4 - Chromosomes and Their Abnormalities

CHROMOSOMES AND
THEIR
ABNORMALITIES
Heritable traits are passed down to offspring through genes
Chromosomes
Chromosomes carry genes in a linear
sequence that is shared by members of a
species
The Asian rice (Oryza sativa) genome can be seen illustrated above. Rice
possesses up 63,000 genes divided up between 12 chromosomes.
Below is a map of part of the first chromosome showing the gene loci present on it. Although different
varieties (estimated 40,000 worldwide) will possess different alleles for genes, all individuals will share the
same twelve chromosomes and the alleles of each variety will occur at the same position on same
chromosome, i.e. at the same gene loci.
What is a Chromosome?
◦ What is a Chromosome?
CELL STRUCTURE
◦ Each cell has four common components:
1. Plasma membrane
2. Region containing DNA
3. Cytoplasm
4. Biochemical molecules &
biochemical pathways
NUCLEUS
ENDOPLASMIC
RETICULUM
RIBOSOMES
MITOCHONDRIA
HUMAN CHROMOSOMES
STRUCTURE
◦ Eucaryotic chromosomes are visible
only during cell division
◦ Types:
- Metacentric
- Submetacentric
- Acrocentric
- Telocentric
Chromosome Anatomy
Replicated
centromere
p
short arm
q
long
arm
Submetacentric Metacentric Acrocentric Telocentric

◦ Chromatin
◦ Nucleosomes
◦ Histones with wrapped DNA
◦Active (euchromatin) and non-
active (heterochromatin) chromatin
- Barr bodies
◦ Constitutive chromatin
Prokaryotes have one chromosome consisting of a circular DNA molecule
Some prokaryotes also have plasmids but eukaryotes do not
Prokaryotes have two types of DNA:
• single chromosome
• plasmids
The single prokaryotic chromosome is coiled up

and concentrated in the nucleoid region
Because there is only a single chromosome there
is only one copy of each gene
A copy of the chromosome is made just

before cell division (by binary fission)
Some prokaryotes also have plasmids but eukaryotes do not
Prokaryote bacteria may have plasmids, but these structures are not found in
eukaryotes.*
Features of Plasmids:
• Naked DNA - not associated with histone
proteins
• Small circular rings of DNA
• Not responsible for normal life processes –
these are controlled by the nucleoid chromosome
• Commonly contain survival characteristics, e.g. antibiotic resistance
• Can be passed between Prokaryotes
• Can be incorporated into the nucleoid chromosome
n.b. Plasmid characteristics mean that Scientists have

found them useful in genetic engineering
Plasmids can be used to transfer genes into bacteria
*Scientists have found plasmids in archea and eukaryota, but very rarely
Cairns’ technique for measuring the length of DNA molecules by autoradiography
Nature of Science: Developments in research follow improvements in techniques - autoradiography was
used to establish the length of DNA molecules in chromosomes
John Cairns produced images of DNA molecules from Escherichia coli (E.coli)
• E. coli was grown with thymine containing a radioactive
isotope of hydrogen (the DNA was labelled)
• The E. coli cells were broken by enzymes to release the
cell contents
• The cell contents were applied to a photographic
emulsion and placed in the dark (for two months)
• The radioactive isotopes reacted with the emulsion
(similarly to light does)
• Dark areas on the photographic emulsion indicated the
presence of DNA
• The images showed that E. coli possesses a single
circular chromosome which is 1,100 μm long (E. coli
cells have a length of only 2 μm)
• Cairns images also provided evidence to support the Cairn's Technique
theory of semi-conservative replication
n.b. The insights and improvements in theory would not have been possible without the
development and use of autoradiography (exposure of photographic emulsion by
radioactive isotopes)
Eukaryote chromosomes are linear DNA molecules associated with histone proteins
Linear strands of DNA held in a helix
Eukaryotic chromosomes may be up to 85mm in

length
To fit such a length of DNA into a nucleus with a
diameter of 10 μm it has to be coiled in a
predictable fashion that still allows for processes,
such as replication and protein synthesis, to
occur
Nucleosomes are formed by wrapping DNA
around histone proteins
n.b. Prokaryotic DNA is, like eukaryotic DNA, supercoiled, but

differently: Prokaryotic DNA may be associated with
proteins, but it is not organised by histones and is therefore
sometimes referred as being ‘naked’.
http://en.wikipedia.org/wiki/File:DNA_to_Chromatin_Formation.jpg
In a eukaryote species there are different chromosomes that carry different genes
Eukaryotes possess multiple chromosomes

All individuals of a species possess the same
chromosomes, with the same gene loci
-- all humans have 23 pairs
Chromosomes can vary by:
• Length – the number of base pairs in the DNA molecule
• Position of the centromere
• Genes occur at a specific locus (location), i.e. it is always
found at the same position on the same chromosome (the
locus and genes possessed vary between species)
https://public.ornl.gov/site/gallery/originals/
Use of databases to identify the locus of a human gene and its polypeptide product
Use the online database (http://www.genecards.org/) to search for the genes

and the loci responsible for synthesizing the following polypeptides:
• Rhodopsin
• 3 different types of Collagen
• Insulin
• One other protein of your choice
The number of chromosomes is a characteristic feature of members of a species
The chromosome number is an important characteristic of the species
Organisms with different numbers of

chromosomes are unlikely to be able to
interbreed successfully
Chromosomes can fuse or split during

evolution – these are rare events and
chromosome numbers tend to stay the
same for millions of years
The number of chromosomes possessed by a

species is known as the N number, for example
humans have 23 different chromosomes
https://commons.wikimedia.org/wiki/File:NHGRI_human_male_karyotype.png
Diploid nuclei have pairs of homologous chromosomes
Haploid nuclei have one chromosome of each pair
A diploid nucleus has two of each chromosome (2N)

Therefore, diploid nuclei have two copies of every gene, apart from the genes on the sex chromosomes
For example, the diploid nuclei in humans contain 46 chromosomes
The fertilized egg cell (zygote)

therefore is a diploid (2N) cell
containing two of each
chromosome
Gametes are the sex cells that fuse

together during sexual reproduction
Gametes have haploid nuclei, so in A haploid nucleus has one of
humans both egg and sperm cells each chromosome (N)
contain 23 chromosomes Haploid nuclei in humans have 23
different chromosomes
n.b. Diploid nuclei are less susceptible to genetic diseases: have two copies of a
gene means organisms are more likely to possess at least one healthy copy
http://www.biologycorner.com/resources/diploid_life_cycle.gif
Comparison of diploid chromosome numbers of Homo sapiens, Pan troglodytes, Canis familiaris, Oryza
sativa, Parascaris equorum
Humans (Homo sapiens) 46
46 is the number of diploid

chromosomes in each human cell
https://upload.wikimedia.org/wikipedia/commons/f/f6/Usain_Bolt_100_m_Daegu_2011.jpg
sativa, Parascaris equorum
Asian rice (Oryza sativa)
Equine roundworm (Parascaris equorum)
http://pic20.picturetrail.com/VOL176/4853602/20795519/357799225.jpg
How many diploid
chromosomes does each
species possess?
https://commons.wikimedia.org/wiki/File:Hinohikari.jpg
Domestic Dog (Canis familiaris)
Chimpanzee (Pan troglodytes)

https://commons.wikimedia.org/wiki/File:Dog_%28Canis_lupus_fa https://commons.wikimedia.org/wiki/File:Pan_troglodytes_Sweetwaters_Chim
miliaris%29_%281%29.jpg panzee_Sanctuary,_Kenya.jpg
sativa, Parascaris equorum.
Asian rice (Oryza sativa) 24
2 Equine roundworm (Parascaris equorum)
http://pic20.picturetrail.com/VOL176/4853602/20795519/357799225.jpg
How many diploid
chromosomes does each
species possess?
https://commons.wikimedia.org/wiki/File:Hinohikari.jpg
Domestic Dog (Canis familiaris) 78
48 Chimpanzee (Pan troglodytes)

https://commons.wikimedia.org/wiki/File:Dog_%28Canis_lupus_fa https://commons.wikimedia.org/wiki/File:Pan_troglodytes_Sweetwaters_Chim
miliaris%29_%281%29.jpg panzee_Sanctuary,_Kenya.jpg
Homologous chromosomes carry the same sequence of genes but not necessarily the same alleles of
those genes
Sex is determined by sex chromosomes and autosomes are chromosomes that do not determine sex
Sex Determination: It’s all about X and Y…

Humans have 23 pairs of chromosomes in
diploid somatic cells (n=2)
22 pairs of these are autosomes, which are

homologous pairs
One pair is the sex chromosomes

XX gives the female gender, XY gives male
Karyotype of a human male, showing X and Y chromosomes:

http://en.wikipedia.org/wiki/Karyotype
SRY
The X chromosome is much larger than the Y
X carries many genes in the non-homologous
region which are not present on Y
The presence and expression of the SRY gene on

Y leads to male development
Chromosome images from Wikipedia:

http://en.wikipedia.org/wiki/Y_chromosome
Sex is determined by sex chromosomes and autosomes are chromosomes that do not determine sex.
Chromosome pairs segregate in meiosis
Females (XX) produce only eggs containing the X

chromosome
Males (XY) produce sperm which can contain

either X or Y chromosomes
Segregation of the sex chromosomes in meiosis.

SRY gene determines maleness.
gametes X Y
X XX XY
X XX XY
Therefore, there is an even chance*
of the offspring being male or female
Comparison of genome size in T2 phage, Escherichia coli, Drosophila melanogaster, Homo
sapiens and Paris japonica
Humans (Homo sapiens)
3.2 billion base pairs
Genome size is the total number of

DNA base pairs in one copy of a
haploid genome
https://upload.wikimedia.org/wikipedia/commons/f/f6/Usain_Bolt_100_m_Daegu_2011.jpg
sapiens and Paris japonica
T2 phage
Canopy plant (Paris japonica)
Escherichia coli
https://s-media-cache-ak0.pinimg.com/736x/2d/0e/3e/2d0e3ea8d
df652f25a5f2c3b1050af79.jpg
n.b. T2 phage (orange) is a virus that attacks E. Coli

bacterium (green and white).
What is the genome size of

each species?
Fruit fly (Drosophila melanogaster)
https://commons.wikimedia.org/wiki/File:Dr
osophila_melanogaster_-_side_%28aka%29.j
pg
https://commons.wikimedia.org/wiki/File:Paris_japonica_Kinugasasou_in_Hakusan_2003_7_27.jpg
sapiens and Paris japonica.
T2 phage
Canopy plant (Paris japonica)
164 thousand base pairs
150 billion base pairs
Escherichia coli
4.6 million base pairs
https://s-media-cache-ak0.pinimg.com/736x/2d/0e/3e/2d0e3ea8d
df652f25a5f2c3b1050af79.jpg
n.b. T2 phage (orange) is a virus that attacks E. Coli

bacterium (green and white).
What is the genome size of

each species?
Fruit fly (Drosophila melanogaster)
https://commons.wikimedia.org/wiki/File:Dr
140 million base pairs
osophila_melanogaster_-_side_%28aka%29.j
pg
https://commons.wikimedia.org/wiki/File:Paris_japonica_Kinugasasou_in_Hakusan_2003_7_27.jpg
A karyogram shows the chromosomes of an organism in homologous pairs of decreasing length
Karyogram is a diagram or photograph of the chromosomes present in a nucleus (of

a eukaryote cell) arranged in homologous pairs of decreasing length.
The chromosomes are visible in cells that are undergoing

mitosis – most clearly in metaphase
Stains used to make the chromosomes visible also give each

chromosome a distinctive banding pattern
A micrograph are taken, and the chromosomes are arranged according to their
size, shape and banding pattern
They are arranged by size, starting with the longest pair and ending with the
smallest
https://commons.wikimedia.org/wiki/File:NHGRI_human_male_karyotype.png
A karyogram shows the chromosomes of an organism in homologous pairs of decreasing length
Karyotype is a property of the cell described by the number and type of

chromosomes present in the nucleus (of a eukaryote cell)
a Karyogram is a diagram
that shows, or can be used to
determine, the karyotype
http://learn.genetics.utah.edu/content/chromosomes/karyotype/
Description of methods used to obtain cells for karyotype analysis e.g. chorionic villus sampling and amniocentesis and the
associated risks
Studies showing age of parents influences chances of non-disjunction
The risk of a child having a
trisomy such as Down
Syndrome increases greatly in
older mothers
It is often advisable for

mothers in a high-risk
category to choose to have a
prenatal (before birth) test
Amniocentesis or chorionic
villus samples can be taken
and from them a karyotype
can be constructed
Data from a positive test can

be used to decide the best
course of action, which at
times be to abort the fetus
https://commons.wikimedia.org/wiki/File:Down_Syndrome_Risk_By_Age.png
Description of methods used to obtain cells for karyotype analysis e.g. chorionic villus sampling and
amniocentesis and the associated risks
amniocentesis and the associated risks.
Can be carried out in the 16th week of the pregnancy with around
a 1% chance of a miscarriage
http://www.medindia.net/animation/amniocentesis.asp
amniocentesis and the associated risks.
Can be carried out in the 11th week of the

pregnancy with around a 2% chance of a
miscarriage
These tests may be necessary in pregnant
women:
◦ A high-risk screening result from a screening test ( FTS / Quadruple /Triple
Test) for genetic disorders
◦ Advanced maternal age
◦ Family or previous pregnancy history of a genetic disorder
◦ Found fetal structural abnormality
The test
◦ Amniocentesis is a procedure in which a small amount of the amniotic fluid
surrounding the baby in the womb is removed by passing a fine needle through
the mother’s abdomen
◦ Amniocentesis is performed after 15 weeks of pregnancy
◦ CVS is a procedure in which a small number of fetal tissues from the placenta in
the womb is removed by passing a fine needle through the mother’s abdomen
◦ CVS is performed at 11-13 weeks of pregnancy
The risk
◦ Most women say that having amniocentesis / CVS is uncomfortable rather than painful, a bit
like a period pain
◦ a sharp stinging feeling when the needle goes in and a feeling of pressure when the needle comes out
◦ Cramping for a few hours afterwards -- This is normal.
◦ Experience of any unusual symptoms after the test, such as feeling shivery (as if you have flu),
fluid loss, bleeding or contractions requires advice immediately
◦ Every pregnancy carries a risk of miscarriage
◦ Amniocentesis / CVS involves putting a needle through the wall of the womb. It may sometimes
cause a miscarriage due to injury or infection in the womb
◦ The additional overall risk of miscarriage is approximately 1%
The Interpretation
◦ For most women the laboratory test will give a definite ‘yes’ or ‘no’ answer
◦ Many women who have amniocentesis / CVS will have a ‘normal’ result -- their baby will be
born without the disorder(s) the test was looking for
◦ Some women will be informed that the baby has the disorder that the test was looking for
◦ If the results are abnormal, these will be discussed fully
◦ For the majority of disorders, there is no treatment or cure so there are options to be
considered:
◦ 1. Terminate this pregnancy
◦ 2. Or continue with the pregnancy and use the information you have gained to help prepare for the
birth and aftercare of baby
Both Amniocentesis and CVS are outpatient
procedures and will not need admission
◦ In Amniocentesis, using an ultrasound probe for accurate guidance and to ensure a safe
distance from the baby, a fine needle is pushed into skin, through abdomen and womb, under a
local anesthetic
◦ A small sample (15-20 ml) of the fluid surrounding the baby is removed using a syringe
◦ This fluid is amber/yellow color but may sometimes be stained with blood
◦ The needle is then taken out and the baby’s heartbeat is checked on ultrasound
◦ The amniotic fluid, which contains some of the baby’s cells, is sent to the laboratory for
testing
The Procedure
◦ In CVS, a small amount of placental sample (Chorionic Villi) is removed using a syringe more
or less in the same way
◦ For a very small group women having Amniocentesis/CVS, not enough fluid/ chorionic tissues
can be taken and the needle may need to be re-inserted
◦ If blood group is Rh negative, the patient will be advised to have an injection of anti-D
immunoglobulin after the procedure to prevent from developing antibodies against the baby’s
blood cells
◦ After the procedure, the rest is required for at least half an hour before going home
Use of karyogram to deduce sex and diagnose Down syndrome in humans
Can you use a karyogram to determine sex and whether a person has Down
Syndrome?
Use the Biology Project activity to practice

your skills and understanding:
http://www.biology.arizona.edu/human_bio/activities/karyotypin
g/karyotyping.html
http://learn.genetics.utah.edu/content/disorders/chromosomal/down/
CHROMOSOMAL
DISORDERS
NONDISJUNCTION
AND AUTOSOMAL
POLYPLOIDY
Chromosomal mutation – change in the
structure or number of chromosomes arising
spontaneously or under the influence of
mutagenic agents (eg ionizing radiation,
ultraviolet radiation, high temperature)
CHROMOSOMAL Numerical
ABERRATIONS
Structural
Chromosomal Disorders Come in 2 Forms
1.0
O
Incidence among newborns (%)
v
e 1/154 40–50% of spontaneous abortions have
r chromosomal abnormalities
0.5 a
l 1/263
1/375
l 1/500
0.25 1/475
1/700
i 1/1600
0 n
c
All chromosomal Total X and Y Total Balanced Unbalanced
abnormalities
i Autosomes chromosomes
d
e
n Aneuploidy Structural
c Abnormalities
e
◦ Rearrangement: Bcr-Abl - chronic myeloid leukemia
◦ Rearrangement: Alk – lung cancer

◦ Different number of chromosomes comes from errors during meiosis
◦ Gametes with incorrect number of chromosomes produce organism with same
number of incorrect genetic material in all cells
◦ Improper mitosis results in somatic cells with different karyotypes within one
organism – a mosaic
◦ Ploidy – multiplication of genetic material: 23-haploid, 46-diploid, 69-triploid

etc.
◦ Polyploidization produces offspring that has the potential to be distinctly different
from both of its parents
◦ These changes mostly concern plant evolution
◦ Aneuploidy – multiplication or deletion of one or more chromosomes:

- Monosomy
- Disomy
- Trisomy
◦ Most ploids are spontaneously aborted
◦ There are different diseases connected with aneuploids in humans
Aneuploidy
◦ Aneuploidy is the presence of an abnormal number of
chromosomes in a cell, for example a human cell having 45 or 47
chromosomes instead of the usual 46
Aneuploidies Result from Nondisjunction
MEIOSIS
I Nondisjunction
MEIOSIS II
Nondisjunction
FERTILIZATION
aneuploid
ANEUPLOIDY – DISEASES
Chromosome Number Appearance
Autosomy
Edwards syndrome 18 1:5000
Pateau syndrome 13 1:5000
Down syndrome 21 1:750
Sex chromosome
Turner syndrome XO 1:10000
Klinefelter syndrome XXY 1:2000
Triple X chromosome syndrome XXX 1:2000
RISK OF
ANEUPLOIDY
DEPENDING
ON AGE
POLYPLOIDITY AND
EVOLUTION
◦ Autopolyploid – all genomes are identical or very similar and arise via genome duplication
within the same species
- Triploids are usually sterile – salmon / bananas
◦ Allopolyploid – contain two or more distinct genomes, and can arise via hybridization of two
different species concomitant with genome doubling
◦ Segmental allopolyploid – carry more than two partially differentiated genomes, which can
lead to the formation of both bivalents and multivalent during chromosome pairing
Only 3 Autosomal Polyploidies Are Viable
Down Syndrome Edward syndrome Patau Syndrome

(Trisomy 21) (Trisomy 18) (Trisomy 13)
Trisomy 21 – Down Syndrome
Karyotype from a male patient with Down syndrome, showing 3 copies of chromosome 21
Trisomy 21 – Fluorescence in Situ Hybridization Analysis
Chromosome 21
Chromosome 21
Chromosome 21
Trisomy 21 – Whole Genome Chromosomal Microarray
Trisomy 21 – Whole Genome Sequencing
Trisomy 21 – Statistics
.1
2
• 1 in 850 children .1 At amniocentesis
are born with Down 1 At birth
Syndrome .1
Frequency of Down syndrome

0
• Much higher .09
incidence in .08
mothers over 35 .07
.05
.06
.04
• Only approximately
20% to 25% of .03
trisomy 21 .02
conceptuses .0
survive to birth. 1
0
0 20 25 30 35 40 45 50
Maternal age (years)
Trisomy 21 – Statistics
.1
2
• 1 in 850 children .1 At amniocentesis
are born with Down 1 At birth
Syndrome .1
Frequency of Down syndrome

0
• Much higher .09
incidence in .08
mothers over 35 .07
.05
.06
.04
• Only approximately
20% to 25% of .03
trisomy 21 .02
conceptions survive .0
until birth 1
0
0 20 25 30 35 40 45 50
Maternal age (years)
Trisomy 21 – Clinical
Diagnosis
Sparse hair Eyes
• Short, sparse lashes
• Brushfield spots Developmental
Small head delays of varying
with flat face degrees
Small, low-set ears
Hypotonic muscles
Dental anomalies,
arched palate,
protruding tongue
Broad, short
neck
Trisomy 21 – Clinical Diagnosis
Variations on Down Syndrome – Chromosomal Mosaicism
2% of Down syndrome patients are mosaic for trisomy 21.

Mosaicism
◦ Mosaicism occurs when a person has two or more genetically
different sets of cells in his or her body
◦ If those abnormal cells begin to outnumber the normal cells, it
can lead to disease that can be traced from the cellular level to
affected tissue, like skin, the brain, or other organs
Variations on Down Syndrome – Robertsonian Translocation
Lost short
arms
2 acrocentric Robertsonian
chromosomes translocation
4% of Down syndrome patients have 45 or 46 chromosomes

Robertsonian translocation
◦ Robertsonian translocation (ROB) is a chromosomal
abnormality wherein a certain type of a chromosome becomes
attached to another
◦ It is the most common form of chromosomal translocation in
humans, affecting 1 out of every 1,000 babies born
Variations on Down Syndrome – Partial Trisomy
Only 3 Autosomal Polyploidies Are Viable
Edward and Patau

Syndrome are much
less common and
have much more
deleterious effects
Down Syndrome Edward Syndrome Patau Syndrome

(Trisomy 21) (Trisomy 18) (Trisomy 13)
Structural abnormalities
◦ Structural abnormalities are when part of an individual chromosome is missing,
extra, switched to another chromosome, or turned upside down
◦ Deletion - loss of the chromosome segment
◦ Deficiency - loss of the final segment of the chromosome
◦ Inversion - inversion of the chromosome fragment by 180 degrees
amplification of the chromosome segment
◦ Duplication - doubling the sections between nonhomogeneous chromosomes
◦ Translocation - separation of the chromosome arm
◦ Centromere crack - the chromosome arms combine to form a ring
◦ usually accompanied by the deletion of fragments located at the ends of the chromosome
◦ Chromosomal abnormalities can occur as an accident when the egg or the sperm
is formed or during the early developmental stages of the fetus
Structural Abnormalities Can Arise in Several Ways
Duplication Deletions Translocations

s
Results in haploinsufficiency or overexpression of one or more genes encoded in that region

Haploinsufficiency
◦ Haploinsufficiency in genetics describes a model of dominant
gene action in diploid organisms, in which a single copy of the
wild-type allele at a locus in heterozygous combination with a
variant allele is insufficient to produce the wild-type phenotype
◦ Haploinsufficiency may arise from a de novo or inherited loss-
of-function mutation in the variant allele, such that it yields little
or no gene product (often a protein)
Cri-du-chat Syndrome (5p Deletion Syndrome)
0
15.3
15.2
Speech 15.1
Cat cry 14
13.3
Mental retardation 13.2
Facial phenotype 10 13.
• Called Crie-du-chat due to the typical 1
Mental retardation
cat-like cry of affected children
• Terminal or interstitial deletion of the 20
short arm of chromosome 5 (5p)

Mental retardation
• Highly variable break points mean 30

variable expression
40
Cri-du-chat Syndrome (5p Deletion Syndrome)
0
15.3
15.2
Speech 15.1
Cat cry 14
13.3
Mental retardation 13.2
Facial phenotype 10 13.
1
Mental retardation
• Symptoms due to haploinsufficiency 20
• 90% due to de novo mutation Mental retardation
30
40
Cri-du-chat Syndrome
Hypertelorism – increased distance between two body parts

Epicanthus – skin fold covering the medial angle of the eye

Retrognathia
Retrognathia – used to describe an unusual position of the mandible

Retro implies that there is deficient growth and 'gnathia' means about the jaws (particularly
mandible)
This individual with cri-du-chat syndrome is shown at 2, 4, 9, and 12 years of age

Translocations
• Quadrivalent formation
is necessary to align
homologous segments
during meiosis I
• Formation of balanced or
unbalanced gametes
Balanced Translocations
• 1 in 2000 newborns
• Generally no obvious
phenotypic effect
• Some involve direct

disruption of a gene
Segregation of Chromosomes with Inversions
Paracentric Pericentric
Segregation of inversions is generally uneventful
Recombination within the inverted segment can result in unbalanced gametes

Autosomal Disorders Associated with Genomic
Imprinting
Prader- Angelman‘s
Willi syndrome
syndrome
Both result from microdeletions on chromosome 15

Genomic imprinting
Genomic imprinting is the process by which only one copy of a gene in
an individual (either from their mother or their father) is expressed,
while the other copy is suppressed
Unlike genomic mutations that can affect the ability of inherited genes to be
expressed, genomic imprinting does not affect the DNA sequence itself
Instead, gene expression is silenced by the epigenetic addition of chemical
tags to the DNA during egg or sperm formation
Epigenetic tags on imprinted genes usually stay in place

for the life of the individual
Genomic imprinting
◦ Genomic imprinting is an epigenetic phenomenon that causes
genes to be expressed or not, depending on whether they are
inherited from the mother or the father
◦ Genes can also be partially imprinted  Partial imprinting
occurs when alleles from both parents are differently expressed
rather than complete expression and complete suppression of one
parent's allele
Autosomal Disorders Associated with Genomic Imprinting
• Genes are expressed in a parent of

origin specific manner
Autosomal Disorders Associated with Genomic Imprinting
Chromosome 15 contains a genomically imprinted region
Genes are expressed only on the paternal (blue) and maternal (pink) chromosomes
Each region is hypermethylated (imprinted/ turned-off) on the opposing chromosome
Thus, a deletion in the expressed region results in PWS or AS
Prader-Willi Syndrome
Prader-Willi Syndrome results from a microdeletion of
paternal chromosome 15
1 in 15,000 live births
Paternal
Chromosom
e
Maternal
Chromosom
e
Paternal
Chromosom
e
Maternal
Chromosom Imprinted Region
e
Paternal
Chromosom Microdeletion
e
Maternal
e
Paternal
e
Maternal
e
No PWS Gene
expression = PWS
Major Phenotypic Features
• Age of onset: Infancy
• Infantile feeding difficulties
• Childhood hyperphagia and

obesity
• Hypotonia
• Cognitive impairment
• Short stature
• Dysmorphism
Angelman Syndrome
Angelman Syndrome results from a microdeletion in
maternal chromosome 15
Paternal
Chromosom
e Imprinted
region
Maternal
e
No AS gene
expression = AS
Angelman Syndrome
Major Phenotypic Features
• Microcephaly
• Short stature
• Seizures
• Minimal speech
• Frequent smiling and laughing
• Developmental delays
• Severe intellectual disabilities
• Widely spaced teeth

Genomic Mechanisms of Prader-Willi and Angelman Syndromes
Mechanism Prader-Willi syndrome Angelman syndrome
15q11.2–q13 deletion 70% 70%

(paternal) (maternal)
Uniparental disomy 20–30% 7%

(maternal) (paternal)
Uniparental Disomy
Nondisjunction
Meiosis I Non-
disjunction
Meiosis II
Paternal ejected to Normal

rescue trisomy
Heterodisomy Isodisom
y
Uniparental disomy (UPD)
◦ Occurs when a person receives two copies of a chromosome, or part of a chromosome, from one parent and no
copies from the other parent. UPD can occur as a random event during the formation of egg or sperm cells or
may happen in early fetal development
◦ In many cases, UPD likely has no effect on health or development
◦ Because most genes are not imprinted, it doesn’t matter if a person inherits both copies from one parent instead
of one copy from each parent. In some cases, however, it does make a difference whether a gene is inherited
from a person’s mother or father
◦ A person with UPD may lack any active copies of essential genes that undergo genomic imprinting  This loss
of gene function can lead to delayed development, intellectual disability, or other health problems
Single-gene Disorders
Pedigrees and Autosomal Patterns of
Inheritance
Single-gene Disorders
Victor A. McKusick’s
Mendelian inheritance in man

A classic that lists all known
single-gene disorders
Single gene disorders
◦ Single gene disorders are caused by DNA changes in one
particular gene, and often have predictable inheritance patterns
A Terminology Recap
The haplotype is A–B.
• Homologs
The locus 1
• Locus/loci genotype is
Aa.
• Heterozygous/homozygous
• Compound heterozygote
• This individual is
Genotype
heterozygous at
both locus A
• Haplotype and locus B.
• Phenotype
Compound heterozygote: 2 different mutant alleles, rather
than 1 wild-type and one mutant allele
A Concept Recap: Pleiotropy
Blindness
Beta globin
gene mutation
(sickle cell
anemia) Pleiotropy
Liver failure
Multiple traits
Heart attack
Single gene
Pleiotropy
◦ Pleiotropy refers to the phenomenon in which a single locus
affects two or more apparently unrelated phenotypic traits and is
often identified as a single mutation that affects two or more
wild-type traits
A Concept Recap: Penetrance vs. Expressivity
BB x bb
Bb
Variable Variable Variable penetrance

penetrance expressivity and expressivity
Penetrance and expressivity
◦ Penetrance is the percentage of animals of a specific genotype
who express the phenotype associated with that underlying
genotype
◦ Expressivity refers to the degree that a particular genotype is

expressed as a phenotype within an individual
The Pedigree: A Graphical Representation of the Family
Tree
The Pedigree –
a Graphical
Representation of
the Family Tree
Patterns of Inheritance are Dependent Upon
• Autosome
• Sex chromosome
• Mitochondrial
• Dominant
• Recessive
Autosomal Recessive Inheritance
Carrier father Carrier mother
Autosomal recessive disease
occurs in individuals with 2
mutant alleles and no wild-
type allele
Loss-of-function
Mutations
Compensation
Mutant allele
Wild-type allele Unaffected Carrier Carrier son Affected

son daughter daughter
3 Types of Mating Leads to Affected
Offspring
Carrier by affected Parent 2 genotype Risk for disease
R/r gametes
R r
¼
Parent 1 unaffected
genotype R R/R R/r (R/R), ½
R/r unaffected
gametes carriers
(R/r), ¼
affected
r R/r r/r (r/r)
3 Types of Mating Leads to Affected Offspring
r/r gametes
r r
Parent 1 ½
genotype R R/r R/r unaffected
R/r carriers
gametes (R/r),
½ affected
(r/r)
r r/r r/r
Offspring
r/r gametes
r r
Parent 1
genotype r r/r r/r All
r/r affected
gametes (r/r)
r r/r r/r
A Typical Autosomal Recessive Pedigree
Parents are carriers, apparent generation skip
About 1 in 4 offspring is affected

Male and female are affected equally
Cystic Fibrosis – a Relatively Common Autosomal Recessive
Disorder
Normal CFTR channel moves chloride Mutant CFTR channel does not move
ions to the outside of the cell chloride ions, causing sticky mucus to
build up on the outside of the cell
Outside cell Mucus
Inside cell
Chloride ions
1 child in 2.000 has CFTR mutation

1 in 23 people are silent carriers
On Occasion, Autosomal Recessive Disorders Are Sex-
influenced
Hereditary hemochromatosis is 5–10x more likely in males than females
Symptoms
• Enhanced absorption of dietary iron
• Causes iron overload
• Serious damage to the heart, liver, and pancreas
Affected Individuals Are Generally Compound
Heterozygotes
Alleles for recessive disorders are

uncommon so an affected individual is
usually a compound heterozygote
rather than being truly homozygous.
The exception is in consanguinity

Some Autosomal Recessive Disorders
• Sickle cell anemia
• Cystic fibrosis
• Albinism
• Phenylketonuria (PKU)
• Tay-Sachs disease
(hexosaminidase A deficiency)
• Hemochromatosis
• Glycogen storage deficiency

• Cystic fibrosis
• Albinism
• Hemochromatosis

Some Autosomal Recessive
Disorders
• Cystic fibrosis
• Albinism
• Hemochromatosis

• Cystic fibrosis
• Albinism _ _
• Phenylketonuria (PKU) + 3
O2 H2O + 3
tetrahydro- dihydro-
• Tay-Sachs disease Phenylalanin biopterin biopterin Tyrosin
(hexosaminidase A deficiency) e e
• Hemochromatosis

• Cystic fibrosis
• Albinism
• Hemochromatosis

Some Autosomal Recessive
Disorders
• Cystic fibrosis
• Albinism
• Hemochromatosis

