2. Human genome project - 5min
Gene therapy -10min
Population genetics - 5min
Preventive and social measures in genetics – 15min
Aug 16, 2015 2Dept. Community Medicine
3. Attempt to systematize the research on mapping
and isolating human genes
Aims at identifying and sequencing all the genes in
the human genome
Aug 16, 2015 Dept. Community Medicine 3
4. 1990: Project initiated as joint effort of U.S.
Department of Energy and the National Institutes of
Health.
June 2000: Completion of a working draft of the
entire human genome
February 2001: Analyses of the working draft were
published
April 2003: Sequencing was completed and Project
was declared finished two years ahead of schedule
Aug 16, 2015 4Dept. Community Medicine
5. •Chromosome 1 -2706 genes(highest), Y chromosome –
104genes (fewest)
•The human genome - 3 billion chemical nucleotide bases (A, C,
T, and G)
• The average gene consists of 3000 bases, but sizes vary
greatly, with the largest known human gene being dystrophin
at 2.4 million bases.
• Almost all (99.9%) nucleotide bases are exactly the same in all
people.
• The functions are unknown for over 50% of discovered genes.
Aug 16, 2015 5Dept. Community Medicine
6. Improve diagnosis of disease
Detect genetic predispositions to disease: Screening advice,
risk factor modification
Create drugs based on molecular information
Design “custom drugs” (pharmacogenomics) based on
individual genetic profiles
Use gene therapy for treatment
Identify potential suspects whose DNA may match
evidence left at crime scenes
Exonerate persons wrongly accused of crimes
Aug 16, 2015 6Dept. Community Medicine
7. Data generated by the Human Genome Project is
publicly accessible via web browsers such as
Ensembl (http:/www.ensembl.org)
UCSC (http://edu/cgi-bin/hgGateway)
Aug 16, 2015 Dept. Community Medicine 7
8. The Human Genome Project (HGP) was in full swing
that the idea of a large-scale systematic study of
human genomic variation was raised
Aimed - resource that promotes worldwide research
on human genetic diversity
Objective : define genetic relationship between
human population and interpret them in terms of
natural selection, genetic drift, migration.
Aug 16, 2015 Dept. Community Medicine 8
10. The main limitations of the current HGDP collection
are that the present list of populations is small and
does not evenly cover the inhabited regions of the
world
India and Polynesia are not represented at all, and
Europe, northern Asia, the Americas and Oceania
have limited representation.
Aug 16, 2015 Dept. Community Medicine 10
11. Difficulties in HGDP
Fear that indigenous people might be exploited by
the use of their DNA for commercial purposes ('bio-
piracy')
HGDP data would feed 'scientific racism'
Aug 16, 2015 Dept. Community Medicine 11
12. • Gene therapy – medical intervention based on
modification of the genetic material of living cells
through either in vivo or ex vivo therapy.
• Gene therapy typically aims to supplement a
defective mutant allele with a functional one.
Aug 16, 2015 12Dept. Community Medicine
13. A normal gene is inserted into the genome to
replace an abnormal disease-causing gene.
A vector is used to deliver the therapeutic gene to
the patient's target cells
Target cells such as the patient's liver or lung cells
are infected with the vector.
The vector then unloads its genetic material into the
target cell
The generation of a functional gene
Aug 16, 2015 13Dept. Community Medicine
16. 1) A normal gene may be inserted into a non-specific
location within the genome to replace a non-
functional gene.
2) An abnormal gene could be swapped for a normal
gene through homologous recombination.
3) The abnormal gene could be repaired through
selective reverse mutation, which returns the gene
to its normal function.
4) The regulation (the degree to which a gene is turned
on or off) of a particular gene could be altered.
Aug 16, 2015 16Dept. Community Medicine
17. Basically there are two types either by using
Somatic cells (most cells of the body)
Germ line cells (such as sperm cells, ova)
Somatic therapy
ex vivo
in vivo
Recombination-based approaches
Aug 16, 2015 17Dept. Community Medicine
18. In vivo = intravenous or intramuscular or non-invasive (‘sniffable’)
Ex vivo = hepatocytes, skin fibroblasts, haematopoietic cells (‘bioreactors’)
Aug 16, 2015 18Dept. Community Medicine
19. • Monogenic gene therapy
-Cystic fibrosis, Muscular dystrophy, Sickle cell
disease, Haemophilia, SCID
• Suicide gene therapy
- Cancer
• Antisense gene therapy
-AIDS/HIV
Aug 16, 2015 19Dept. Community Medicine
20. Viruses - Retroviruses
Adenoviruses
Adeno-associated viruses
Herpes simplex viruses
Non-viral methods - Naked DNA
oligodeoxynucleotides
lipoplexus
polyplexus
Hybrid methods- virosomes,ie virus+liposomes
Direct introduction of therapeutic DNA into target
cells
Aug 16, 2015 20Dept. Community Medicine
22. In vivo techniques usually utilize viral vectors
• Virus: carrier of desired gene, e.g. adenovirus,
retroviruses, herpes simplex virus.
• Virus is usually “crippled” to disable its ability to
cause disease
• Viral methods have proved to be the most
efficient to date
• Many viral vectors can stably integrate the desired
gene into the target cell’s genome
Aug 16, 2015 22Dept. Community Medicine
23. Ex vivo manipulation techniques
• Electroporation
• Liposomes
• Calcium phosphate
• Gold bullets (fired within helium pressurized gun)
• Retrotransposons (jumping gene)
• Human artificial chromosomes
Aug 16, 2015 23Dept. Community Medicine
24. On September 14, 1990 at the U.S. National
Institutes of Health, W. French Anderson M.D. and
his colleagues performed the first approved gene
therapy procedure on four-year old Ashanthi
DeSilva.
Born with a rare genetic disease called severe
combined immunodeficiency (SCID)
Aug 16, 2015 24Dept. Community Medicine
25. In Ashanthi's gene therapy
procedure, doctors
removed white blood cells
from the child's body, let
the cells grow in the
laboratory, inserted the
missing gene into the cells,
and then infused the
genetically modified blood
cells back into the patient's
bloodstream
Aug 16, 2015 25Dept. Community Medicine
26. Short Lived
Immune Response
Viral Vectors
Multigene Disorders
May induce a tumor if integrated in a tumor
suppressor gene because insertional mutagenesis
Aug 16, 2015 26Dept. Community Medicine
27. First human death from gene therapy
Jesse Gelsinger, a 17 year-old boy
Partial OTC deficiency (somatic mosaicism)
In September 1999 – ill , succumbed to death I a
month
Adequacy and quality of informed consent?
Aug 16, 2015 27Dept. Community Medicine
28. What is normal what is disability or disorder, and
who decides?
Do they need to be cured or prevented?
Does searching for a cure demean the lives of
individuals presently affected by disabilities?
Is somatic gene therapy more or less ethical than
germline gene therapy.
Gene therapy are exorbitantly expensive.
Who will have access to these therapies?
Who will pay for their use?
Aug 16, 2015 28Dept. Community Medicine
29. 1.Scientist at the National Institutes of Health
(Bethesda, MD) have successfully treated metastatic
melanoma in two patients using killer Tcells
genetically retargeted to attack the cancer cells.
2.University of California, Los Angeles, research team
gets genes into the brain using liposome's coated in
a polymer called polyethylene glycol (PEG). This
method has potential for treating Parkinson's
disease
Aug 16, 2015 29Dept. Community Medicine
30. 3.RNA interference or gene silencing may be a new
way to treat Huntington's disease
4.New gene therapy approach repairs errors in
messenger RNA derived from defective genes.
Technique has potential to treat the blood disorder
thalassaemia, cystic fibrosis, and some cancers.
