Chapter 11
Chromosomes
Cytogenetics
• Sub-discipline within genetics that links
chromosome variations to specific traits,
including illnesses.
Portrait of a Chromosome
• A chromosome consists of:
– DNA
– Associated RNA
– Histone proteins
– DNA replication enzymes
– Transcription factors
• During metaphase key physical features can
be seen.
Heterochromatin
versus Euchromatin
Heterochromatin will
form regions of the
centromere and
telomeres
Euchromatin will form
the protein encoding
regions on the
chromosome
• Five human chromosomes: 13,14,15,21, & 22
• Contain satellites that extend from a thinner,
stalklike bridge from the rest of the
chromosome.
• The stalk – codes ribosomal proteins
Visualizing Chromosomes
• Any cell other than mature red blood cells can be
used to examine chromosomes.
• White Blood Cells – Generally used for family
history or infertility tests
• Cancer Cells – may indicate which drugs are most
likely to be effective.
• Bone Marrow Cells- Blood-borne cancers –
(leukemias and lymphomas)
• Fetal Cells – reveal medical problems of the fetus
Amniocentesis
• Sampling fetal cells shed
into the amniotic fluid.
• Procedure
– 10 days of culturing
– 20 cells are karyotyped
– Can detect 400 of more
than 5,000 chromosomal
abnormalities.
– Done around the 15th or
16th week of gestation
Who gets them done?
• If the risk that the fetus has a detectable
condition EXCEEDS the risk that the procedure
will cause a miscarriage (1 in 350)
• Woman over 35
• Several prior miscarriages
• Blood test reveals low levels of fetal liver
protein called alpha fetoprotein and high
levels of hCG (human chorionic gonadotropin)
Chorionic Villus Sampling
• Obtain cells from the chorionic villi, which
develop into the placenta (fetal derived cells)
• Karyotype is performed
• Chromosomal Mosaicism
– Cells of the villus differ from the embryo cells.
– False negative or false positive results.
• 1 in 1000 to 3000
procedures cause
fatal limb defect.
• Couples need to
choose:
– Earlier results
– Greater risk of
spontaneous abortion
• Additional .8%
compared to an
addition .3%
Fetal Cell Sorting
• A new technique that separates fetal cells
from the woman’s bloodstream.
• Fetal blood enters maternal circulation in up
to 70 percent of pregnancies.
• Device: Fluorescence-activated cell sorter.
– Looks for identifying cell surface markers.
– Then the fetal cells can be karyotyped.
Flow Cytometry
Preparing Cells for Chromosome
Observation
• 1923 – chromosome sketches published = 48
chromosomes
• Obtained cells from three castrated prisoners
in Texas.
• Since 1950, colchicine (chrysanthemum plant
extract) is used to arrest cells during division.
Science happens on accident,
sometimes…
• Problem: How to untangle
spaghetti like mass of
chromosomes.
• Mistakenly washed human
cells with a hypotonic
solution. Water rushed into
the cells, which separated
them.
Karyotyping
Old School/North Penn Method
• Taking a picture
• Cutting out the pieces and
aligning them based on size
and shape.
• Placing them in order from
largest to smallest.
New School / Research
• Device scans a ruptured cell
in a stain and selects one in
which the chromosomes are
the most visible and wide
spread.
• Image software recognizes
band patterns.
• If a strange band pattern is
recognized, a database pulls
out identical karyotypes
from other patients.
Staining
• Earlier Stains – stained chromosomes all one
color.
• 1959 – first chromosomal abnormalities
– Down Syndrome
– Turner Syndrome (Thought to once be genetic
males) – lack of barr body
– Klinefelter Syndrome (Thought to once be genetic
females) - barr body present
Staining
• 1970’s – stains that
created banding
patterns unique to
each chromosome.
– AT rich areas
– GC rich areas
– Heterochromatin
FISHing
• Fluorescence in situ
hybridization
• Uses DNA probes that
are complementary to
DNA sequences found
only on one
chromosome.
• “Paint” chromosomes
– 13, 18, & 21.
• FISH Process
Chromosomal Shorthand
• Total Number of
Chromosomes
followed by the sex
chromosome
constitution, then any
abnormal
chromosomes.
• Ex:
–
–
–
–
–
46, XY
46, XX del (7q)
47, XXY
47, XX, +21
46XY t (7;9)
Ideogram
• Indicates p
and q arms
• Delineated
by banding
patterns
• Loci of
known genes
•
•
•
•
•
•
Abnormal Chromosome Number
Polyploidy – Extra “sets” of chromosomes
Aneuploidy – An extra or missing chromosome
Deletion
Duplication
Inversion
Translocation
Polyploid
• 2/3rds of cases from
two sperm uniting with
one egg.
