Medical Genetics
Mohammed El-Khateeb
Dental Postgraduate
MG - Lec. 1
3ed July 2013
OBJECTIVES
 Basic understanding of clinical 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 in human beings.
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
History of Medical Genetics
• Early Genetics - Biblical, Talmud
• Mendel - 1860s
• Modern Experimental Genetics - 1900s
• Maize, drosophila, mouse
• Medical Genetics - 1960s to the
present
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
Gregor Mendel
Charles Darwin
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
Alleles: alternative versions of a gene.
The gene for a particular inherited character resides at a specific locus
(position) on homologous chromosome.
For each character, an organism
inherits two alleles, one from each
parent
Medical Genetics: 1960s
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
C19th: Mendel discovers basis of inheritance
Darwin’s theory of natural selection
1953: Watson and Crick discover structure of DNA
1985: PCR
1986: Duchenne muscular dystrophy gene
1989: Cystic Fibrosis gene
1998: Decision to sequence entire human genome
2001: Human genome sequence completed
What is DNA Day?
April 1953
Drs. James Watson and
Francis Crick determined
the structure of DNA
(double helix)
What is DNA Day?
April 1953
April 2003
Drs. James Watson and
Francis Crick determined
the structure of DNA
(double helix)
Human Genome Project
determined the entire DNA
sequence of a human
(3 billion letters)
What is DNA?
• It's a history book - a narrative of the journey of
our species through time.
• It's a shop manual, with an incredibly detailed
blueprint for building every human cell.
• And it's a transformative textbook of medicine,
with insights that will give health care providers
immense new powers to treat, prevent and cure
disease."
Francis Collins
Importance of Genetics to Medicine
 >12 million Americans with genetic disorders (GD)
 80% of MR due to genetic component
 2-3% background population risk for a major birth





defect (BD)
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
Importance of Genetics to Medicine
Triple theme:
 Genetic traits as they segregate through families
allows insights into health of the population
 Flow of information from DNA to RNA to protein
links genetics to physiology
 Ethical issues linked to treatment, therapy
options, research, decision-making and quality of
life
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
Classification of genetic
disorders
• Single gene
• Chromosomal
• Mitochondrial
• Multifactorial
• Somatic mutations (cancer)
Single Gene Defects
Autosomal recessive
Autosomal dominant
X-linked recessive
X-linked dominant
Basic Gene Structure
Exons
Polyadenylation
signal
Start of
transcription
Promoter
Initiation
codon
ATG
5’ untranslated
region
Termination
codon
Introns
UAA
UAG
UGA
3’ untranslated
region
Sickle Cell
Anemia
Inheritance
R
D
X
•
Single-Gene “Mendelian”
Disorders
Structural proteins
• Osteogenesis imperfecta and Ehlers-Danlos (collagens); Marfan
•
syndrome (fibrillin); Duchenne and Becker muscular dystrophies
(dystrophin)
Enzymes and inhibitors
• 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
Single gene disorders
• Single mutant gene has a large effect
•
•
•
on the patient
Transmitted in a Mendelian fashion
Autosomal dominant, autosomal
recessive, X-linked, Y-linked
Osteogenesis imperfecta - autosomal
dominant
• Sickle cell anaemia - autosomal recessive
•
Haemophilia - X-linked
Fertilization: Diploid Genome
•
•
Each parent contributes one genome copy
Offspring cells have two near-identical copies
Genes & chromosomes
Chromosomes
• Linear agglomerates
of proteins & DNA
in the cell’s nucleus
• Distributed evenly
upon division
• Morgan (1910):
Genes reside along
the chromosomes
Mitosis vs. meiosis
Meiosis KM
28
Cell Cycle
Chromosomes
Homologous chromosome: one of a matching pair of
chromosomes, one inherited from each parent.
Sister chromatids are identical
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
Genetic Material (chromosomes pairs)
Pair of homologous
chromosomes
Sister
chromatids
Centromere
ISCN 1995
International System for Human Cytogenetic Nomenclature
Group A (1-3)
Group B (4-5)
Group C (6-12, X)
Group D (13-15)
Group E (16-18)
Group F (19-20)
Group G (21-22)
Chromosomal Rearrangements
•Numerical chromosome changes/aneuploidy
Result from errors occurring during meiotic or mitotic segregation
• Structural chromosome changes
Multifactorial inheritance
• Familial clustering which does not
•
•
conform to any recognized pattern of
Mendelian inheritance
Determined by the additive effects of
many genes at different loci together
with the effect of environment
Examples include congenital
malformations, asthma, schizophrenia,
diabetes , hypertension
Etiology of diseases.
For any condition the overall balance of genetic and
environmental determinants can be represented by a point
somewhere within the triangle.
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
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
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
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
Human Genome
Project (HGP)
Human Genome Project
• Initiated by the same laboratories that
•
•
•
•
brought you thermonuclear devices
1990 taken over by NIH
Actually involved sequencing many
genomes
First draft sequence in 2001, “completed” in
2003 (public effort and Celera Corp.)
DNA sequence in any two human beings is
99.9% identical only 0.1% is unique
The human Genome project Goals
The study of the genome
 To determine the DNA sequence (exact order of A,T,G,C,)
For all the DNA in human
 To determine which segment of DNA represent individual
genes (Protein Coding Unit
Model organisms
Mapping Human Geneticbased Diseases
• Thousands
known
• Most genes
mapped
and
sequenced
OMIM Synopsis of the Human Gene Map
(Updated 8 June 2012)
Chromosome
1
2
3
4
5
6
7
8
9
10
11
12
Count
1,309
848
710
517
618
793
610
475
503
494
818
702
Chromosome
13
14
15
16
17
18
19
20
21
22
X
Y
Count
250
426
399
548
770
190
843
337
144
330
724
46
Number of Entries in OMIM
(Updated 7 June 2013)
:
Prefix
* Gene description
+ Gene and phenotype,
combined
# Phenotype description,
molecular basis known
% Phenotype description or
locus, molecular basis
unknown
Other, mainly phenotypes
with suspected mendelian
basis
Totals
Autosomal
X Linked
Y Linked
Mitochondr
ial
Totals
13,197
641
48
35
13,921
146
5
0
2
153
3,216
263
4
28
3,511
1,631
136
5
0
1,772
1,779
126
2
0
1,907
19,969
1,171
59
65
21,264
Applications of the Human Genome
Project
• Genetic testing ( diagnostic,
presymptomatic screening, prenatal)
• Gene therapy
•
Pharmacogenomics: Moving Away from
“One-Size-Fits-All” Therapeutics
Diagnosis and Prevention of
Genetic Diseases
 Diagnosis
• Chromosomal Abberations
• Single Gene Disorders
 Preventions
• Genetic Counseling
• Prenatal Dignosis
• Preimplantation Diagnosis
New Technologies
Technology Advancement
Technological Advances
ENIAC
iPad
1946
2012
Genome Sequencing Technology
Applied Biosystems 3730
DNA Analyzers
Oxford Nanopore MinION
2002
2012
• Because of major technological advances, the
•
•
cost of sequencing a human genome has
fallen rapidly.
And within the next 5 years, the cost of
sequencing a human genome will be under
$1,000 and will take only hours or days.
When the cost is low enough, perhaps
reading human genomes will be as routine as
blood tests and easy enough to be carried out
in your doctor’s office.