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Medical Genetics
Mohammed El-Khateeb
Dental Postgraduate
MG - Lec. 1
22nd June 2014
OBJECTIVES
 Understanding of Basic genetics
 Be able to draw, and understand, a
family tree
 Have awareness of when you should be
considering a genetic condition
 Have a working knowledge of the most
important genetic conditions
 Know how & when to refer to local
specialist genetics services
What’s a ___?
• Genetics : Is the branch of biology that
deals with heredity and
variation in all living
organisms
• The subfields of genetics :
 Human genetics,
 Animal genetics,
 Plant genetics
 Medical genetics
What’s a Medical Genetics?
• Is the science or study of biological
variation as it pertains to health and
disease
• Any application of genetic principles to
medical practice.
“Genetics – study of individual genes and
their effects”:
Includes studies of inheritance, mapping
disease, genes, diagnosis, treatment,
and genetic counseling
Foundations of Heredity
Science
 Variable traits are inherited
 Gene – trait-specific unit of heredity
 Alternative versions of a gene (alleles)
determine the trait
 Each parent transmits an allele to the
offspring
History of Medical Genetics
• Early Genetics
• Mendel - 1860s
• Modern Experimental Genetics - 1900s
• Maize, drosophila, mouse
• Medical Genetics - 1960s to the
present
Mendel Inheritance
Australian monk who formulated
fundamental law of heredity in early 1860s.
 Theories of inheritances
 Reshuffling of genes from
generation to generations
Gregor Mendel
(1822-1884)
He studied mathematics at
University of Vienna
Mendel studies seven characteristics
in the garden pea
Mendel deduced the underlying principles
of genetics from these patterns
1. Segregation
2. Dominance
3. Independent
assortment
A Conceptual History of Medical Genetics
1900
1901
1902
1918
1931
1937
1955
1970
1970
1976
Mendel’s Laws rediscovered
Dominant inheritance of brachydactyly
Inborn errors of metabolism
Anticipation described
Cytoplasmic inheritance of mitochondrial DNA
Linkage of color blindness and hemophilia
Human diploid chromosome number is 46
Amniocentesis for chromosomal disorders
Tay-Sachs screening
Human globin genes cloned
A Conceptual History of Medical Genetics
1985
Mendel’s Laws rediscovered
PCR
1986
Duchenne muscular dystrophy gene
1986
Cystic Fibrosis gene
1987
Predictive genetic testing for Huntington
Disease
1998
Decision to sequence entire human
genome
Medical genetics became an ABMS specialty
1991
1991
2001
Draft sequence for the human genome
Human genome sequence completed
Genetics – history and key concepts…
1860s Mendel’s
work on peas
allows the
conclusion that
traits are inherited
through discrete
units passed from
one generation to
the next
1870s Friedrich
Miescher describes
nucleic acids
1909 The word ‘gene’
coined by Danish botanist
Wilhelm Johannsen
1910 Thomas
Morgan’s work
on fruitflies
demonstrates
that genes lie on
chromosomes
1940s Barbara
McClintock
describes
mobile genetic
elements in
maize
1977 Phillip Sharp and
Richard Roberts find
that protein-coding
genes are carried in
segments
1944 Oswald
Avery shows
in bacteria
that nucleic
acids are the
‘transforming
principle’
1953 James Watson
and Francis Crick
publish the double helix
model for DNA’s
chemical structure
1958 Crick proposes
the ‘central dogma’ for
biological information
flow: that DNA makes
RNA makes protein
2001 initial results
from the Human
Genome Project
published
Medical Genetics: 1950s
to the present
 DNA Genetics
• 1953 - Watson and Crick’s Double Helix
• 1992 –2003 Human Genome Project
• 2003 -> the future of medical dx & tx
 Prenatal Genetics
• 1970s - Prenatal Ultrasound & Amniocentesis
 Inheritance of Genetically Complex Disorders
•
•
•
•
•
Non-Mendelian Genetics
Genomic Imprinting
Triple Nucleotide Repeats
Mitochondrial Inheritance
1990s - Neuropsychiatric Disorders, Diabetes,
Cardiovascular
 Interaction of genes with environmental triggers
Human Genome Project





Proposed in 1985
1988. Initiated and
funded by NIH and US
Dept. of Energy ($3
billion set aside)
1990. Work begins.
1998. Celera announces
a 3-year plan to complete
the project years early
Published in Science and
Nature in February, 2001
What we’ve learned from our
genome so far…
 There are a relatively small number of human
genes, less than 30,000, but they have a complex
architecture that we are only beginning to
understand and appreciate.
 We know where 85% of genes are in the sequence.
 We don’t know where the other 15% are because we
haven’t seen them “on” (they may only be expressed
during fetal development).
 We only know what about 20% of our genes do so far.
 So it is relatively easy to locate genes in the
genome, but it is hard to figure out what they
do.
Human genome content
 1-2 % codes for protein products
 24% important for translation
 75% “junk”
 Repetitive elements
• Satellites (regular, mini-, micro-)
• Transposons
• Retrotransposons
• Parasites
Some Facts

In human beings, 99.9% bases are same

Remaining 0.1% makes a person unique


Different attributes / characteristics / traits
 how a person looks
 diseases he or she develops
These variations can be:



Harmless (change in phenotype)
Harmful (diabetes, cancer, heart disease, Huntington's
disease, and hemophilia )
Latent (variations found in coding and regulatory regions, are
not harmful on their own, and the change in each gene only
becomes apparent under certain conditions e.g. susceptibility
to heart attack)
Importance of Genetics to Medicine
 10% of the patients seen in GP have a disorder with a
genetic component
 80% of MR due to genetic component
 2-3% background population risk for a major birth defect
15% overall miscarriage risk for any pregnancy
 25-50% first trimester miscarriage risk
 30-50% first trimester losses due to chromosome
anomalies
 >30% pediatric hospital admissions due to GD
 GD affect all major systems, any age, any race, male or
female
Importance of Genetics to Medicine
 Changing focus of medicine:

Primary care physicians vs specialists
Prevention vs treatment

Genetic causation for both rare and common diseases

Human Genome Project
Designer drugs


 Problem based approach taken in medical schools
 Genetics as the link between basic research &
clinical observation
Categories of Genetic Disease
• Genetic component of multifactorial illnesses
– Polygenic conditions
– Interaction of genetic & environmental factors
• Addition or deletion of entire chromosomes or
parts of chromosomes
• Single gene disorders
 Autosomal dominant
 Autosomal recessive
 X-linked
Genetic
Diseases
Genetic
Diseases
Unifactorial
Chromosomal
Multifactorial
AD
Numerical
AR
Structural
X-linked
Microdeletions
Mitochondrial
The contributions of genetic and environmental
factors to human diseases
Haemophilia
Osteogenesis imperfecta
Club foot
Pyloric stenosis
Dislocation of hip
Duchenne
muscular dystrophy
GENETIC
Phenylketonuria
Galactosaemia
Rare
Genetics simple
Unifactorial
High recurrence rate
Peptic ulcer
Diabetes
Tuberculosis
ENVIRONMENTAL
Spina bifida
Ischaemic heart disease
Ankylosing spondylitis
Common
Genetics complex
Multifactorial
Low recurrence rate
Scurvy
Multifactorial – Genes or Environment?
100%
Environmental
Struck by lightning
Infection
Weight
Cancer
Diabetes
Height
100%
Genetic
PKU –genetic basis
but the damage is by
an environmental agent
Sex, Down syndrome, achondroplasia
Polygenic diseases
The most common yet still the least
understood of human genetic
diseases
Result from an interaction of multiple
genes, each with a minor effect
The susceptibility alleles are common
Type I and type II diabetes, autism,
osteoarthritis
What about mapping polygenic
disorders?
Environment
Gene1
Gene 2
Gene 3
Gene 4
PHENOTYPE
Polygenic Diseases
• The most common yet still the least understood
of human genetic diseases
–
–
–
–
Type I and type II diabetes
Primary generalised osteoarthritis
Hypertension
Autism
• Result from an interaction of multiple genes,
each with a minor effect
• Some inherited mutations and some
environmental factors (somatic mutations)
Population Genetics
 Identifies how much genetic variation
exists in populations
•
Investigates factors, such as migration,
population size, and natural selection,
that change the frequency of a specific
gene over time
 Coupled with DNA technology,
investigates evolutionary history and
DNA identification techniques
Chromosomal Disorders
Most mutations happen in the parent’s egg/ sperm
- “one off” with no established family history
Duplications (whole or part)


Autosome trisomies (Down, Edwards, Patau)
XY duplications (Klinefelter XXY, Triple X)
Deletions


Autosome deletions (Cri du chat, di George’s)
XY deletions (Turner XO)
Translocations


Leukaemias (Philedelphia Chromosome)
Sarcomas (Ewings)
Inversions
Rings…..
Fertilization: Diploid Genome
•
•
Each parent contributes one genome copy
Offspring cells have two near-identical copies
Mitosis vs. meiosis
Meiosis KM
30
Chromosome Number Constancy
in Different Species









