Transcript BIOL 112 – Principles of Zoology

chromosomal mutations
I.
Chromosomal mutations
A.
B.
II.
Changes in chromosome number
Changes in chromosome structure
Chromosome testing
A.
B.
C.
Karyotyping
High resolution analysis
Postnatal genetic testing
I. Chromosomal Mutations
possibly affecting more than one gene (multigene level)
A. Changes in NUMBER
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Monoploid number (2n – 1)
Euploidy (multiples of n)
Polyploid (3n, 4n, 5n…)
Triploid, tetraploid, pentaploid, hexaploid
1. Polyploidy
Usually lethal in mammals
Does occur in some animals - Reproduction via
parthenogenesis, Flatworms, leeches, brine
shrimp, lizards, salamanders, salmonids
Polyploidy in plants: much more common because it can be
tolerated by plants, can reproduce asexually…
Important role in the evolution of plants –
wheat: 2n = 14, 28, 42
chrysanthemum: 2n = 18, 36, 54, 72, 90
sympatric speciation:
e.g. polyploidy in
plants..
•Autopolyploidy: due to
meiosis error. Offspring
can self fertilize.
•Allopolyploidy:
2 different species
mating, produce a
hybrid that is polyploid:
•The hybrid is fertile
because the polyploid
condition provides the
homologous
chromosomes for
pairing during meiosis…
Endopolyploidy
only certain cells in
the organism are
polyploid
Liver cells, plant
tissue (stem),
larval gut tissue
(mosquitos)
2. Aneuploidy – the total # is not an
exact multiple of a set
(2n +/- x)
Caused by Nondisjunction = failure of
normal chromatid division during
meiosis, two chromosomes go to one
pole, none in the other.
Results in the wrong number of
chromosomes.
Results in a gene imbalance
Fertilization of one of these
affected gametes produces a
zygote w/ either 3 members
(trisomy) or only one member
(monosomy) of the chromosome.
gene imbalance - THE problem
Aneuploids are more abnormal than polyploids, why?
(polyploid plants are completely viable and usually
bigger, whereas in Drosophila the only aneuploids that
survive are trisomics and monosomics for chromosome
4, the smallest chromosome)
 Normal physiology of a cell depends on the
proper ratio of gene products in the euploid cell.
The amount of expression is correlated with the
number of genes in a cell
 If 3 copies present: 150% of the normal amount of
protein will be made
 If 1 copy present: 50% of the normal amount of
protein will be made
Nondisjunction responsible for
Turner’s syndrome and Kleinfelter’s
syndrome…
Turner’s syndrome produces sterile
females with a normal # of
autosomes and 1 X chromosome
(XO). These are the only human
monosomics that survive…
Klienfelter’s syndrome individuals
are trisomic: XXY, they are sterile
males that are typically tall, and thin
and some degree of mental
retardation.
XYY – trisomic males have mild
mental retardation
Aneuploid Conditions in Humans
Condition
Frequency
syndrome
Trisomy-21
1/800
Down
Trisomy-18
1/6,000
Edward
Trisomy-13
1/15,000
Patau
XXY
1/1,000
Klinefelter
XYY
1/1,000
Jacobs
XXX
1/1,500
Superfemale
X
1/5,000
Turner
Inherited disorders associated with aneuploidy. Trisomies
and variations in the sex chromosomes result in mental
retardation, organ defects, sexual immaturity, etc.
Trisomy 21, abnormal creases
Trisomy 18, diaphragmatic hernia
Turner’s syndrome, developmental abnormality
polydactyly
Why is monosomy so bad?
Monosomics for all human
autosomes die in utero
Any deleterious recessive
alleles present on monosomic
autosome will be automatically
expressed
B. Changes in chromosome
structure
1)
2)
3)
4)
A) Deletions
B) Duplications
C) Inversion
D) Translocation
Deletion
loop
1. Deletions
a) Spontaneous
breakage and
rejoining
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Interstitial deletion
Terminal deletion
b) Crossing over
between repetitive
DNA
Region w/centromere usually maintained
during division, the other part will be lost
Multigenic deletions
If both homologs have the same deletion
then it will be lethal
If only on one homolog, the deletion can
“uncover” lethal recessives in the
heterozygous condition
Psuedodominance = when recessive
alleles are expressed due to a deletion
event
“partial monosomy”
Caused by a heterozygous deletion of the tip of the p arm of
chromosome #5 – phenotype: distinctive cat-like cry made by
infants, microencephaly & moon-like face
2. Duplications
Extra copy of some particular region…
Rare, and difficult to detect
Usually due to unequal crossing over
during meiosis, or through replication error
prior to meiosis
Not as problematic as deletions, but some
problems are associated:

Bar eye in Drosophila (gene imbalance)
3. Inversions
Region breaks, rotates 180 degrees and rejoins
Generally viable, and show no abnormalities at the
phenotypic level
Paired homologs form an
During synapsis, one
chromosome must twist into
a loop to pair up w/the
genes on the other…
Types of inversions
1) Paracentric – centromere outside of the inversion
Cross over products: dicentric and acentric
chromosome
2) Paricentric – inversion spans centromere
Cross over products: duplication, and deletion
During meiosis,
homologs still pair up,
even w/inversions
-Inversion loop makes
this possible
Crossing over
produces affected
chromatids:
Duplication &
Deletion events
4. Translocation-movement of chromosomal
fragments to a new location.
Semisterility = an organism that is heterozygous for a reciprocal translocation
usually produces about half as many offspring as normal
due to difficulty in chromosome segregation in meiosis.
Translocation cross = because of the translocations, the pairing of homologous
regions leads to the unusual structure that contains four pairs of sister
chromatids.
Nonreciprocal translocation – (unbalanced)
Centromeric regions of two nonhomologous
acrocentric chromosomes become fused to form
single centromere.
-Down Syndrome
chromosome 21 & 14
rearrangement leads to familial Down
Syndrome. The heterozygote is
normal, the 3 chromosomes must
separate during meiosis (only 2/6 are
normal, the rest either monosomic or
trisomic)
-Cancer
(CML) type of leukemia, translocation between
chromosome 9 & 22, leads to the movement of a gene
where it will be overexpressed
Fragile sites – susceptible to
breakage
Fragile X syndrome
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Most common form of inherited mental retardation (1/4000
males, 1/8000 females)
FMR1 gene, has several trinucleotide repeats CGG in the
5’UTR region
Normal individuals = 6 to 54 repeats
Affected individuals = >230 repeats, region becomes modified (bases
are highly methylated & gene NOT expressed)
Link between fragile sites & cancer

Chromosome #3 FRA3B region, FHIT gene often altered or
missing in tumor cells taken from individuals w/ cancer
II. Chromosome Testing
Chromosomes:
A. Karyotyping
B. High resolution chromosome analysis
A. karyotyping
adding a dye to metaphasic chromosomes; different dyes that
affect different areas of the chromosomes are used for a range
of identification purposes.
Giemsa dye is effective because it markedly stains the bands
on a chromosome; Each chromosome can then be identified
by its banding pattern
Amniocentesis
Chorionic Villi Biopsy
Prenatal genetic testing cont.
Maternal Serum & Amniotic fluid
Alpha-fetoprotein (AFP)
Unconjugated estriol (uE3)
Dimeric inhibin A (DIA)
Fetal cell sorting
B. High resolution chromosome analysis
1) SKY – uses probes. Each of the
individual probes complementary
to a unique region of one
chromosome - together, all of the
probes make up a collection of
DNA that is complementary to all
of the chromosomes within the
human genome.
Each probe is labeled with a
fluorescent color that is
designated for a specific
chromosome..
the probes hybridize, the
fluorescent probes essentially
paint the full set of chromosomes,
can be analyzed to determine
whether any of them exhibits
translocations or other structural
abnormalities.
2) In situ hybridization –
used to map specific
deletions & insertions
No binding, 13.1-13.3 deleted
(FISH) analysis of a normal individual (D) and patient with a
chromosome 22 deletion using a probe for the UFD1 gene. The patient
has only one copy of UFD1 seen in blue (white arrows). Chromosome
22 was labeled with a red fluorescent marker (yellow arrows).
http://www.ggc.org/clinical.htm