Page 154 - Genetics_From_Genes_to_Genomes_6th_FULL_Part2

Problems 313

d. Frameshift mutations occurring in the sequences k. G­to­A substitution in the 5′ UTR
encoding amino acids near the C terminus of the l. insertion of 1000 base pairs into the sixth intron
protein (this particular insertion does not alter splicing)
e. Silent mutations 44. Considering further the mutations described in
f. Conservative missense mutations Problem 43:
g. Nonconservative missense mutations affecting the a. Which of the mutations could be null mutations?
active site of the protein b. Which of the mutations would be most likely to re­
h. Nonconservative missense mutations not in the ac­ sult in an allele that is recessive to a wild­type allele?
tive site of the protein c. Which of the mutations could result in an allele
42. Null mutations are valuable genetic resources because dominant to a wild­type allele? What mechanism(s)
they allow a researcher to determine what happens to an could explain this dominance?
organism in the complete absence of a particular pro­ 45. Adermatoglyphia (described previously in Problem 18
tein. However, it is often not a trivial matter to determine in Chapter 3) is an extremely rare condition where
whether a mutation represents the null state of the gene. people are born without fingerprints; only four fami­
a. Geneticists sometimes use the following test for lies on earth are known to have this condition. The
the nullness of an allele in a diploid organism: If the condition is inherited in an autosomal dominant
abnormal phenotype seen in a homozygote for the fashion and is due to point mutations in a gene on
allele is identical to that seen in a heterozygote chromosome 4 called SMARCAD1.
(where one chromosome carries the allele in ques­ The following figure shows that different point
tion and the homologous chromosome is known to mutations—all near the 5′ end of the same intron of
be completely deleted for the gene) then the allele SMARCAD1—were found in each of the four families.
is null. What is the underlying rationale for this All four mutations prevent the expression of a skin­
test? What limitations might there be in interpret­ specific transcript that uniquely contains exon 1, the
ing such a result? first exon of this transcript; no other SMARCAD1
b. Can you think of other methods to determine mRNAs contain this exon. In the figure, the final
whether an allele represents the null state of a par­ three bases in the RNA­like strand of exon 1 are shaded,
ticular gene? while the first five bases of intron 1 are unshaded.
43. The following is a list of mutations that have been Exon 1 Intron 1
discovered in a gene that has more than 60 exons and
encodes a very large protein of 2532 amino acids. Normal CTG GTA AGT
Indicate whether or not each mutation could cause a Family 1 CTG TTA AGT
detectable change in the size or the amount of mRNA Family 2 CTG GCA AGT
CTG GTA
Family 3
ACT
and/or a detectable change in the size or the amount Family 4 CTG ATA AGT
of the protein product. (Detectable changes in size or a. No ATG sequence normally exists in exon 1
amount must be greater than 1% of normal values.) upstream of the sequence shown. Which part of
What kind of change would you predict? the skin­specific mRNA corresponds to exon 1?
a. Lys576Val (changes amino acid 576 from lysine
into valine) b. What aspect of gene expression is likely to be
affected most directly by these mutations?
b. Lys576Arg c. Are these mutations more likely to cause loss of
c. AAG576AAA (changes codon 576 from AAG to function or gain of function?
AAA)
d. AAG576UAG 46. Homozygosity for extremely rare mutations in a human
gene called SCN9A cause complete insensitivity to
e. Met1Arg (at least two possible scenarios exist for pain (congenital pain insensitivity or CPA) and a total
this mutation) lack of the sense of smell (anosmia). The SCN9A gene
f. promoter mutation encodes a sodium channel protein required for trans­
g. one base pair insertion into codon 1841 mission of electrical signals from particular nerves in
h. deletion of codon 779 the body to the brain. The failure to feel pain is a dan­
gerous condition as people cannot sense injuries.
i. IVS18DS, G–A, + 1 (this mutation changes the The SCN9A gene has 26 exons and encodes a
first nucleotide in the eighteenth intron of the gene, 1977­amino acid polypeptide. Consanguineous mat­
causing exon 18 to be spliced to exon 20, thus ings in three different families have resulted in indi­
skipping exon 19) viduals with CPA/anosmia. In Family 1, a G­to­A
j. deletion of the poly­A addition site transition in exon 15 results in a truncated protein that is