5. Liposomes coated in polymer PEG – can cross the
blood-brain barrier (viral vectors are too big)
(January 2003)
Aug 16, 2015 30Dept. Community Medicine
31. Study of the precise genetic composition of
population and various factors determining the
incidence of inherited traits in them
The study of the change of allele frequencies,
genotype frequencies, and phenotype frequencies
Aug 16, 2015 Dept. Community Medicine 31
32. Gene pool = the complete set of genetic information
in all individuals within a population
Genotype frequency = proportion of individuals in a
population with a specific genotype
Genotype frequencies may differ from one
population to another
Allele frequency = proportion of any specific allele in
a population
Allele frequencies are estimated from genotype
frequencies
Aug 16, 2015 Dept. Community Medicine 32
33. One important implication of the HW Principle is
that the relative frequencies of each gene allele
tends to remain constant over time if the following
conditions are met:
The population is sufficiently large
Mating is random
Allelic frequencies are the same in males and
females
Selection does not occur -all genotypes have equal
in viability and fertility
Mutation and migration are absent
Aug 16, 2015 Dept. Community Medicine 33
34. When gametes containing either of two alleles, A or a,
unite at random to form the next generation, the
genotype frequencies among the zygotes are given by
the ratio
p2
: 2pq : q2
this constitutes the Hardy–Weinberg (HW) Principle
p = frequency of a dominant allele A
q = frequency of a recessive allele a
p + q =1
Aug 16, 2015 Dept. Community Medicine 34
35. Selection - variation in fitness; heritable
Mutation -change in DNA of genes
Migration - movement of genes across populations
Recombination = exchange of gene segments
Non-random Mating = mating between neighbors rather
than by chance
Random Genetic Drift = if populations are small enough, by
chance, sampling will result in a different allele frequency
from one generation to the next
Public health measures
Aug 16, 2015 Dept. Community Medicine 35
36. 1. Health promotional measures
Eugenics: Positive and Negative Eugenics
Euthenics
Genetic counseling
Nutritional genomics
1. Specific protection
2. Early diagnosis and treatment
3. Rehabilitation
Aug 16, 2015 36Dept. Community Medicine
37. In 1883 coins the word
‘Eugenics’ from the Greek for
good (‘eu’) and born
(‘genics’).
Defined as “the science of
improvement of the human
race through better
breeding.”
Francis Galton (1822-1911)
Aug 16, 2015 37Dept. Community Medicine
38. AIM-Reduce the frequency of hereditary diseases
and disability in the community as low as possible
But even after doing eugenic sterilization new cases
of hereditary diseases occur its because of
Fresh mutation
Marital alliance between hidden carriers of
Recessive defects
Aug 16, 2015 38Dept. Community Medicine
39. Producing genetically enhanced children, giving
them genetic characteristics (genotypes) they
ordinarily would not be born with, and encouraging
desirable individuals to bear more children.
Its being applied to in a prolific way
Improving cattle breeding by artificial insemination
to have increase yield of milk and have better quality
of animals for other purposes
Improving yields of grains
Aug 16, 2015 39Dept. Community Medicine
40. Negative eugenics: improving the quality of the
human race by eliminating or excluding biologically
inferior people from the population.
Preventing the births of children, with characteristics
(genotypes/phenotypes) viewed as unhealthy or
undesirable or preventing child bearing by
"undesirable" individuals.
Elderly and sick people killed under Hitler's policy
Aug 16, 2015 40Dept. Community Medicine
41. Euthenics: a science concerned with improving the
well-being of mankind through improvement of the
environment
Mere improvement of genotype is of no use unless
the improved genotype is given access to a suitable
environment
E.g. Children with mild mental retardation when
placed in an encouraging environment showed
improvement in their IQ.
Aug 16, 2015 41Dept. Community Medicine
42. Measures to improve the individual or phenotype
(the body) by biological or medical mean
Greek word meaning: “good appearing"
Eg. Phenylketonuria –stay on low phenylalanine diet
Aug 16, 2015 42Dept. Community Medicine
43. It is a communication of information about genetic
conditions, in a way which allows to make a
decision, as autonomous as possible
Safeguarding the emotional and ethical character of
the person who asks for the consultation.
Aug 16, 2015 43Dept. Community Medicine
44. Establish a diagnosis of hereditary or congenital
diseases in affected patients
Predict the probability of development of a
disease in individuals or families not yet affected
Take measures to alleviate the clinical expression of
such disease, to decrease the risk of its development
and possibly prevent it .
Predict birth of an offspring with a genetic disease
and allow decisions on the fate of the fetus.
Offer means for avoiding conception or
implantation of embryos with genetic diseases.
Aug 16, 2015 44Dept. Community Medicine
45. Mentally retarded babies, for congenital anomalies,
Psychiatric illness, Inborn error of metabolism
Populations at risk due to - reproductive age,
environment like exposure to radiations or
mutagens, lifestyle, geographical considerations like
areas with high prevalence of genetic disease
Screening programs for population at large scale
like "supermarket" genetic testing.
