Transcript Wendy Weisz has Down syndrome.

Chromosomes
Genetics
2005
Chromosomal
Anomalies
Cytogenetics


The subdivision of genetics that
focuses on chromosomes and cell
division
Abnormal cell divisions can lead to
abnormal chromosomal numbers or
other anomalies
Chromosome anomalies
may cause phenotype
abnormalities.
Wendy Weisz has Down syndrome.
A chromosome karyotype revealed she
carries three copies of chromosome 21,
a condition called trisomy 21.
Karyotype
A chart
arranging
chromosome
pictures
according to
their size,
Chromosomes were
grouped by
named in order of their
pairs
of
size
and centromere
position.
homologs.

Anatomy of a
chromosome
Centromeres
are the largest
constriction of the chromosome
•Site of attachment of spindle
fibers
•100,000s of 171 base pair
repeat, called alpha satellite
sequences
•Centromere associated proteins
are bound
Anatomy of a
chromosome
 Telomeres are:
•At the tips of chromosomes
•Many repeats of the sequence TTAGGG
•Subtelomeres have more varied short re
Subtelomeres
The
chromosome region next to the
telomere consists of 8,000 - 300,000
bases including:
Repeats similar to the telomere
sequence
Shorter repeats
Multigene families of genes
(e.g. olfactory receptor genes)
Anatomy of a
chromosome
Chromosomes
are categorized
by the relative
location of their
centromere.
•At tip - telocentric
•Close to tip - acrocentric
•At midpoint - metacentric
•Displaced from center submetacentric
Largest,
Metacentric
Smallest
acrocentric
Sex chromosomes
XX (shown)
Metaphase chromosomes
are squashed on a slide
and stained with DNA
binding dyes.
Banding patterns help
define different
chromosomes.
Chromosome Spreads
Ideograms
Chromosome Map
P arm
Chromosome #1
Centrome
re
Q arm
An
Chromosomal
shorthand
ideogram
represents a
chromosome
schematically.
The
major banding
regions are
indicated with
numbers.
Sucrose
intolerance is
located at 3q.26
Chromosomes carry
different genes
Chromosomes differ
in size
Chromos
ome
Size in
million
bases
% of
genome
5
194
6
16
98
3
19
60
2
21
33.55
1
22
33.46
1
in situ hybridization
DNA probes labelled
with fluorescing dye
bind complementary
DNA
telomeres
centromeres
Metaphase Chromosomes
Karyotyping
Visualizing
chromosomes
 Obtain tissue from person
Fetal tissue: amniocentesis

chorionic villi
sampling

fetal cell sorting

Adult tissue: blood (white blood
cells)

cheek swab
(buccal cells)

skin cells

tissue biopsy
 Prepare cells on slide to remove rest
of cell matter
 Stain DNA with dyes or DNA probes

karyotype:
23 diploid
chromosome
 Human somatic cells contain 46
s
chromosomes:
paired homologs of
chromosomes 1 to 22 and
 sex chromosomes (XX or XY)



• Diploid refers to the
presence of two copies of each
different chromosome.
Gametes have one set of each
chromosome and are called
haploid.
Chromosome
Abnormalities
Polyploidy
Extra chromosome set
Aneuploidy
 monosomy
 trisomy
Extra
or missing
chromosome
 one chromosome absent
 one chromosome extra
Deletion
Part of a chromosome
Duplication
missing
Inversion
Part of a chromosome
Translocation
present twice
Segment of chromosome
Iso
reversed
chromosome Two chromosome arms
Ring
exchanged
chromosome in part or entirely
A chromosome with
identical arms
Chromosomal
Abbreviatioshorthand
What it means
n
46, XY
Normal male
46, XX
Normal female
45, X
Turner syndrome female
47, XXY
Klinefelter syndrome male
47, XYY
Jacobs syndrome male
46, XY del
(7q)
47, XX+21
Male missing part of long
arm of chromosome 7
Female with trisomy 21
46, XY t
Male with translocation
(7;9)
between short arm of
(p21.1;q34.1) chromosome 7 band 21.1
Polyploidy
Individuals
with
three copies of each
chromosome are
triploid.
Polyploidy
accounts
for 17% of all
spontaneous
abortions and 3% of
stillbirths/newborn
deaths.
Result
of:
Two sperm fertilize
one egg.
Aneuploidy
Cells with extra or missing
chromosomes
are aneuploid.