Buffalo
Cat
Dog
Donkey
Goat
Horse
Human beings
Pig
Sheep
60
38
78
62
60
64
46
38
54
DNA DIFFERENCES
TWO BASIC FACTORS
and the same number of
chromosomes and genes
Chromosomes: A Review
MALE
FEMALE
Chromosomal Rearrangements
•Numerical chromosome changes/aneuploidy
Result from errors occurring during meiotic or mitotic segregation
• Structural chromosome changes
Single Gene Disorders
Autosomal recessive
Autosomal dominant
X-linked recessive
X-linked dominant
Inheritance
R
D
X
Basic Gene Structure
Exons
Start of
transcription
Polyadenylation
signal
Promoter
Initiation
codon
ATG
5’ untranslated
region
Termination
codon
Introns
UAA
UAG
UGA
3’ untranslated
region
Single-Gene “Mendelian”
Disorders
•
Structural proteins
•
Enzymes and inhibitors


Osteogenesis imperfecta and Ehlers-Danlos (collagens);
Marfan syndrome (fibrillin); Duchenne and Becker muscular
dystrophies (dystrophin)
Lysosomal storage diseases; SCID (adenosine deaminase);
PKU (phenylalanine hydroxylase); Alpha-1 antitrypsin
deficiency
• Receptors
 Familial hypercholesterolemia (LDL receptor)
• Cell growth regulation

•

Neurofibromatosis type I (neurofibromin); Hereditary
retinoblastoma (Rb)
Transporters
Cystic fibrosis (CFTR); Sickle cell disease (Hb); Thalassemias
What Can The Genes Tell Us?
 Give us a better understanding of the
underlying biology of the trait in question
 Serve as direct targets for better treatments
 Pharmacogenetics
 Interventions
 Give us better predictions of who might
develop disease
 Give us better predictions of the course of the
disease
 Lead to knowledge that can help find a cure or
prevention
Mapping Human Geneticbased Diseases
 Thousands
known
 Most genes
mapped and
sequenced
Founders
I
2
1
II
1
2
2
3
3
4
5
5
6
III
1
4
IV
V
2
1
Proband
IV - 2
1
3
2
4
5
6
6
Standard pedigree symbols
Male,
affected
Male, heterozygous for
autosomal recessive trait
Female,
unaffected
Female, heterozygous for
Autosomal or X-linked
recessive trait
Male,
deceased
Mating
Consanguineous
mating
Pregnancy
Dizygotic
(non-identical)
twins
Monozygotic
(identical)
twins
Spontaneous abortion
or still birth
Hemophilia is a sex-linked recessive trait defined by the absence of one
or more of the proteins required for blood clotting.
Non-Traditional Inheritence
 Mitochondrial genes
 Trinucleotide repeats
 Genetic imprinting
Mitochondrial Inheritance
• Matrilineal mode of inheritance: only mother
•
•
•
•
passes mitochondrial DNA to offspring
Higher spontaneous mutations than nuclear DNA
affects both males and females , but transmitted
only through females
range of phenotypic severity due to
heteroplasmy
Example: diabetes mellitus with sensorineuronal
deafness
Mitochondrial inheritance
 This type of inheritance


applies
to
genes
in
mitochondrial DNA.
Mitochondrial
disorders
can
appear
in
every
generation of a family and
can affect both males and
females, but fathers do not
pass mitochondrial traits
to their children.
E.g. Leber's hereditary
optic neuropathy (LHON)
What are Genetic Variations?
• Variations are simply differences in
•
genetic sequence
Variation can be seen at every genetic
level:





In the DNA
In the genes
In the chromosomes
In the proteins
In the function of proteins
Technology Advancement
Technological Advances
ENIAC
iPad
1946
2012
Genome Sequencing Technology
Applied Biosystems 3730
DNA Analyzers
Oxford Nanopore MinION
2002
2012
New Technologies
REFERNCES
1. MEDICAL GENETICS
Jorde, Carey, Bamshad, White
Published by:
Mosby
2. ELEMENTS OF MEDICAL GENETICS
Robert Muller and Ian Young
Published by:
Churchill Livingstone
3. ESSENTIAL MEDICAL GENETICS
Connor, Ferguson-Smith
Published:
Blackwell Science
Journals
• Nature Genetics
– http://www.nature.com/ng/index.html
• Nature Reviews Genetics
– http://www.nature.com/nrg/index.html
• Trends in Genetics
– http://www.trends.com/tig/default.htm