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.

He studied mathematics at University of Vienna

Gregor Mendel

(1822-1884) Theories of inheritances

Reshuffling of genes from

generation to generations

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

1900

1901

1902

1918

1931

1955

1937

Mendel’s Laws rediscovered

Anticipation described

Dominant inheritance of brachydactyly

Cytoplasmic inheritance of mitochondrial DNA

Linkage of color blindness and hemophilia

Human diploid chromosome number is 46

Amniocentesis for chromosomal disorders

Tay-Sachs screening 1970

1970

A Conceptual History of Medical Genetics

Inborn errors of metabolism

Human globin genes cloned 1976

1985

1986

1986

1987

1991

Mendel’s Laws rediscovered

Cystic Fibrosis gene

Predictive genetic testing for Huntington

Disease

1991

A Conceptual History of Medical Genetics

Duchenne muscular dystrophy gene

Draft sequence for the human genome

Medical genetics became an ABMS specialty

PCR

Human genome sequence completed 2001

Decision to sequence entire human

genome 1998

1953 James Watson

and Francis Crick

publish the double helix

model for DNA’s

chemical structure

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

1910 Thomas

Morgan’s work

on fruitflies

demonstrates

that genes lie on

chromosomes

1940s Barbara

McClintock

describes

mobile genetic

elements in

maize

1958 Crick proposes

the ‘central dogma’ for

biological information

flow: that DNA makes

RNA makes protein

1909 The word ‘gene’

coined by Danish botanist

Wilhelm Johannsen

1944 Oswald

Avery shows

in bacteria

that nucleic

acids are the

‘transforming

principle’

1977 Phillip Sharp and

Richard Roberts find

that protein-coding

genes are carried in

segments

2001 initial results

from the Human

Genome Project

published

Genetics – history and key concepts…

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: 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

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

Unifactorial Chromosomal Multifactorial

AD

AR

X-linked

Mitochondrial

Numerical

Structural

Microdeletions

Genetic Diseases

GENETIC ENVIRONMENTAL

Duchenne muscular dystrophy

Haemophilia Osteogenesis imperfecta

Club foot Pyloric stenosis Dislocation of hip

Peptic ulcer Diabetes

Tuberculosis

Phenylketonuria Galactosaemia

Spina bifida Ischaemic heart disease Ankylosing spondylitis

Scurvy

The contributions of genetic and environmental factors to human diseases

Rare Genetics simple

Unifactorial High recurrence rate

Common Genetics complex Multifactorial Low recurrence rate

100% Environmental

Struck by lightning

Infection

Weight

Cancer

Diabetes

Height

Sex, Down syndrome, achondroplasia 100% Genetic

Multifactorial – Genes or Environment?

PKU –genetic basis

but the damage is by

an environmental agent

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?

Gene1 Gene 2 Gene 3 Gene 4

PHENOTYPE

Environment

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

Meiosis KM 30

Mitosis vs. meiosis

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

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

D

R

X

Basic Gene Structure

Promoter

Initiation

codon

ATG

Start of

transcription

Termination

codon UAA

UAG

UGA

Polyadenylation

signal

5’ untranslated

region

3’ untranslated

region

Exons

Introns

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

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 Genetic-

based Diseases

Thousands

known

Most genes

mapped and

sequenced

I

II

III

IV

1 2

1 2 3 4 5 6

1 2 3 4 5 6

1 2 3 4 5 6

Founders

Proband IV - 2 V

1 2

Standard pedigree symbols Male,

affected

Female,

unaffected

Male,

deceased

Mating

Consanguineous

mating

Pregnancy

Male, heterozygous for

autosomal recessive trait

Female, heterozygous for

Autosomal or X-linked

recessive trait

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

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)

Mitochondrial inheritance

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

iPad

2012

ENIAC

1946

Technological Advances

Oxford Nanopore MinION

2012

Applied Biosystems 3730 DNA Analyzers

2002

Genome Sequencing Technology

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