•Nondisjunction is a common cause of
aneuploidy resulting in a gamete with
one extra chromosome and another
gamete with one missing chromosome.
•Nondisjunction during the first
meiotic division results in a copy of
each homolog in the gamete.
•Nondisjunction during the second
meiotic division results in a both sister
chromatids in one gamete.
Nondisjunction causes aneuploidy
Nondisjunction
in meiosis I
Anaphase I
Anaphase II
Nondisjunc
in meiosis I
Gametes
Abnormal gametes
Abnormal gametes
Normal gametes
Nondisjunction in
meiosis I
Anaphase I
Homologs of
small
chromosome fail
to separate
Anaphase II
Sister
chromatids
separate
normally Gametes
trisomic
monosomic
Abnormal gametes
Nondisjunction in
meiosis
II
Anaphase
I
Homologs segregate
normally
Anaphase II
Sister
chromatids
fail to
separate Gametes
(left)
trisomic
monosomic
Abnormal gametesNormal gametes
Sex Chromosome
Aneuploidy
Situation Oocy Spe Consequence
te
Normal
Female
Nondisjun
ction
rm
X
Y
46, XY normal male
X
X
46, XX normal female
XX
Y
47, XXY Klinefelter
syndrome
XX
X
47, XXX triplo-X
Y
45, Y nonviable
X
45, X Turner syndrome
Male
Nondisjun
ction
(meiosis
I)
X
45, X Turner syndrome
X
XX
47, XXX triplo-X
Male
X
YY
47, XYY Jacobs
Turner syndrome
45, X
1 in 2,000
female births
99% of
Turner die in
utero





Absence of Y
leads to
development as
a female.
Absence of two
copies of Xlinked genes in
Relative risk of
disease among
Turner syndrome
adults
Triplo-X aneuploidy

47, XXX
1 in 1,000 female births
 Extra copy of every X-linked
gene


Few modest effects on
phenotype include tallness,
menstrual irregularities and
slight impact on intelligence

X-inactivation of two X
chromosomes occurs while
Klinefelter syndrome
47, XXY
 1 in 1,000 male births
 Extra copy of each X-linked gene
 Phenotypes include incomplete
sexual development (rudimentary
testes and prostate), long limbs,
large hands and feet, some breast
tissue development.
 Some cases are not diagnosed
until fertility problems arise or
remain undiagnosed.

XYY syndrome
47, XYY
 1 in 1,000 male births
 Extra Y chromosome




96% phenotypically normal
Modest phenotypes may include
great height, acne and minor
speech and reading problems.
Studies suggesting some increase
in aggressive behaviors remain
controversial.
Trisomies
Trisomies and
Monosomies
 One extra
or one missing chromosome
results in extra or missing copies of all
of the genes on that chromosome.

Most trisomies and monosomies produce
inviable embryos.

Some fetuses with trisomy of smaller
autosomes
trisomy survive to birth
% with
syndromic
(syndro conditions:
conceptions
me)
Incidence at
birth
13
(Patau)
1/12,500 to
1/21,700
18
1/6,000 to
(Edward
that survive
>1 year
<5%
< 5%
Down
Syndrome –
Trisomy, 21
EDWARDS
SYNDROME
Three Forms



Full form (severe) - in this every cell in the
body has three no.18 chromosomes instead
of two.
Mosaic form (less severe) - in this some
cells have two no.18 chromosomes while
others have three. The extent and severity
of the condition will depend upon the ratio
of normal to abnormal cells.
Partial form - in some cases there may be
an extra copy of part of chromosome 18.
This is referred to as partial trisomy 18.
The effects of this may be milder and
would require further medical advice.
Unusually large uterus during pregnancy
Low birth weight infant
Mental deficiency
Low-set ears
Small jaw
Clenched hands
Hypoplastic fingernails
Umbilical hernia or inguinal hernia
Diastasis recti
Cryptorchidism
Crossed legs (preferred position)
Congenital heart disease
VSD (ventricular septal defect)
ASD (atrial septal defect)
PDA (patent ductus arteriosus)
Congenital kidney abnormalities
Horseshoe kidney
Hydronephrosis
Polycystic kidney
Coloboma of iris
Microcephaly
Motormental retardation
Pectus carinatum
Ventricular Septal Defect - A hole between
the lower chambers of the heart which
prevents the heart from pumping blood
correctly; a heart murmur is generally heard
with this congenital defect.
Atrial Septal Defect - A hole between the
two upper chambers of the heart which
makes it difficult for the heart to pump
sufficient oxygen-rich blood to the bodys
tissues; a heart murmur can be heard.
Patent Ductus Arteriosus - A congenital
heart defect in which closure of a duct fails
to occur, resulting in abnormal direction of
blood flow.
Diagnosis in utero
Examination of the pregnant
woman may show
polyhydramnios. At the birth
of the child, an unusually small
placenta may be noted.
 Physical examination may show
an excess of arched type
finger print patterns. X-rays
may reveal a short breast
bone. Chromosome studies
show trisomy 18, partial
trisomy, or translocation.

