ADVANCEMEDICAL

GENETICS
Prof.Dr.Shaukat Iqbal
PhD (Biochemistry & Molecular Biology/
Cancer Cytogenetics)
Postdoc Lineberger Comprehensive Cancer
Center, UNC-CH,North Carolina, USA
Postdoc USEPA , NHEERL-RCD, RTP-USA
PhD, NU, Athens
[email protected]
 INTRODUCTION
 Medical genetics is the branch of
medicine that involves the diagnosis and
management of hereditary disorders.
(Medicine is the science and practice of
establishing the diagnosis, prognosis,
treatment, and prevention of disease.)
 Medical genetics differs from human
genetics in that human genetics is a field
of scientific research that may or may not
apply to medicine, while medical
genetics refers to the application of
genetics to medical care.
 Medical genetics

In contrast, the study of typically non-

medical phenotypes such as the genetics
of eye color would be considered part of
human genetics, but not necessarily
relevant to medical genetics
(except in albinism).
Genetic medicine is a newer term for
medical genetics and incorporates areas
such as gene therapy, personalized
medicine, and the rapidly emerging new
medical specialty, predictive medicine.
 Medical genetics
 For example, research on the
causes and inheritance of genetic
disorders would be considered
within both human genetics
 and medical genetics, while the
diagnosis, management,
 and counselling people with
genetic disorders would be
considered part of medical
genetics
 Scope
 Medical genetics encompasses many different areas,
including clinical practice of physicians, genetic counselors,
and nutritionists, clinical diagnostic laboratory activities, and
research into the causes and inheritance of genetic disorders.
 Examples of conditions that fall within the scope of medical
genetics include birth defects and dysmorphology, mental
retardation, autism, mitochondrial disorders, skeletal
dysplasia, connective tissue disorders, cancer genetics,
teratogens, and prenatal diagnosis. Medical genetics is
increasingly becoming relevant to many common diseases.
 Overlaps with other medical specialties are beginning to
emerge, as recent advances in genetics are revealing
etiologies for neurologic, endocrine, cardiovascular,
pulmonary, ophthalmologic, renal, psychiatric, and
dermatologic conditions.
 The medical genetics community is increasingly involved with
individuals who have undertaken elective genetic and
genomic testing.
 Genetic Disorder
A genetic disorder is a genetic problem caused by
one or more abnormalities formed in the genome.
Most genetic disorders are quite rare and affect
one person in every several thousands or millions
 Genetic disorders may be hereditary, meaning
that they are passed down from the parents'
genes. In other genetic disorders, defects may be
caused by new mutations or changes to the DNA.
 In such cases, the defect will only be passed down
if it occurs in the germline. Some types of
recessive gene disorders confer an advantage in
certain environments when only one copy of the
gene is present.
 Clinical Genetics
Clinical genetics is the practice of clinical medicine
with particular attention to hereditary disorders.
Referrals are made to genetics clinics for a variety
of reasons, including birth defects, developmental
delay, autism, epilepsy, short stature, and many
others.
Examples of genetic syndromes that are commonly
seen in the genetics clinic include chromosomal
rearrangements, Down syndrome, Fragile X
syndrome, Marfan syndrome, Turner syndrome, and
Williams syndrome. (Fragile X syndrome (FXS) is a
genetic disorder, Symptoms often include mild to
moderate intellectual disability)
 Marfan syndrome
Marfan syndrome
(MFS) is a genetic
disorder of the
connective tissue.
The degree to
which people are
affected varies.
People with Mrarfan syndrome (MFS) is a
Marfan tend to be genetic affected varies.People
with Marfan tend to be positive
tall and thin, with
wrist sign in a person with Marfan
long arms, legs, syndrome (the thumb and little
fingers and toes. finger overlap when grasping the
wrist of the opposite hand)
Human Genetics
 Human genetics is the study of
inheritance as it occurs in human
beings.
 Human genetics encompasses a
variety of overlapping fields
including: classical genetics,
cytogenetics, molecular genetics,
biochemical genetics, genomics,
population genetics,
developmental genetics, clinical
genetics, and genetic counseling.
Human Genetics
 Genes can be the common factor of the
qualities of most human-inherited traits.
Study of human genetics can be useful as
it can answer questions about human
nature, understand the diseases and
development of effective disease
treatment, and understand genetics of
human life. This article describes only
basic features of human genetics; for the
genetics of disorders .
 A single-gene disorder
(Monogenic)

A single-gene (or monogenic) disorder is

the result of a single mutated gene.
 Over 6000 human diseases are caused by
single-gene defects.
 Single-gene disorders can be passed on to
subsequent generations in several ways.
 Genomic imprinting and uniparental
disomy, however, may affect inheritance
patterns.
A single-gene disorder

 The divisions between recessive and

dominant types are not "hard and
fast", although the divisions
between autosomal and X-linked
types are (since the latter types are
distinguished purely based on the
chromosomal location of the gene).
 A single-gene disorder
 For example, achondro-plasia is typically considered
a dominant disorder, but children with two genes
for achondroplasia have a severe skeletal disorder
of which achondroplasics could be viewed as
carriers. Sickle-cell anemia is also considered a
recessive condition, but heterozygous carriers have
increased resistance to
 When a couple where one partner or both are
sufferers or carriers of a single-gene disorder wish
to have a child, they can do so through in vitro
fertilization, which enables preimplantation genetic
diagnosis to occur to check whether the embryo has
the genetic disorder.
Albinism

 Albinism is the "congenital absence

of any pigmentation or coloration in
a person, animal or plant, resulting
in white hair, feathers, scales and
skin and pink eyes in mammals,
birds, reptiles, amphibians and fish
and other small invertebrates as
well
 Population Genetics
 PG is a subfield of genetics that deals with genetic
differences within and between populations, and is a part
of evolutionary biology.
 Studies in this branch of biology examine such phenomena
as adaptation, speciation, and population structure.
 Population genetics was a vital ingredient in the
emergence of the modern evolutionary synthesis. Its
primary founders were Sewall Wright, J. B. S. Haldane and
Ronald Fisher who also laid the foundations for the
related discipline of quantitative genetics. Traditionally a
highly mathematical discipline, modern population
genetics encompasses theoretical, lab, and field work.
Population genetic models are used both for statistical
inference from DNA sequence data and for proof/disproof
of concept
 Genetics
 Genetics is the study of heredity and variations. Heredity
and variations are controlled by genes—what they are,
what they do, and how they work.
 Genes inside the nucleus of a cell are strung together in
such a way that the sequence carries information: that
information determines how living organisms inherit
various features.
 For example, offspring produced by sexual reproduction
usually look similar to each of their parents because they
have inherited some of each of their parents' genes.
 Genetics identifies which features are inherited, and
explains how these features pass from generation to
generation. In addition to inheritance, genetics studies
how genes are turned on and off to control what
substances are made in a cell—gene expression; and how a
cell divides—mitosis or meiosis.
 Genes and inheritance
 Genes are pieces of DNA that contain information for
synthesis of ribonucleic acids (RNAs) or polypeptides.
 Genes are inherited as units, with two parents
dividing out copies of their genes to their offspring.
 This process can be compared with mixing two hands
of cards, shuffling them, and then dealing them out
again.
 Humans have two copies of each of their genes, and
make copies that are found in eggs or sperm—but they
only include one copy of each type of gene.
 An egg and sperm join to form a complete set of
genes. The eventually resulting offspring has the same
number of genes as their parents, but for any gene
one of their two copies comes from their father, and
one from their mother.
 Metabolic/biochemical genetics
Metabolic (or biochemical) genetics involves the
diagnosis and management of inborn errors of
metabolism in which patients have enzymatic
deficiencies that perturb biochemical pathways
involved in metabolism of carbohydrats, amino acids,
and lipids.
 Examples of metabolic disorders include
galactosemia, glycogen storage disease, lysosomal
storage disorders, metabolic acidosis,
phenylketonuria, and urea cycle disorders.
Galactosemia (meaning galactose + blood,
accumulation of galactose in blood) is a rare genetic
metabolic disorder that affects an individual's ability
to metabolize the sugar galactose properly.
Galactosemia follows an autosomal recessive mode
of inheritance that confers a deficiency in an enzyme
responsible for adequate galactose degradation.
 Phenylketonuria (PKU) is an inborn error of metabolism
that results in decreased metabolism of the amino acid
phenylalanine.
 Untreated, PKU can lead to intellectual disability,
seizures, behavioral problems, and mental disorders.
 It may also result in a musty smell and lighter skin.
 Babies born to mothers who have poorly treated PKU
may have heart problems, a small head, and low birth
weight.
 Phenylketonuria is a genetic disorder inherited from a
person's parents. It is due to mutations in the PAH gene,
which results in low levels of the enzyme phenylalanine
hydroxylase.
 It is autosomal recessive, meaning that both copies of
the gene must be mutated for the condition to develop
 Cytogenetics
 Cytogenetics is the study of
chromosomes and
chromosome abnormalities.
While cytogenetics The three
historically relied on major single-
microscopy to analyze chromosome
chromosomes, new molecular mutations:
technologies such as array deletion (1),
comparative genomic duplication
hybridization are now (2) and
becoming widely used. inversion (3).
 Examples of chromosome
abnormalities include
aneuploidy, chromosomal
rearrangements, and
genomic deletion/duplication
disorders.
 Molecular genetics

Molecular genetics involves the

discovery of and laboratory testing
for DNA mutations that underlie
many single gene disorders.
Examples of single gene disorders
include achondroplasia, cystic
fibrosis, Duchenne muscular
dystrophy, hereditary breast cancer
(BRCA1/2), Huntington disease,
Marfan syndrome, Noonan syndrome,
and Rett syndrome.
Molecular tests are also used in the
diagnosis of syndromes involving
epigenetic abnormalities, such as
Angelman syndrome, Beckwith-
Wiedemann syndrome, Prader-willi
syndrome, and uniparental disomy. A 15-year-old female with Rett
syndrome and severe scoliosis
 Uniparental Disomy
 Uniparental disomy (UPD) occurs when a person
receives two copies of a chromosome, or of part
of a chromosome, from one parent and no copy
from the other parent.
 UPD can be the result of heterodisomy, in which
a pair of non-identical chromosomes are
inherited from one parent (an earlier stage
meiosis I error) or isodisomy, in which a single
chromosome from one parent is duplicated (a
later stage meiosis II error).
 Uniparental disomy may have clinical relevance
for several reasons. For example, either
isodisomy or heterodisomy can disrupt parent-
specific genomic imprinting, resulting in Animation of
imprinting disorders. Additionally, isodisomy uniparental isodisomy
leads to large blocks of homozygosity, which may
lead to the uncovering of recessive genes, a Medical
Specialty
similar phenomenon seen in children of genetics
consanguineous partners.
EVOLUTION OF THE
ENVIRONMENTAL
 POLICY
Reflected the state of scientific knowledge and the development of
sophisticated detection instruments. These instruments are able to
detect the presence of a pollutant in parts per billion.
 Cataclysmic events like the 1969 oil spill in Santa Barbra, CA.
 Public pressure.
THE SEVENTIES
THE ENVIRONMENTAL DECADE
 Three books inspired the environmental awareness:
 1. Silent Spring; by Rachel Carson.
 2. The Population Bomb; by Paul Ehrlich.
 The Closing Circle; by Barry Commoners.
1970’s

 The creation of the Environmental Protection Agency,

EPA
 The passage of the National Environmental Policy Act,
NEPA.
 The passage of 27 laws designed to protect the
environment.
1980’s
 Getting government off the back of business,
Reagan’s deregulation.
 Cutting EPA personnel by 20%, and EPA budget
by more than 33%
 Much of the administrative burden associated
with environmental policy was shifted to the
states.
 Decimated CEQ by drastic cuts in its budget.
 At the end of the decade, congress faced public
pressure to oppose Reagan’s environmental
policies.
 Voluntary Programs: ISO 14000.
1990’s
 Passage of the CLEAN AIR ACT in 1990.
 Federal courts were dominated by Reagan’s conservative appointees.
 Greater use market forces, make the polluter pay.
 1994 House of Representatives were committed to weaken environmental
regulations.
 Clinton maintained that he would veto any bill that would undermine
existing environmental protection.
1990’s continued
 Very few proposals became law by the end of 1995.
 A Republican pollster disclosed that only 35% of the public would vote to
reelect congressmen who voted to cut EPA funding.
 President Clinton enacted a series of environmental regulations through
executive order.
2001
 Bush’s first acts as president was to order agencies to suspend
implementation of Clinton’s environmental executive orders.
 Bush’s and his appointees Gale Norton, Christine Whitman, Spencer
Abraham, and others are committed to weaken environmental regulations.
 More than 80% of the public oppose drilling for oil in the Arctic National
Wildlife Refuge.
NATIONAL
ENVIRONMENTAL
 POLICY
Establishes the Council on Environmental Quality, CEQ; the federal

