4. Ch7_Nov_30_Dec_2_ - 11/29/09
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Unformatted text preview: 11/29/09
 Chromosomal
Rearrangements
 • Reorganiza7on
of
DNA
sequence
in
1
or
more
chromosomes
 • Change
in
chromosome
number
(loss/gain
en7re
chromosomes
or
 sets
of
chromosomes)
 • Both
can
alter
gene
ac7vity
or
gene
transmission
 •  Karyotypes
~
very
similar
within
a
species.

 •  More
closely
related

more
similar
karyotype
 • More
distantly
related

more
rearrangements
result
in
differences 
 in
karyotypes
 • Correla7on
b/w
evolu7on
of
new
species
&
karyotypic
 rearrangements?
 108
 Expansion
&
Contrac7on
of
Trinucleo7de
Repeats
 • CAG
 • GTG
 • GAA
 • CGG
 Can
be
unstable:
 • Diff
#
repeats
increases/decreases
in
different
cells
of
same



 individual
 • #
repeats
can
be
altered
during
gametogenesis
 • thus
can
get
change
in
#
repeats
1
genera7on

next
 • Larger
#
repeats
–
more
likely
expansion/contrac7on
event
 • Increased
risk
of
‘slippage’
&
resul7ng
‘stuZer’
or
‘skip’
 • Repair
mechanisms
not
efficient
at
correc7ng
 • E.g.,
Fragile
X
syndrome

trinucleo7de
repeat
expanion,
Hun7ngton
 disease
 1
 11/29/09
 Problems
with
studying
muta7ons…
 • Rare
events
 • Phenotypes
of
muta7ons
are
ocen
recessive,
therefore
 they’re
difficult
to
detect.
 • Forward
muta7on
–
change
from
WT

another
allele
 • A+

a
(recessive);

b+

B
(dominant)
 • (0
‐
2.5
x10‐6
muta7ons/gene/gamete)
 • Reverse
muta7on
–
mutant
allele
reverts
to
WT
 • Rate
varies
gene
to
gene;
significantly
lower
rate
than
 forward
muta7ons…

WHY?
 110
 Muta7ons
affec7ng
phenotype
 •  Muta7ons
affec7ng
phenotype
occur
naturally
at
very
low
rate
 •  Makes
them
difficult
to
study
 •  Average
=
2
‐
12
x
10‐6
muta7ons/gene/gamete
 •  Fig.
7.3

rates
of
spontaneous
muta7on
 •  Muta/on
rate
varies
gene
to
gene
 •  Depends
on
gene
size
 •  Eukaryotes
higher
rates
of
muta7on
cf
bacteria
–
WHY?
 •  Forward
muta/ons
>
reversions
 •  Are
muta7ons
random?
 111
 2
 11/29/09
 Es7ma7ng
Muta7on
Rates
–
Recessive
Lethals
 •  Propor7on
F1
females
produce
no
male
offspring
=
rate
of
muta7on
to
 recessive
lethals
 
 
 
 
=
0.1%


X
chromosome
(rate
for
en7re
chr)
 •  Many
genes
likely
can
mutate
to
recessive
lethal
 •  If
all
chromosomes
were
equal
(muta7on
rate
to
recessive
lethals)…






 
 
 
=
‐.1%
x
4
(4
chromosomes)
=
0.4%

(this
is
in
Drosophila)
 # recessive lethal alleles in average individual •  Drosophila
melanogaster
 
=
0.5
–
3
 •  Xenopus
laevis

(frog) 
=
1.9
 •  Ambystoma
mexicanum
(salamander)

=
1.6
 •  Zebrafish
 
=
1.9
 •  On
average
–
individuals
have
~
1‐2
recessive
lethal
alleles 

 112
 Implica7ons
of
Recessive
Lethal
Alleles
 •  Gene7c
counselling
 •  E.g.,

probability
of
cousins
having
children
with
recessive
disorder
 •  Conserva7on
efforts
 •  E.g.,
small
popula7on
size
leads
to
greater
inbreeding;
affects
 health
of
popula7on
 * •  Evolu7on
of
ma7ng
systems 

 •  E.g.,

cost
of
inbreeding
 inbreeding depression * * * * * * * 113
 3
 11/29/09
 Can
external
substances
affect
muta7on
rates?
 •  H J Muller control (no addition) test (addition of X-rays) Spontaneous mutation rate (0.1%) Elevated mutation rate (10%) •  X‐rays,
other
types
of
radia7on,
&
some
chemical
compounds
elevate
 muta7on
rate.
 •  Impacts
human
health
&
environment
 •  Usefulness
mutagens
used
as
tool
in
gene7cs
to
↑
rate
of
muta7on
 114
 Test:
is
a
compound
mutagenic?
 •  Ames test his- Salmonella typhimurium Minimal media his- Salmonella typhimurium Minimal media Minimal media + his NB: reversion rate usually << inactivation rate no growth growth some growth • Represents mutation 115
 • Reversion his- his+ 4
 11/29/09
 Ames
Test
 116
 Nature
of
Muta7ons…
 • 
Are
muta7ons
random
with
respect
to
the
environment?
 
 
 
OR
 • 
Do
environmental
stresses
drive
muta7on?
 media + antibiotic some growth 1) 
muta7ons
arose
randomly

 OR
 2)
muta7ons
arose
as
a
 consequence
of
the
 an7bio7c
 mutations to resistance 5
 11/29/09
 Replica
Pla7ng
 • 
showed
bacterial
resistance
b/c
of
pre‐exis/ng
muta/ons
 Luria‐Delbruck
Fluctua7on
Test
 6
 11/29/09
 Muta7on
is
Random
wrt
Environment…
 • Implications for Evolution: • Consistent with Darwin’s theory of evolution by natural selection • Random variation introduced into population • Natural selection then acts on that variation • Most mutations are deleterious to a population • Eventually removed by natural selection Ques7ons
about
the
nature
of
muta7on…
 • What is the rate of deleterious mutation? • Conservation, health, mating system evolution • What is the rate of beneficial mutation? • Adaptive evolution, health (e.g., bacterial resistance to antibiotics) • Mutations & Disease • Hereditary diseases persist b/c mutation can continually reintroduce them into the population • Balance b/w mutation introducing harmful mutations & natural selection removing them from the population. 7
 11/29/09
 How
do
Muta7ons
Arise?
 •  Depurination; •  Deamination •  X-ray damage •  UV damage Altera7ons
due
to
mutagens…
 8
 11/29/09
 Altera7ons
due
to
mutagens…
 Altera7ons
due
to
mutagens…
 9
 11/29/09
 With
so
many
ways
to
make
mistakes,
why
 are
muta7on
rates
low? 
 1) Excision repair Fig. 7.7 With
so
many
ways
to
make
mistakes,
why
are
 muta7on
rates
low? 
 2) Proofreading by DNA polymerase 10
 11/29/09
 With
so
many
ways
to
make
mistakes,
why
are
 muta7on
rates
low? 
 3) Mismatch repair With
so
many
ways
to
make
mistakes,
why
are
 muta7on
rates
low? 
 • only when all proofreading and error-correcting mechanisms fail do mutations appear • these rare mistakes generate all variation in nature! 11
 ...
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