MEDICAL GENETICSINTRODUCTION

Brig Nuzhat Mushahid

March 2015

ALL DISEASE
(WITH THE POSSIBLE EXCEPTION
OF TRAUMA)

ARE GENETIC!
Traditional category of genetic
diseases represents only those
conditions in which the genetic
contribution is particularly marked

Importance of Genetics to Medicine

Globally 7.6 million children are born annually with severe

genetic or congenital malformations
1 % of all newborn infants possess gross chromosomal
abnormality
90% of these infants are born in mid- and low-income
countries.
In the developed world, genetic and congenital disorders are
the second most common cause of infant and childhood death
Serious disease with significant genetic component develops
in approx 5% individuals younger than 25 years
Life time frequency of genetics disease estimation 670 per
1000

Prevalence of more common conditions for referral

Down syndrome (1/600 live births and increases with
advanced maternal age)
Cystic Fibrosis (1/2500 Caucasian Americans)
Fragile X syndrome (1/1,000 males and 1/800 female
carriers of which 30% will be mentally retarded)
Sickle cell disease (1/500 of African American births)
Hemophilia - Factor VIII Deficiency (48/100,000 male
births)
Duchenne muscular dystrophy (200/million male births)
Hemochromatosis (1/450 individuals)
Breast cancer (1/8 women of which 5-10% of will have a
genetic predisposition)

 If you were offered the sequencing of whole of your genome

Would you consent for that?
YES
NO

Why??

The Human Genome Project

Sequencing of first genome by

Fredrick Sanger
5,000 bases long and from
a virus called phiX174 that
infects bacteria
Sangers team sequenced
others including the DNA
from human mitochondria
Two important discoveries
made Sangers work
possible
PCR
Electrophoresis
technique

Born

13 August 1918[
Rendcomb, Gloucestershire,
England

Died

19 November 2013 (aged 95)

Cambridge, Cambridgeshire,
England[

Nationality

British

Fields

Biochemistry

Institutions

University of Cambridge
Laboratory of Molecular
Biology

Alma mater

St John's College,
Cambridge[

Robert Sinsheimer
University of California
Catalyst for scientists to start
thinking about sequencing
the human genome.

 By 1986
two of the organisation
provided considerable
amounts of funding
the US Department of
Energy and
the National Institutes
of Health.
Launched in 1986 by
Charles DeLisi.
James Watson came on
board

In 1989
support of the Prime
Minister Margaret
Thatcher,
Medical Research
Council (MRC) released
11m towards the
project for the next
three years.

Definitions
GENETICS: a branch of biology that deals with the
heredity and variation of organisms
GENOME the whole hereditary information of an
organism that is encoded in the DNA
HEREDITARY: Derived from ones parents
FAMILIAL: derived from ones parents and are
transmitted in the germ line through the generations
CONGENITAL: born with Some congenital diseases
are not genetic

Aims of the project:

to identify the approximate 100,000 genes in the
human DNA.
determine the sequences of the 3 billion bases that
make up human DNA.
store this information in databases.
develop tools for data analysis.
address the ethical, legal, and social issues that arise
from genome research.

$3 billion over 13 years

the International Human Genome Sequencing Consortium,
scientists from 20 institutions in six countries:
France, Germany, Japan, China, the UK and the USA
G5 were:

Broad Institute/Whitehead Institute for

Biomedical Research (MIT) in Cambridge, USA
Washington University in St Louis, USA
Baylor College of Medicine in Houston, USA
Department of Energys Joint Genome Institute
in Walnut Creek, USA
Wellcome Trust Sanger Institute (previously
known as the Sanger Centre) in Cambridge, UK

Prof John Sulston &

Robert H. Waterston

During the 1990s, Fred

Sangers sequencing
method was automated
used successfully, to
sequence the genome of
the nematode
worm, Caenorhabditis.
Elegans.
This work acted as a test
project for sequencing the
human genome

DNA sequencing is the process of working out the order of

the bases, A, C, G and T, in a strand of DNA.

Chain Termination Method

Sangers sequencing

 DNA sequencing by hand was a long and

laborious process for scientists,
mistakes were often made and using
radioactively-labelled bases could be dangerous.
improvements and changes had to be made,
particularly if scientists were going to eventually
sequence the DNA of larger organisms, such as
humans!
They needed a technique that was safe, easily
scaled-up and efficient.

Automated Sequencing :80s

Automatic sequencing machines became commercially
available
It was easier to avoid making mistakes.
Fragments of DNA were still separated by size
DNA bases were now labelled with coloured dyes (A =
Green, C = Blue, G = Yellow and T = Red).
All four DNA bases could be loaded in the same lane.
Automated sequencing
Cost to sequence 1 million bases: 10,000
Time to sequence a human genome: 600 years

Capillary sequencing
1990s
Cost to sequence 1 million bases: 3,457
Time to sequence a human genome: 12 years

Whose genome is being sequenced?

- the first reference genome is a composite genome
from several different people.
- generated from 10-20 primary samples taken from
numerous anonymous donors across racial and
ethnic groups.

Ethical, legal and social implications of the

Human Genome Project

How is each area benefited specifically by the

Human Genome Project?
- Improvements in medicine:
improved diagnosis of disease.
- Microbial research: new energy
sources, bio fuels.
- DNA forensics: identifying
potential suspects at a crime
scene.
- Agriculture: more nutritious
produce.
- Evolution and human migration:
study migration of different
population groups based on
female genetic inheritance.
- Risk assessment: reduce the
likelihood of heritable mutations.

Medical Genetics

Application of genetic principles

to medical practice.
Includes studies of inheritance, mapping
disease genes, diagnosis and treatment,
and genetic counseling.

Long history of Genetics

http://wellcomelibrary.org/

Eugenic movements

Eugenics comes from the Greek roots for good

and origin, or good birth and involves applying
principles of genetics and heredity for the purpose of
improving the human race
Galton (1822-1911) advocated a selective breeding
program for humans in his book Hereditary
Genius (1869)
1910, Davenport founded the Eugenics Record
Office (ERO) at Cold Spring Harbor Laboratory on
Long Island to improve the natural, physical, mental,
and temperamental qualities of the human family
920s and 30s. the American Eugenics Society was
founded
legislation for their forced sterilization
forced sterilization of over 64,000 people in the
United States
Buck v. Bell (1927), the state of Virginia sought to
sterilize Carrie Buck for promiscuity
lose power in the 1940s and was completely
discredited following the horrors of Nazi Germany.

Terminology:

Gene
Alleles
Nucleotides
Codon
Genetic Code

GENE and ALLELE

Biological unit of heredity.
Gene hold the information to build and maintain their cells and
pass genetic traits to offsprings
In cells, a gene is portion of DNA
Allele
Is one member of a pair or series of different forms of a gene.
Homozygous-an organism in which 2 copies of genes are identical
i.e. have same alleles
Heterozygous-an organism which has different alleles of the gene

 NUCLEOTIDE: group of molecules that when linked

together, form the building blocks of DNA and RNA;
composed of phosphate group, the bases:
adenosine,cytosine,guanine and thymine and a pentose
sugar(In case of RNA,thymine base is replaced by uracil)

CODON: series of three adjacent bases in one

polynucleotide chain of a DNA or RNA molecule which
codes for a specific amino acid.
GENETIC CODE: the sequence of nucleotides in a DNA or
RNA molecule that determines the amino acid sequence in
the synthesis of proteins.

Genes and dominance

A trait is a specific characteristic that varies from one

individual to another.
The offspring of crosses between parents with
different traits are called hybrids.
Today, scientists call the factors that determine traits
genes.

Gene (DNA)

RNA formation

Protein formation
Cell structure

Cell enzymes

cell function

 Mutations:
Permanent changes in the DNA.
Those that affect germ cells are
transmitted to the progeny.
Mutations in the somatic cells are not
transferred to the progeny but are
important in the causation of cancer
and some congenital diseases.

Classification of genetic
disorders
Multifactorial

+ environment

Single gene
Male

Chromosomal
Mitochondrial
Somatic mutations (cancer)

Mandelian Disorders (single gene mutations)

Follow the classic Mandelian pattern of inheritance
Disorders related to mutations in single gene with large effects
Mutations cause the disease or predispose to the disease
Typically not present in normal population
Highly penetrant
Very informative in medicine
Generally rare

Chromosomal disorders
Structural or numerical alteration in the autosomes and sex
chromosomes
Uncommon
High penetrance

Complex multigenic (polygenic) disorders

Common
Interactions between multiple variant forms of genes and
environmental factors
Variant genes are called polymorphisms
Each variant gene confers a small increase in disease risk
Low penetrance
No single susceptibility gene is necessary or sufficient to
produce the disease
Several polymorphism are present when disease occurs

 Mutation in mitochondrial genes

Mitochondrial genes
Inherited in different manner

Somatic mutations
Not transmitted to progeny
Gives rise to cancers

 Mendel's first conclusion was that biological inheritance is

determined by factors that are passed from one generation to
the next.
Mendels second conclusion is called the principle of
dominance.

Mendels Laws
Mendels Law of Segregation
The alleles for each character segregate
(separate) during gamete production
(meiosis).
Mendels Law of Independent Assortment
The two pairs of alleles segregate
independently of each other.