1. GENETICS AND HEALTH
DR. RAGHAVENDRA
HUCHCHANNAVAR
JUNIOR RESIDENT

2. contents
• Introduction
• Genetic disorders
• Disease burden
• Human genomic project
• Gene therapy
• Preventive and social measures in genetics
• Research in India
• