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Learning Objective
• Chromosome and chromosomal abnormalities
FUNDAMENTAL MEDICAL SCIENCE 1 • Principles of Inheritance in Genetics in Medicine
• The cause and inheritance of genetic disorder
Genetics in Medicine • Clinical Genetics
• Trend in Genetics in Medicine

Lecturer : Ivet Suriapranata

Mochtar Riady Institute for Nanotechnology
ivet.suriapranata@mrinstitute.org

Topics which will be covered in week 3 Types of Chromosomal Abnormalities

• Review Cell Division, DNA, Genes and Chromosomes,
Mutation and DNA Repair
• Definition, Type, Cause, Mechanisms of chromosome 1. Numerical Abnormalities
abnormalities 2. Structural Abnormalities
• Methods of Chromosomal Analysis
3. Mosaicism and Chimerism (Mixoploidy)
• Review of Mendelian Law, Variations of Mendelian
Inheritance
• Polygenic and Multifactorial Inheritance
• Genetic Disorder and its Inheritance
• Trend in Genetics in Medicine

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Inversions Structural abnormalities observed in cancer cells

involve two chromosomal breaks and rejoining, with the broken piece reincorporated in
the opposite orientation from which it naturally occurs

Inversion of chr 16 has been observed in rare cases of Acute myeloid leukemia
(AML).

Paracentric This inversion involves the breakage of chr 16 in two places; the resulting
Centromere is NOT involved piece of DNA is reversed and re-inserted into the chromosome. This form of
AML is characterized by a high rate of remission and a favorable outcome

Pericentric
Centromere is involved

chr 16 inv(16)(p13q22)

Isochromosomes Structural abnormalities observed in cancer cells

An isochromosome is an abnormal chromosome with two identical arms, either two short
(p) arms or two long (q) arms.
Isochromosome 17q is commonly found in a cancer of blood-forming tissue called
chronic myeloid leukemia (CML).

It also has been identified in certain solid tumors, including

a type of brain tumor called a medullo-blastoma and tumors of the brain
and spinal cord known as primitive neuroectodermal tumors.

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Dicentric chromosome Structural abnormalities observed in cancer cells

Dicentric chromosomes result from the abnormal fusion of two chromosome pieces, each
of which includes a centromere.
Dicentric chromosomes involving the short arm of chr 9 have been observed in B cell
precursor acute lymphoblastic leukaemias (BCP-ALL).

The short arm of chr 9 predominantly rearranges with chr 7, 12, and 20, giving
rise to the dic(7;9)(p11;p11∼13) (4), dic(9; 12)(p11∼13;p13) (5), and
dic(9;20)(p11∼13;q11), respectively

Ring chromosome RING 18

In nearly all cases of ring chromosomes,
Ring chromosomes usually occur when a chromosome breaks in two places and the
pieces of the long and the short arms of the
ends of the chromosome arms fuse together to form a circular structure.
chromosome are missing. These pieces may
be large or very small. They may or may not
contain genes that are important in growth
and development.
In most individuals, ring 18 changes the way
the brain develops and works. It is important
to remember that every person with ring 18 is
different. Some may be more severely
affected than others.

Generally infants, toddlers, and young children with ring 18 may develop more slowly than
those without ring 18. Almost all children with ring 18 will require some type of therapy,
such as speech, occupational, or physical therapy. Based on literature reports, people with
ring 18 appear to have IQ scores ranging from mild to severe mental impairment

Symptoms associated with ring 18: congenital heart anomaly, strabismus, nystagmus,
hearing loss, growth hormone deficiency, foot abnormalities, dysmorphology of ears, etc.

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Examples of Ring Chromosomes

Structural Abnormalities
Type of chromosomal Clinical Features
aberrations
Ring 20 Epilepsy and Seizures: Complex partial seizures (epileptic
seizures with impairment of consciousness and awareness);
• Deletion
Subtle nocturnal seizures
• Duplication
Ring 22 moderate-to-profound learning difficulties and delay or
absence of speech affected all individuals ; Autistic traits; • Translocation
dysmorphic features
Ring 6 growth retardation; varying degrees of mental retardation; • Inversion
mild to severe delays in the acquisition of skills requiring
the coordination of mental and physical activities • Isochromosome
(psychomotor retardation); and/or various abnormalities of
the skull and facial (craniofacial) region • Dicentric chromosome
Ring chromosomes have also been found with some regularity in cancer cells, such as in • Ring chromosome
mesenchymal tumors, dermatofibrosarcoma protuberans, salivary gland adenomas.

Types of Chromosomal Abnormalities Mixoploidy

When an organism having an unequal number

of chromosome sets in adjacent cells or tissues.
1. Numerical Abnormalities
2. Structural Abnormalities
3. Mosaicism and Chimerism (Mixoploidy) 1. Chimerism
2. Mosaicism

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Mosaicism Chromosomal Mosaicism

When an individual has two or more cell

populations with a different chromosomal
makeup the result of non-disjunction
occurring in an early embryonic
occurs from an error in cell division in cells mitotic division
other than eggs and sperm

Mosaicism
exist at a molecular level and specific to a cell type

Normal and abnormal cells

in most tissues

46 47 46 47

47 46 47 46

blood skin

Normal and abnormal cells

in specific tissues

46 46 46 47

46 46 47 46

blood skin Blaschko’s lines

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Down Syndrome Mosaicism Chimerism

the genetically different cell types originate from more

than one zygote

chr 21

most likely
not survive

The resulting embryo would be expected to show Trisomy 21

1-2% of clinically recognized Down Syndrome Chimera Mosaic

Types of chimerism
Types of chimerism
Dispermic chimeras
Blood chimeras
Twin embryos often share a blood supply in the placenta, allowing blood
stem cells to pass from one and settle in the bone marrow of the other.
It is estimated that 8% of fraternal twins are actually blood chimeras

Dispermic chimeras
• The result of double fertilization
• Two genetically different sperm fertilize two egg cells
• the resulting two zygotes fuse to form one embryo.
If the two zygotes are of different sex, the chimeric embryo can develop into an individual with
true hermaphroditism and an XX/XY karyotype

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Mendel’s Basic Experiments

Lecture 2
The Cause and Inheritance of Genetic Disorder
Mendelian Inheritance
Variations of Mendelian Inheritance
Genetic Disorders

Mendel’s Experiment Monohybrid Cross

Monohybrid Cross : cross involving a single trait

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Monohybrid Cross Mendel’s Experiment

The 3:1 ratio

Dominant traits in the F2 Generation
appeared in the F1 generation

Recessive traits
did not appear in the F1
generation

Genes = units of inheritance

The Law of Segregation

During gamete formation,

alleles of a gene separate
Mendel’s First Law so that each gamete only
The Law of Segregation receives one allele for
each gene

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Mendel’s Experiment
Punnett Square
Dihybrid Cross : cross involving two traits

Used to predict the

outcome of a particular
cross or breeding
experiment
seeds form

seeds color

Results from Mendel’s Experiment

Mendel’s Second Law

The Law of Independent Assortment

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The Law of Independent Assortment The Fly Room

Columbia University

During gamete formation, Fruitfly

Thomas Morgan Hunt Calvin Bridges Alfred Sturtevant

the alleles of different Drosophila melanogaster

genes assort independently

of each other

Do you notice
the 3:1 ratio here?

Some genes were inherited together Genetics Terminology

Genes that are located on the same
Chromosome and do not assort
independently are said to be genetically
linked
For his work on the discovery
of chromosome’s role in heredity,
Morgan was awarded the Nobel Prize
in Physiology and Medicine in 1933.
Alleles
any of the alternative forms of a gene that may occur
at a given locus (dominant and recessive)
Dominant
stronger of two genes expressed in the hybrid
represented by a capital letter (Y)
Recessive
gene that shows up less often in a cross
represented by a lowercase letter (y)

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Genetics Terminology Genetics Terminology

Genotypes
Genotype
gene combination for a trait (e.g. YY, Yy, yy) Homozygous genotype
gene combination involving 2 dominant
Phenotype or 2 recessive genes (e.g. YY or yy)
observed expression of a genotype (e.g. Heterozygous genotype
yellow, green) gene combination of one dominant and
one recessive allele (e.g. Yy); also called hybrid

Lecture 2
Variations on Mendel’s Themes
The Cause and Inheritance of Genetic Disorder
Incomplete Dominance
F1 hybrids have an appearance somewhat in between the phenotypes of the two
parental varieties

Mendelian Inheritance Codominance

Variations of Mendelian Inheritance
Genetic Disorders
Two or multiple alleles are expressed in heterozygous individuals
Epistasis
A genetic interaction whereby the expression of one gene affects the phenotypic
expression of another gene
Pleiotropy
a single gene is responsible for a variety of traits
Polygenic inheritance
two or more genes are responsible for a single trait

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Incomplete Dominance Incomplete Dominance

A a
a a
A AA Aa
A Aa Aa
a Aa aa
A Aa Aa
Ratio
AA : Aa : aa
All Aa = pink
Red : Pink : White
(heterozygous pink) 1 : 2 : 1

Codominance
Codominance
Blood Type
One allele of the gene codes
for an enzyme that functions
in the production of the red color

The other allele codes for the

gene to make white color

If both alleles are present, both

are expressed, resulting in a
species that has some red and
some white colors

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Epistasis
Variations on Mendel’s Themes

Incomplete Dominance
Codominance B = Black
b = brown
Epistasis
C = pigment
Pleiotropy deposit
c = colorless
Polygenic Inheritance

Pleiotropy
Polygenic inheritance

body height

influenced by genes
that control growth
hormone, metabolism

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Lecture 2
Polygenic inheritance The Cause and Inheritance of Genetic Disorder
Skin color

Mendelian Inheritance
Variations of Mendelian Inheritance
Genetic Disorders

Genetic Disorder Genetic disorders

Disease that is caused by an abnormality in
an individual's DNA
Dominant inheritance
when the trait (disorder) is expressed in the heterozygote (Dd)
Recessive inheritance
when the trait (disorder) is expressed in the homozygote (dd)

Abnormalities can range from a small mutation in a single gene Autosomal inheritance
to the addition or subtraction of an entire chromosome or affect genes on chromosome 1-22
set of chromosomes
Sex-linked inheritance
affect genes on the X or Y chromosome

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Genetic disorders Autosomal dominant inheritance

Father
D d

Autosomal dominant inheritance

d Dd dd

Mother
Autosomal recessive inheritance d Dd dd
X-linked dominant inheritance
X-linked recessive inheritance

Autosomal dominant inheritance Pedigree

What happens if both parents are affected ?
• Chart that shows genetic connections among
Father individuals, to study the inheritance of genes in
D d humans

D DD Dd • Standardized symbols
Mother

d Dd dd
• Knowledge of probability and Mendelian patterns
used to suggest basis of a trait
• Conclusions most accurate when drawn from
large number of pedigrees

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Principal Symbols for Pedigree

Autosomal dominant inheritance

The dominant allele D is passed

from generation to generation
both males and females may be
affected
every affected person has an
affected parent
males can transmit the condition
to males and females (and vice
versa)

Autosomal dominant inheritance Autosomal dominant inheritance

Example I : Achondroplasia Example 2: Familial hypercholesterolemia

affect lipid metabolism

disorder of bone growth causes high levels of LDL
(low density lipoprotein)
short-limbed dwarfism cholesterol levels beginning
mutations in FGFR3 gene, at birth, and heart attacks
which is necessary for the at an early age
development and most common genes affected:
maintenance of bone and APOB (chr 2)
brain tissue LDLR (chr 19)
PCSK9 (chr 1)

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How are changes in these genes related to Examples of autosomal dominant inheritance
familial hypercholesterolemia?
Disorder or Abnormality Main Symptoms
Achondroplasia One form of dwarfism
Camptodactyly Rigid, bent fingers
Mutation in the APOB gene prevents LDL Familial hypercholesterolemia High cholesterol levels in blood; eventually clogged
arteries
to effectively binding to LDL receptors
Huntington disease Nervous system degenerates progressively,
on the cell surface
irreversibly
Marfan syndrome Abnormal or no connective tissue
Polydactyly Extra fingers, toes, or both
Reduced number of LDL receptors Progeria Drastic premature aging
result in increased blood cholesterol level Neurofibromatosis Tumors of nervous system, skin
and gene product of PCSK9 induces
LDL receptor degradation

Reference
• Books:
– Tom Strachan and Andrew Read: Human Molecular Genetics,
Garland Science. The second edition in available online at NC
BI Books (http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=h
mg)
– Robert F. Mueller, Ian D. Young:
Emery's Elements of Medical Genetics, Churchill Livingstone
• Websites:
– http://www.dnaftb.org
– http://www.dnalc.org
– http://www.ncbi.nlm.nih.gov/disease/
– http://ghr.nlm.nih.gov/
– http://ornl.gov
– http://www.cellsalive.com

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