Aug 16, 2015 45Dept. Community Medicine
46. Genetic counseling is done by specialized physicians,
or by primary care providers with
more or less certification training in medical
genetics, like
Medical geneticists: MDs,
pediatricians
PhDs in medical genetics –
Counselors: MSc level
Aug 16, 2015 46Dept. Community Medicine
50. .2) Retrospective:
Disorder has already occurred in family
contraception
Abortion
sterilization
Aug 16, 2015 50Dept. Community Medicine
51. Not well established
Available at AIIMS,JIPMER,SGPGI,Sri Gangaram
Hospital New Delhi.
Basically sought for congenital malformations,
mental retardation
W.H.O recommends establishment of genetic
counseling centres in significant numbers in regions
where nutritional and infectious diseases are
brought under control and in areas where genetic
diseases always constitutes a major health problemAug 16, 2015 51Dept. Community Medicine
52. 1. Lethal in childhood or grave malformations:
Tay-Sachs (GM2 ganglioside, hexaminidase
deficiency, life-span 4 years)
Mucopolysaccharidoses ( death in 2nd decade)
Gaucher Type II (betaglucosidase, lethal in
childhood)
Cystic fibrosis (respiratory disease, median life-span
25 years)
Achondroplasia ( malformations, )
Trisomy 21 (Down’s syndrome,)
Aug 16, 2015 52Dept. Community Medicine
53. 2. Treatable hereditary diseases
Phenylketonuria (low phenylalanine diet)
Galactosemia (exclusion of milk)
Hemophilia (X-linked, Factor VIII or IX replacement)
Aug 16, 2015 53Dept. Community Medicine
54. 3. Late appearing genetic diseases
Huntington’s chorea (40 years;)
Myotonic dystrophy (onset in adult life,)
Familial hypercholesterolemia (onset 30-40 years,
responds to treatment)
Alzheimer disease (at least 3 genes, Presenilin I, II,
APO-E)
Aug 16, 2015 54Dept. Community Medicine
55. 4.Multifactorial diseases and their genes
Diabetes 5% incidence but 6 genes
e.g. MODY = glucokinase gene
Cardiovascular diseases
e.g. cholesterol receptors, angiotensin locus,
coagulation factor V
Aug 16, 2015 55Dept. Community Medicine
56. Establishment of diagnosis : clinical examination,
pedigree analysis, laboratory tests and follow up.
Calculating the risk: using mendelian or empiric risk
figures or Bayesian analysis.
Discussing the option
Communication and support.
Aug 16, 2015 56Dept. Community Medicine
57. The study of how different foods can interact with
particular genes and alter the diseases process, as in
type 2 diabetes, obesity, heart disease and some
cancers.
Aug 16, 2015 57Dept. Community Medicine
58. Potential Benefits:
– Increased focus on a healthy diet and lifestyle
– Motivate positive behavior change
– Improve health and quality of life
– Focus on prevention
– Decrease morbidity and premature mortality
– Reduce health care costs
– Identify subgroups who might be particularly responsive or
resistant to environmental (dietary) intervention
– Better understanding of the mechanisms involved in
disease susceptibility
Aug 16, 2015 58Dept. Community Medicine
59. Potential Harms:
– Focus on specific nutrients/foods
– Attention is drawn away from other modifiable risk
factors
– Decreased use of other services
– Increased costs associated with personalized diets and
designer foods
Aug 16, 2015 59Dept. Community Medicine
60. Genetic relationshipGenetic relationship Proportion of sharedProportion of shared
genesgenes
Risk of abnormality inRisk of abnormality in
offspringoffspring
1.First degree1.First degree
Parent/ChildParent/Child
1/21/2 5050
2.Second degree2.Second degree
Uncle/NieceUncle/Niece
Aunt/NephewAunt/Nephew
Double first cousinDouble first cousin
1/41/4 5-105-10
3.Third degree3.Third degree
First cousinsFirst cousins
1/81/8 3-53-5
Aug 16, 2015 60Dept. Community Medicine
61. Protection of individuals and whole community
against mutagens such as X-rays and other
ionizing radiations
Patients undergoing X-ray examination should be
protected against unnecessary exposure of
gonads to radiations.
Prevention of Rh hemolytic disease of newborn by
immunization with anti-D globulin
Aug 16, 2015 61Dept. Community Medicine
62. Congenital rubella :immunization
Neural tube defect : folic acid
Fetal macrosomia and malformation: dectection
and control of maternal diabetes.
Congenital malformation of heart : avoidance of
mutagens and teratogens.