• Cystic fibrosis
• Albinism
• Hemochromatosis

HINT:
Almost all diseases that show

up in childhood are AR
So think about learning the

shorter list of X-linked
recessive
Autosomal Dominant Inheritance
Heterozygote (affected) father Heterozygote (affected) mother
Mutant allele
Wild-type allele Unaffected Affected Affected Affected
son daughter son daughter
Autosomal dominant disease occurs in any individual that carries 1 deleterious allele.
Offspring
d/d gametes
d d
Parent 1
genotype D D/d D/d
½ affected (D/d), ½
D/d
unaffected (d/d)
gametes
d d/d d/d
Offspring
D/d gametes
D d
Strictly dominant
Parent 1 ¾ affected (D/D and D/d),
genotype D D/D D/d ¼ unaffected (d/d)
D/d Incompletely dominant
gametes ¼ severely affected
(D/D),
½ affected (D/d), ¼
d D/d d/d unaffected (d/d)
• Dominant conditions have a higher
incidence
• Polycystic kidney disease

occurs in 1 in 1,000 individuals in
the United States
• The incidence of familial

hypercholesterolemia is 1 in
100 for afrikaner populations in
South Africa
• Dominant conditions have a higher
incidence
• Polycystic kidney disease

occurs in 1 in 1,000 individuals in
the United States
• The incidence of familial

hypercholesterolemia is 1 in
100 for african populations in
South Africa
Pure Dominant Inheritance
Huntington’s disease exhibits pure dominant inheritance

Incompletely Dominant Inheritance
• Achondroplasia is an
incompletely dominant
skeletal disorder
• Short-limbed dwarfism
• Large head
• Mutations in the
fibroblast growth factor
receptor (FGFR3) gene
Incompletely Dominant Inheritance
• Achondroplasia is an
incompletely dominant
skeletal disorder
• Short-limbed dwarfism Parents were

heterozygous and
• Large head had much less
severe symptoms
• Mutations in the
The deceased
fibroblast growth factor
child was
receptor (FGFR3) gene
homozygous
Inheritance Can Also be Sex Limited in Dominant Disorders
In male-limited precocious puberty, boys develop secondary sexual
characteristics. They undergo an adolescent growth spurt around 4 years old
Male-to-male transmission Transmission through carrier

shows that inheritance is females shows that inheritance
autosomal, not X-linked cannot be Y-linked
Understanding Inheritance Can Get Complicated
• Incomplete penetrance and

variable expressivity can
interfere with understanding the
inheritance of certain diseases
• Factors that must be taken into

account in genetic counseling Failure of penetrance
in mother and sister
Split-hand
deformity
Some Autosomal Dominant Disorders
• Familial Hypercholesterolemia
(LDL receptor deficiency)
• Huntington's disease
• Neurofibromatosis – 1
• Osteogenesis imperfecta
• Acute intermittent porphyria
• Adult polycystic kidney disease

Xanthomas, seen here on the knuckles, are often seen in patients with familial
hypercholesterolemia




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CHROMOSOMES AND

Submetacentric Metacentric Acrocentric Telocentric

The single prokaryotic chromosome is coiled up

A copy of the chromosome is made just

n.b. Plasmid characteristics mean that Scientists have

Eukaryotic chromosomes may be up to 85mm in

n.b. Prokaryotic DNA is, like eukaryotic DNA, supercoiled, but

Eukaryotes possess multiple chromosomes

Use the online database (http://www.genecards.org/) to search for the genes

The chromosome number is an important characteristic of the species

Organisms with different numbers of

Chromosomes can fuse or split during

The number of chromosomes possessed by a

A diploid nucleus has two of each chromosome (2N)

The fertilized egg cell (zygote)

Gametes are the sex cells that fuse

Humans (Homo sapiens) 46

46 is the number of diploid

Asian rice (Oryza sativa)

Equine roundworm (Parascaris equorum)

Domestic Dog (Canis familiaris)

Chimpanzee (Pan troglodytes)

Asian rice (Oryza sativa) 24

2 Equine roundworm (Parascaris equorum)

Domestic Dog (Canis familiaris) 78

48 Chimpanzee (Pan troglodytes)

Sex Determination: It’s all about X and Y…

22 pairs of these are autosomes, which are

One pair is the sex chromosomes

Karyotype of a human male, showing X and Y chromosomes:

The presence and expression of the SRY gene on

Chromosome images from Wikipedia:

Chromosome pairs segregate in meiosis

Females (XX) produce only eggs containing the X

Males (XY) produce sperm which can contain

Segregation of the sex chromosomes in meiosis.

Humans (Homo sapiens)

3.2 billion base pairs

Genome size is the total number of

n.b. T2 phage (orange) is a virus that attacks E. Coli

What is the genome size of

Fruit fly (Drosophila melanogaster)

n.b. T2 phage (orange) is a virus that attacks E. Coli

What is the genome size of

Fruit fly (Drosophila melanogaster)

Karyogram is a diagram or photograph of the chromosomes present in a nucleus (of

The chromosomes are visible in cells that are undergoing

Stains used to make the chromosomes visible also give each

Karyotype is a property of the cell described by the number and type of

It is often advisable for

Data from a positive test can

Can be carried out in the 11th week of the

Use the Biology Project activity to practice

◦ Rearrangement: Alk – lung cancer

◦ Ploidy – multiplication of genetic material: 23-haploid, 46-diploid, 69-triploid

◦ Aneuploidy – multiplication or deletion of one or more chromosomes:

Down Syndrome Edward syndrome Patau Syndrome