Page 71 - Genetics_From_Genes_to_Genomes_6th_FULL_Part2

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

Figure 7.12 Expansion of trinucleotide repeats by slipped mispairing during DNA replication. (a) Pausing of DNA
polymerase at repeat sequences during DNA replication allows slippage of the newly synthesized DNA strand (blue) relative to the template
strand (gray). Because of the repeats, the slipped strand can still pair with the template, and DNA polymerization can continue. Another round
of DNA replication will establish the additional repeats in double-stranded DNA. (b) Similarly, slippage of the template strand relative to the
newly synthesized DNA strand can result in the deletion of repeats.
(a) Trinucleotide repeat expansion (b) Trinucleotide repeat contraction
DNA polymerase DNA polymerase
2 3 pauses and newly pauses and template
synthesized strand slips strand slips
CAG CAG
1 4 1 2
5' CAG CAG 3' 5' CAG CAG 3'
3' GTC GTC GTC GTC GTC GTC 5' 3' GTC GTC GTC GTC 5'
1 2 3 4 5 6 1 4 5 6
Polymerization Polymerization
continues 2 GTC GTC 3 continues

2 3
CAG CAG
1 4 5 6 7 8 1 2 3 4
5' CAG CAG CAG CAG CAG CAG 3' 5' CAG CAG CAG CAG 3'
3' GTC GTC GTC GTC GTC GTC 5' 3' GTC GTC GTC GTC 5'
1 2 3 4 5 6 1 4 5 6
GTC 3
Next round of DNA replication Next round of DNA replication
2
GTC
1 2 3 4 5 6 7 8 1 2 3 4
5' CAG CAG CAG CAG CAG CAG CAG CAG 3' 5' CAG CAG CAG CAG 3'
3' GTC GTC GTC GTC GTC GTC GTC GTC 5' 3' GTC GTC GTC GTC 5'
1 2 3 4 5 6 7 8 1 2 3 4
Repeat number >6 Repeat number <6

Researchers do not understand well a curious feature Mutagens Induce Mutations
of trinucleotide repeat diseases: Pre-mutation alleles of
particular genes tend to expand either in the male or female Mutations make genetic analysis possible, but most
germ lines, but not both. For example, in Fig. 7.11b you mutations appear spontaneously at such a low rate that
can see that the alleles causing fragile X syndrome were researchers have looked for controlled ways to increase
inherited from mothers with pre-mutation alleles, but the their occurrence. H. J. Muller, an original member of
repeat number does not expand appreciably in the sperm Thomas Hunt Morgan’s Drosophila group, first showed
produced by a father with a pre-mutation allele. Strangely, that exposure to a dose of X-rays higher than the naturally
for Huntington disease the situation is the opposite: Dis- occurring level increases the mutation rate in fruit flies
ease alleles almost always originate in the male, but not in (Fig. 7.13).
the female, germ line. Muller exposed male Drosophila to increasingly
A variety of biochemical mechanisms could be respon- large doses of X-rays and then mated these males with
sible for trinucleotide repeat expansion and contraction. One females that had one X chromosome containing an easy-
particularly well-characterized mechanism is slipped to- recognize dominant mutation causing Bar eyes. This
mispairing during DNA replication. DNA polymerase often X chromosome (called a Balancer) also carried chromo-
pauses as it replicates through repeat regions, which allows somal rearrangements known as inversions that pre-
one DNA strand (either the newly synthesized strand or the vented it from crossing-over with other X chromosomes.
template strand) to slip relative to the other one (Fig. 7.12). (Chapter 13 explains the details of this phenomenon.)
Because the sequence contains repeats, the slipped strand Some of the F 1 daughters of this mating were heterozy-
and the other strand can pair out of register, forming a loop. gotes carrying a mutagenized X from their father and a
After another round of DNA replication, this slipped mi- Bar-marked X from their mother. If X-rays induced a re-
spairing can result in expansion or contraction of trinucleotide cessive lethal mutation anywhere on the paternally de-
repeat number in both DNA strands. rived X chromosome, then these F 1 females would be