Aug 16, 2015 62Dept. Community Medicine
63. 1) Lowering of consanguineous marriage
2) Early marriage better than late marriages
Aug 16, 2015 Dept. Community Medicine 63
64. Types of genetic testing:
Detection of genetic carriers/ Carrier testing
Prenatal diagnosis
Screening of newborn infant
Predictive and presymptomatic testing/ Recognizing
pre-clinical cases
Diagnostic testing
Preimplantation testing
Forensic testing(legal purpose)
Aug 16, 2015 64Dept. Community Medicine
65. Methods of genetic testing
• Cytogenetic Testing- FISH, aCGH
Cytogenetics involves the examination of whole
chromosomes for abnormalities
• Biochemical Testing
Utilizes techniques that examine the protein instead of
the gene
• Molecular Testing- PCR
Aug 16, 2015 Dept. Community Medicine 65
66. INDICATIONSINDICATIONS METHODSMETHODS
1.Advanced maternal age1.Advanced maternal age
.previous child with chromosomal.previous child with chromosomal
aberrationsaberrations
.intrauterine growth delay.intrauterine growth delay
Cytogenetics(amniocentosisCytogenetics(amniocentosis
Choroinic villous sampling)Choroinic villous sampling)
2.Biochemical disorders2.Biochemical disorders Protein assay,DNA diagnosisProtein assay,DNA diagnosis
3.Congenital anomaly3.Congenital anomaly Sonography,FetoscopySonography,Fetoscopy
4.Screening for neural tube defects4.Screening for neural tube defects
and Trisomyand Trisomy
Chorionic GonadotropinChorionic Gonadotropin
Aug 16, 2015 66Dept. Community Medicine
67. Screening new born:
genetic abnormality
hypothyroidism
PKU
Recognizing preclinical cases
phenyl alanine tolerance test - PKU
urine sugar - DM
Aug 16, 2015 67Dept. Community Medicine
68. Disorder/Effect Test Target Population Intended Use
Diabetes, Type II TCF7L2 General population
Risk assessment;
nutritional/lifestyle
management
Cardiovascular Disease Multigene panels General population
Risk assessment; drug
or nutritional/lifestyle
management
Hereditary
Nonpolyposis
Colorectal Cancer
(HNPCC)
Mismatch repair gene
mutations
Individuals diagnosed
with CRC and their
family members
Management of
individuals and
prevention/early
detection for family
members
Thrombophilia F5, F2
Individuals with family
history or clinical
suspicion of
thrombophilia
Prevention and
management
Breast Cancer
Gene expression
profiles
Women diagnosed with
breast cancer
Treatment and
recurrence risk
Aug 16, 2015 Dept. Community Medicine 68
70. National Centre of Applied Human Genetics: started in March
1980 at the Institute of Medical Sciences, Banaras Hindu
University followed by establishing Human Genetics in a
university setting at Jawaharlal Nehru University since March
1989.
April 2002: Human Genetics Laboratory of JNU was
announced as National Centre of Applied Human Genetics.
71. Research institutes in India:
1. NII (National Institute of Immunology) New Delhi.
2. NCCS (National Centre for Cell Science) Pune.
3. CDFD (Centre for DNA Fingerprinting and Diagnostics) Hyderabad.
4. NBRC (National Brain Research Centre) Manesar.
5. Institute for Bioresources and Sustainable Development, Imphal.
6. Institute of Life Sciences, Bhubaneshwar.
7. Bharat Immunologicals and Biologicals Corporation Limited,
Bulandshehar.
8. Indian Vaccines Corporation Limited Gurgaon.
1. These institutions are equipped with world-class
instrumentation and have been provided with highly
competent human resources.
72. Park’s Textbook of Preventive and Social Medicine-23rd
edition
Sunder Lal. Textbook of Community Medicine
Essentials Medical Genetics – Edward S. – 6th
edition
National Centre of Applied Human Genetics.
Human Genome Project Information. Available from:
www.ornl.gov/sci/techresources/Human_Genome/proj
ect/about.shtml
Diseases and Gene Therapy - ADA-SCID. Available from:
www.bgmoedlingkeim.ac.at/fachbereiche/biologie/gentherap
Genetic Research in India. Available from:
www.chillibreeze.com/articles_various/Genetic-
Research.asp
Aug 16, 2015 72Dept. Community Medicine