ACT

watchdog.
of 1970
Requires federal agencies to take environmental consequences into
account when making certain decisions.
 Requires an Environmental Impact Statement, EIS, for every major
legislative proposal or action having a significant impact on the
environment.
CEQ
 Made up of 3 persons, one is the chair, and staff to serve them.
 Advise the president about environmental matters.
 Gathers data, and publishes the President’s Annual Report on
Environmental Quality, a public report.
POLLUTION PREVENTION
ACT
 of
Remedies 1990
earlier end-of-pipe regulations, finds ways to prevent the
creation of pollution at the source.
 1993; Clinton issued executive order to improve pollution prevention in
the federal government.
 The PPA was very effective, and saved producers money by source
reduction and better engineering designs.
AIR QUALITY CONTROL
 The 1970 Clean Air Act targeted Auto and
Smokestacks Emissions, it significantly
improved air quality.
 The major air pollutants are:
 1. Sulfur Dioxide SO2; sources are volcanic
emissions, and the burning of high-sulfur
containing coal. It is highly corrosive and can
damage the respiratory tract
 2. Nitrogen Oxides; sources are lightning,
decomposing organics, and auto and industrial
emissions. It can damage the respiratory tract
and deplete the ozone layer
Continue; Major air pollutants
 3. Carbon Monoxide; sources are natural and also from incomplete burning
of fossil fuels, mainly auto emissions, it contributes to the global warming
and to the formation of ozone at low altitudes
 4. Ozone; Is the primary ingredient of smog, causes eye irritation, nasal
congestion, asthma, damage to lung and immune system. (The Ozone
layer is ozone at high altitude and protects life by blocking ultraviolet
radiation)
Continue; Major air pollutants
 5. Particulates; Natural sources include soil erosion, pollen, volcanoes.
Human made sources include diesel engines emissions, cement
manufacturing, road construction, wood-burning stoves, etc. Particulates
finer than 10 micrometers may not be filtered from the lungs, some
particulates are carcinogenic, some are irritants
Major air pollutants

 6. Lead; Major source was leaded gasoline which was

phased out in early 1970’s, metal processing is now the
major source. Lead harms the neurological system and
kidneys, may also cause seizures and mental retardation
Major air pollutants

 7. Airborne toxins; 188 airborne toxins are currently, or

will be, regulated after the passage of 1990 Clean Air
Act amendments. Sources include chemical plants,
plastics manufacturing and burning, oil refineries, etc.
They can be toxic or carcinogenic
GLOBAL AIR-QUALITY
PROBLEMS
 Acid rain; primary cause is SO2 and NOx emissions. SO2
and NOx gases can be carried in the atmosphere.
 Lakes on alkaline foundations like limestone will buffer
the harm of acid rain, lakes on granite foundations will
not buffer the acidity, and aquatic life may die
GLOBAL AIR-QUALITY
PROBLEMS
 Depletion of the Ozone Layer; the primary cause is the
use of chlorofluorocarbons, in refrigeration and air
conditioning. The Ozone layer blocks most of the UV
rays, which are harmful to all living organisms including
humans
GLOBAL AIR-QUALITY
PROBLEMS
 Global Warming; The majority of scientists think it
would be devastating if the trend continues. Effects
can be a rise in sea levels, increasing frequency of
severe hurricanes, floods, and droughts, and the
extinction of plant and animal species. We already
witnessed some effects
SOLUTIONS TO HUMAN
INDUCED CLIMATE CHANGE
 The 1997 Kyoto Protocol: An attempt by the global
community to reduce greenhouse emissions by 2012 to
5.2% below 1990 level
 The protocol can not be enforced without the
ratification of developed countries
 In 2001, president Bush pulled out of the Kyoto Protocol
INDOOR POLLUTION

 Poorly ventilated buildings can trap pollutants and

affect human health
 Source may come from outside air pollution, or from
inside from building materials, insecticides, solvents,
Radon, etc.
HISTORICAL APPROACH

 Earlier attempts to improve air quality started in the

1880’s
 Clean Air Act of 1963 did not mandate standards or
define air pollution
 1967 Air Quality Act; created 10 regions within which
pollution could be regulated, was ineffective
 The 1970 Clean Air Act was a success
1990 CLEAN AIR ACT

 Brought more resources under regulation

 More stringent controls on acid rain and air toxins
 Provided compliance deadlines
 Strengthened enforcement provisions