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.