Patau’s Syndrome
Living with
Chromosome 13

Josiah is diagnosed
as a Trisomy 13 with
holoprosencephaly
and a Dandy-Walker
cyst. His left eye has
a coloboma and he is
now fitted with (the
cutest little) glasses.
He has hearing aids,
a "flattened"
windpipe, and one
vocal cord is
paralyzed. His cleft
palate has not been
repaired yet, but his
lip has. A V.S.D. is in
past, and has
dextrocardia. He still
uses a G-tube, and is
just the stoutest
little thing ever. Last
but not least, he has
the cutest sixth toe
Risk of Patau’s
Syndrome
Trisomy 13 occurs in approximately 1
in 12,000 live births. In many cases,
spontaneous abortion (miscarriage)
occurs and the fetus does not
survive. The risks of trisomy 13
seem to increase with the mother's
age, particularly if she is older than
her early 30s. Male and female
children are equally affected, and
the syndrome occurs in all races.
 Patau syndrome is caused by the
presence of three copies of
chromosome 13. The presence of
these three copies---rather then
the normal two--is a random error

Segregation of a
Robertsonian
translocation
Reciprocal
Exchange
of material from one
translocation
chromosome arm to another is called
a reciprocal translocation.
Rearrangement
of the genetic
material results in an individual who
carries a translocation but is not
missing any genetic material unless a
translocation breakpoint interrupts
a gene.
Isochromosomes
Chromosomes
with identical
arms form when
centromeres
divide along the
incorrect plane
during meiosis.
Uniparent
al disomy
Inheritance
of
two chromosomes
from one parent is
called uniparental
disomy.
May
occur when
nondisjunction
occurs in both
parents (one
disomic gamete and
one without
homolog)
Loss
or
nondisjunction of
one homolog in
Chromosome
structural
abnormalities

Chromosomal deletions or
duplications result in extra or
missing copies of genes in the
involved segment.
Causes of chromosomal
abnormalities
Polyploidy Error in cell division in which all
chromatids fail to separate at
anaphase. Multiple fertilizations.
Aneuploidy Nondisjunction leading to extra or
lost chromosomes
Deletions Translocations.
and Crossover between a pericentric
duplications inversion and normal homologue
Translocatio Recombination between
n nonhomologous chromosomes
Inversion Breakage and reunion with wrong
orientation
Dicentric or Crossover between paracentric
acentric inversion and normal homologue.
fragments
Isochromoso Division of centromeres on wrong
me plane
Cri du Chat
 Cri
Du Chat Syndrome
results from the loss or
deletion of a significant
portion of the genetic
material from the short
arm of one of the pair of
number five chromosomes.
 Cri Du Chat Syndrome is
also known as 5P Minus
syndrome, Le Jeune's
 It
Cri du Chat
Incidence
is a relatively rare
genetic condition with an
estimated incidence of
between around 1:25,000
to 1:50,000 births. There
are more children being
diagnosed now that genetic
testing is carried out more
frequently and is more
accurate. In
addition, since records of
this nature are not kept in
Features of the
Disease
The gene causing the cry has
been located in band 15.3. This
would explain why some babies
with other features of the
syndrome do not have the
characteristic cry and some
babies have the cry but not
the other characteristics.
 In most cases the deletion is
spontaneous and no specific
cause can be identified. The
parents did nothing wrong to

Ring chromosomes

Chromosomes shaped like a
ring occur in 1 of 25,000
conceptions.

May arise when telomeres are
lost and sticky chromosome
end fuse.

Ring chromosomes have
phenotypes associated with
the loss or addition of genetic
material.
Ring chromosomes

By two DNA breaks, one in each arm
of the same chromosome, followed
by fusion of the proximal broken
ends. The causes of these DNA
breaks are usually unknown and so is
the mechanism behind ligation of
the ends. It is possible that the
non-homologous end-joining
machinery plays a role in this
process (Smith et al. 2001). A ring
can also be formed by fusion at two
breakpoints in the same chromosome
arm. However, only few examples of
such rings have been described.
Most probably, this is because they
are acentric and will lack
attachment point for the cell
division machinery. Unless there is a
Ring Chromosome
Formation of the
Ring
Translocation
Different
nonhomologous
chromosome exchange portions of
chromosomes.
Two
major types:
Robertsonian translocation
Two nonhomologous acrocentric
chromosomes break at the
centromere and long arms fuse. The
short arms are often lost.
5% of Down syndrome results from
a Robertsonian translocation
between chr 21 and chr 14 .
Reciprocal
translocation
Segregation of a
pericentric inversion
Segregation of a
paracentric
inversion
Chromosome
structure
abnormalities
 Larger regions of deletion or
duplication increase the
likelihood that there will be an
associated phenotype.
Inversions

Inverted chromosomes have a region
flipped in orientation compared to
wildtype chromosomes.

5-10% cause health problems probably
due to disruption of genes at the
breakpoints.

Crossing over within the inverted
segments leads to genetically
imbalanced gametes.

Two types of inversions occur:
Paracentric inverted region does
NOT include centomere
