medical genetics
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Medical Genetics
Mohammed El-KhateebDental Postgraduate
MG - Lec. 13ed 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 versionsof a gene (alleles)determine the trait
Each parent transmitsan 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. Segregation2. Dominance3. 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
• 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
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
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 1953Drs. James Watson and
Francis Crick determined the structure of DNA
(double helix)
April 2003 Human Genome Project
determined the entire DNA sequence of a human
(3 billion letters)
What is DNA Day?
April 1953Drs. James Watson and
Francis Crick determined the structure of DNA
(double helix)
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 DefectsAutosomal recessive Autosomal dominantX-linked recessiveX-linked dominant
Basic Gene Structure
Promoter
Initiation codonATG
Start of transcription
Termination codonUAAUAGUGA
Polyadenylation signal
5’ untranslated region
3’ untranslated region
Exons
Introns
Sickle Cell Anemia
Inheritance
D
R
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 & DNAin the cell’s nucleus
• Distributed evenlyupon division
• Morgan (1910):Genes reside alongthe chromosomes
Meiosis KM 28
Mitosis vs. meiosis
Cell Cycle
ChromosomesHomologous chromosome: one of a matching pair of chromosomes, one inherited from each parent.
Sister chromatids are identical
Chromosome Number Constancy in Different Species
Buffalo 60 Cat 38 Dog 78 Donkey 62 Goat 60 Horse 64 Human beings 46 Pig 38 Sheep 54
Pair of homologouschromosomes
Sisterchromatids
Centromere
Genetic Material (chromosomes pairs)
ISCN 1995International 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.
GENETIC ENVIRONMENTAL
Duchenne muscular dystrophy
HaemophiliaOsteogenesis imperfecta
Club footPyloric stenosisDislocation of hip
Peptic ulcerDiabetes
Tuberculosis
PhenylketonuriaGalactosaemia
Spina bifidaIschaemic heart diseaseAnkylosing spondylitis
Scurvy
The contributions of genetic and environmental
factors to human diseases
RareGenetics simple
UnifactorialHigh recurrence rate
CommonGenetics complexMultifactorialLow recurrence rate
Polygenic diseasesThe 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 commonType 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 GoalsThe 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 Genetic-based Diseases
• Thousands known
• Most genes mapped and sequenced
Chromosome Count1 1,309 2 848 3 710 4 517 5 618 6 793 7 610 8 475 9 503
10 494 11 818 12 702
Chromosome Count13 250 14 426 15 399 16 548 17 770 18 190 19 843 20 337 21 144 22 330 X 724 Y 46
OMIM Synopsis of the Human Gene Map
(Updated 8 June 2012)
:
Prefix Autosomal X Linked Y Linked Mitochondrial Totals
* Gene description 13,197 641 48 35 13,921+ Gene and phenotype, combined 146 5 0 2 153
# Phenotype description, molecular basis known 3,216 263 4 28 3,511
% Phenotype description or locus, molecular basis unknown
1,631 136 5 0 1,772
Other, mainly phenotypes with suspected mendelian basis
1,779 126 2 0 1,907
Totals 19,969 1,171 59 65 21,264
OMIM Entry Statistics:
Number of Entries in OMIM (Updated 7 June 2013)
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
iPad
2012
ENIAC
1946
Technological Advances
Oxford Nanopore MinION
2012
Applied Biosystems 3730 DNA Analyzers
2002
Genome Sequencing Technology
• 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.
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