-type wings, some with two short wings, and major cause of ALS is the unusual expansion of a
some with one short wing and one wild-type wing. hexanucleotide repeat (5′-GGGGCC-3′) that lies
In a second cross, when he mated single F 1 flies with within a gene called C9ORF72, at a location outside of
two short wings to dumpy homozygotes, he found, the gene’s open reading frame (ORF). A single ex-
surprisingly, that only a fraction of these matings panded allele is sufficient to cause ALS, but the reason
produced all short-winged progeny. the disease allele is dominant remains unclear. Some
a. Explain these results in light of the mechanism of experimental results support the theory that the allele
action of EMS shown in Fig. 7.14. makes a toxic RNA containing the expanded repeat. If
this theory is correct, in what ways is the mutant ALS-
b. Should the short-winged progeny of the second causing allele similar to the mutant allele that causes
cross have one or two short wings? Why? Huntington disease? In what ways is it similar to the
17. When a particular mutagen identified by the Ames test mutant allele that causes fragile X syndrome?
is injected into mice, it causes the appearance of many
tumors, showing that this substance is carcinogenic. Section 7.3
When cells from these tumors are injected into other
mice not exposed to the mutagen, almost all of the new 22. Aflatoxin B 1 is a highly mutagenic and carcinogenic
mice develop tumors. However, when mice carrying compound produced by certain fungi that infect crops
mutagen-induced tumors are mated to unexposed mice, such as peanuts. Aflatoxin is a large, bulky molecule
virtually all of the progeny are tumor free. Why can the that chemically bonds to the base guanine (G) to form
tumor be transferred horizontally (by injecting cells) the aflatoxin-guanine adduct that is pictured below.
but not vertically (from one generation to the next)? (In the figure, the aflatoxin is orange, and the guanine
−
18. When the His Salmonella strain used in the Ames test base is purple.) This adduct distorts the DNA double
helix and blocks replication.
+
is exposed to substance X, no His revertants are seen.
If, however, rat liver supernatant is added to the cells a. What type(s) of DNA repair system is (are) most
along with substance X, revertants do occur. Is substance likely to be involved in repairing the damage
X a potential carcinogen for human cells? Explain. caused by exposure of DNA to aflatoxin B 1 ?
+
−
19. The Ames test uses the reversion rate (His to His ) b. Recent evidence suggests that the adduct of guanine
to test compounds for mutagenicity. and aflatoxin B 1 can attack the bond that connects it
to deoxyribose; this liberates the adducted base,
a. Is it possible that a known mutagen, like proflavin, forming an apurinic site. How does this new infor-
−
would be unable to revert a particular His mutant mation change your answer to part (a)?
used in the Ames test? How do you think that the
Ames test is designed to deal with this issue? O O
b. Can you think of a way to use forward mutation
+
−
(His to His ) to test a compound for mutagenic- O
ity? (Hint: Consider using the replica plating tech- HO
nique in Fig. 7.6.) O
N O O
c. Given that the rate of forward mutation is so much HN OCH 3
higher than the rate of reversion, why does the Ames N Aflatoxin-guanine adduct
test use the reversion rate to test for mutagenicity? H N N
2