• Other Cases:
– Diploid gamete +
haploid gamete
• 15% of spontaneous
abortions caused by
Triploids.
Aneuploidy
• “not good set”
• Normal Chromosome
number = euploid – “good
set”
• Most autosomal aneuploids
cause spont. abortion.
• Those surviving generally
suffer mental deficiencies.
• Most survivors are trisomy,
not monosomy
CAUSE: Nondisjunction – failure
of chromosomes to separate
during meiosis.
• 49 types of aneuploids
– Missing or extra copy of each autosome = 44
– Five abnormal sex chromosome combos
• Y, X, XXX, XXY, XYY
– Only 9 types are known to appear in newborns.
• 50% of spontaneous abortions result from
missing or having extra chromosomes
– 45X, triploids, trisomy 16
– Trisomy 13, 18, 21 = common spont. abortions, but
also the most common aneuploids seen in new borns.
Polyploids and Aneuploids
Mitotic Division
• Late onset – may not have
an affect on the overall
health
• Early onset – All future
daughter cells will be
affected, thus causing more
of a chance of health risks.
Meiotic Division
• Will affect every cell in the
developing embryo.
Down Syndrome
• Most common live birth aneuploid
• Sir John Langdon Haydon Down
• Was it an abnormal chromosome number or
not?
• Other Risks:
– Leukemia
– Alzheimer’s disease
Down Syndrome
• Causes
– Nondisjunction
• 90% female
• 10% male
– Translocation
– Mosaic
• Mutation occurs after fertilization
Why is it affecting older woman
• How is meiosis different in woman compared
to men?
– Arrested development
– Hypothesis: Mechanism that can identify
aneuploid oocytes.
• Yellow starburst analogy 
Trisomy 18 – Edward Syndrome
• Most do not survive birth
• Distinct Phenotypes
– Overlapping fingers
– Unusual or absent fingerprints
• Cause:
– Nondisjunction in meiosis II of oocyte
Trisomy 13 – Patau Syndrome
• Rare
• Most striking
characteristic: Fusion of
developing eyes
• Cleft palate
• Highest development age
is 6 months! (Yet on a very
rare occasion someone
has survived to
adulthood)
Extra X syndromes
• 1 in 1,000 females are triplo-X. (47, XXX)
• Lack of symptoms
– X-inactivation
• Klinefelter’s (47,XXY)
– Underdeveloped sexual characteristics
– Long limbs – testosterone injections at
adolescents can control
XYY Syndrome
• 1965 – Patricia Jacobs published these results
– 197 high security prisoners
– 12 had abnormal chromosomes
• 7 had an extra Y
• Today – 96% of XYY are normal
– Acne
– Greater height
– Speech and Reading problems
Abnormal Chromosome Structure
• Deletions
• Cri-du-chat syndrome “cat’s
cry”
– Missing the short arm (p) of
chromosome 5
– High-pitched cry
• Y – chromosome infertility
• Duplications
– Similar to deletions – the more
likely to cause symptoms if they
are extensive.
– 15s chromosome
Cri du chat
Translocation
• Robertsonian Translocation – the short
arms (p) of two different
acrocentric chromosomes break, leaving
sticky ends that cause
two long arms to
adhere.
Translocation
• Reciprocal
Translocation – two
different chromosomes
exchange parts.
• How can FISH be used
to identify
translocation?
• Examples: Alagille
Syndrome
Inversion
• Pericentric –
Includes the
centromere in the
inversion
• Paracentric – Does
NOT include the
centromere
Dicentric Inversion
• When a loop forms during crossing over,
one chromatid will get two centromeres – a
bridge forms.
• Acentric fragment – Due to lack of
centromere, this piece is lost when the cell
divides.
Isochromosome
• A chromosome that has lost one of its arms and
has replaced it with an exact copy of the other
arm.
• Can occur if the replicated chromosomes line up
at the equator in the wrong plane.
Ring Chromosomes
CAT EYE
SYNDROME –
Ring
chromosome
#22
Uniparental Disomy
• What would happen if nondisjunction
occurred at the same chromsome within the
egg AND the sperm…
• …Then the sperm that was missing the
chromosome united with an egg that had
double the chromosomes
• “Two bodies from one parent”
Inversions