You learned in Problem 21 in Chapter 7 that theneurodegenerative disease ALS can be caused by expansion of a hexanucleotide repeat region (5′-GGGGCC-3′)outside of the open reading frame (but within the firstintron) of the gene called C9ORF72. While a normalC9ORF72 allele has 2–23 copies of the hexanucleotiderepeat unit, dominant disease-causing alleles have hundreds or even thousands of copies. Researchers observed that the first intron of theC9ORF72 disease allele is transcribed not only fromthe normal template strand of DNA, but also from thenontemplate strand. Even more unusual, both types ofrepeat-region transcripts are translated in all six readingframes in an AUG-independent manner—a processcalled repeat-associated non-ATG translation, or RANtranslation. These discoveries led to the hypothesisthat the proteins made from the repeats mightcontribute to ALS.a. What polypeptides are made from the repeat-regiontranscripts?b. According to the RAN translation hypothesis, whyare disease-causing C9ORF72 alleles dominant tonormal alleles? c. How would you classify the mutant alleles? Dothey cause a loss of function or a gain of function?Are they amorphic, hypomorphic, hypermorphic,neomorphic, or antimorphic? (Note: More thanone answer might be possible.)
You learned in Problem 21 in Chapter 7 that the
neurodegenerative disease ALS can be caused by expansion of a hexanucleotide repeat region (5′-GGGGCC-3′)
outside of the open reading frame (but within the first
intron) of the gene called C9ORF72. While a normal
C9ORF72 allele has 2–23 copies of the hexanucleotide
repeat unit, dominant disease-causing alleles have hundreds or even thousands of copies.
Researchers observed that the first intron of the
C9ORF72 disease allele is transcribed not only from
the normal template strand of DNA, but also from the
nontemplate strand. Even more unusual, both types of
repeat-region transcripts are translated in all six reading
frames in an AUG-independent manner—a process
called repeat-associated non-ATG translation, or RAN
translation. These discoveries led to the hypothesis
that the proteins made from the repeats might
contribute to ALS.
a. What polypeptides are made from the repeat-region
transcripts?
b. According to the RAN translation hypothesis, why
are disease-causing C9ORF72 alleles dominant to
normal alleles?
c. How would you classify the mutant alleles? Do
they cause a loss of function or a gain of function?
Are they amorphic, hypomorphic, hypermorphic,
neomorphic, or antimorphic? (Note: More than
one answer might be possible.)
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