lecture 11 chromosomal mutations -...
TRANSCRIPT
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A reciprocal translocation demonstrated
by chromosome painting
Lecture 11
Chromosomal
mutations
1. Topography of chromosomes
2. Changes in number
3. Deletions
4. Duplications
5. Inversions
6. Translocations
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Chromosome can be distinguished
from each other based on
chromosome landmarks:
Position of the centromere
acrocentric (off the center) -----------------o-----
metacentric (central) ------------o------------
telocentric (at the end) ------------------------o-
acentric (no single CM) --------------------------
Chromosome size:
length in micrometers
ratio b/w the short arm (p) and the long arm (q)
Other features:
heterochromatin regions (inactive regions of
chromosomes, densely stained G-bands,
e.g. 9q33.1)
euchromatin regions
(active regions, not densely stained,
e.g. 9q34.3)
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Overview of chromosomal mutations
changes in numberchanges in structure
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Changes in chromosome number
Haploidy often refers to number of chromosomes in gametes (haplo = simple, single)
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Domesticated common (bread) wheat is hexaploid:
42 chromosomes = 6 sets of 7 chromosomes
The set of chromosomes in
gametes such wheat is triploid:
21 = 3 sets of 7 chromosomes
Wild wheat is diploid and some agricultural varieties are tetraploid
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Colchicine is used to increase ploidy
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Colchicine is used to increase ploidy
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It is also possible to decrease ploidy (in plants)
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Monoploid plant Perfectly homozygous diploid plantcolchicine
... and increase it back again
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Diploid (left) and tetraploid (right) grapes
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parents: 2n (diploid) x 4n (tetraploid)
gametes: n 2n
zygote:
3n (sterile)
Unbalanced chromosome segregation in triploids
Seedless Vanessa grapes
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Unbalanced chromosome segregation in triploids
Anaphase of Meiosis I
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parents: 2n (diploid) x 4n (tetraploid)
gametes: n 2n
zygote:
3n (sterile)
gametes with unbalanced sets of chromosomes in gametes:
Unbalanced chromosome segregation in triploids
or or etc.
Probability of balanced segregation P = (1/2) n-1
...and for watermelon n = 11
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Triploidy in trout
2n egg + 1n sperm = 3n zygote normal 2n trout
2n egg + 1n sperm = 3n zygote 3n trout, sterilehigher temp., 10 min
trout: 2n = 80
loss of one set of
female chromosomes
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Mule: a sterile hybrid between a
horse and a donkey.
Since 1527, there have been only ~60 cases of mules
giving birth
Morocco’s ‘miracle mule’, 2002,
having given birth to a baby that
looked like donkey.
Mules are sterile due to unbalanced
chromosome segregation
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The liger is the result of a cross between a male lion (Panthera leo) and female
tiger (Panthera tigris)
The hybrid between a male tiger and female lion is a tigon. In both species 2n = 38, and hybrid females are fertile!
Not all
interspecies
hybrids are
sterile
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There are only a few types of viable aneuploids in humans
XO, Turner
monosomy
XXY, Kleinfelter
trisomy
Extra chr. 21, Down
trisomy
Other types (freq. ~2 per 10,000 births), multiple deformities, early death:
Edwards syndrome, trisomy for chr. 18
Patau syndrome, trisomy for chr. 13
All these cases are due to meiotic nondisjunction
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In human females, all oocytes are formed already in
fetus but meiosis becomes arrested at prophase I
(with homologs synapsed) before birth.
In adult females, only ~one oocyte per month
continues meiosis till Metaphase II, then stops again.
Meiosis is completed upon fertilization.
Thus, frequency of non-disjunction increases with
age.
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Chromosomal mutations: changes in structure
http://ghr.nlm.nih.gov/
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Examples of medically
important deletions in
humans
FYI: the syndrome results when a piece of
chromosome 5 is missing. Infants with this condition
often have a high-pitched cry that sounds like that of
a cat. The disorder is characterized by intellectual
disability and delayed development, distinctive facial
features, small head size (microcephaly), low birth
weight, and weak muscle tone (hypotonia) in infancy.
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Fragile X syndrome
FYI: Many males with fragile X
syndrome have characteristic
physical features that become
more apparent with age. These
features include a long and
narrow face, large ears,
prominent jaw and forehead,
unusually flexible fingers,
Expansion of CGG-repeat inhibits transcription of
an important gene and generates the fragile site
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Properties of deletions
• Deletions do not reverse to wild type
• Homozygous deletions are lethal
• Heterozygous deletions are lethal and dominant when large (affect gene dosage)
• Heterozygous deletions are tolerated and recessive when small
• Heterozygous deletions can expose recessive alleles (pseudominance)
A- B- C- D- E- F-
A+ B+ ..... E+ F+
pseudominance of C- and D- due to
partial hemizygocity
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avoids centromere
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Recombinants with these chromosomes
are not viable
In inversion heterozygotes crossovers do occur, but no recombinant progeny can be recovered
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Recombinants
are not viable
In inversion heterozygotes crossovers do occur, but no recombinant progeny can be recovered
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A B C D E F
A E D C B F
5 m.u. 10 m.u. 7 m.u. 8 m.u. 5 m.u.
30 m.u.
35 m.u.
In a cross involving
inversion heterozygote,
e.g. ABCDEF/aedcbf
RF (A, F) = 5% (!!!!!!!!!!!)
In a cross involving
inversion homozygote,
e.g. AEDCBF/aedcbf
RF(A,F) = 35%
Map distances are underestimated in inversion heterozygotes
original chromosome
inversion chromosome
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recombination will not be observed within the region
that includes inversion
(cross-overs do occur but recombinants are not viable)
map distance between the loci that flank the
inversion will be underestimated
it may appear that no cross-overs happen at all
In inversion heterozygotes:
Inversions can also break genes, fuse genes, or move
genes resulting in various consequences
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Translocation - a reciprocal
exchange of segments between
two nonhomologous
chromosomes
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Translocation - a reciprocal
exchange of segments between
two nonhomologous
chromosomes
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adjacent
segregation
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alternate
segregation
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Semisterility -
50% of gametes in
translocation
heterozygotes are not
viable
Pollen in semisterile corn
(clear granules – sterile pollen)
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It is not the same
as the loss of viability of
recombinant gametes in
inversion heterozygotes!
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Down syndrome: trisomy of chromosome 21
In most cases – due to meiotic nondisjunction in a parent
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5% of Down syndrome cases are due to a specific
translocation involving chromosome 21
chr. 21
chr. 14
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High frequency (~30%) of Down syndrome among the
progeny of a heterozygote for Robertsonian translocation
1/3 1/3 1/3
Compare: average frequency of (nondisjunction) cases is 1.5 / 1,000 births
monosomy
for chr. 21
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Translocations are also implicated in some cases of
Duchenne’s muscular dystrophy
Normal X Normal 21
(note: this has nothing
to do with Down syndrome!)
Translocated X
with the disrupted
dystrophin gene
Translocated 21
Translocation involves the very tip
of the two chromosomes
dystrophin
gene
(Xd Y males are affected, Xd X females are carriers )
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Translocations as
a cause of cancer
proto-oncogene abl
oncogene bcr-abl,
causes a certain type of leukemia
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50% reduction of fertility in heterozygotes
some cases of Down syndrome (5%) in humans
(Robertsonian translocation heterozygotes)
certain cases of cancer (activation of proto-
oncogenes)
additional human genetic diseases by breaking
genes or moving genes between euchromatin and
heterochromatin (position effect)
Translocations are responsible for: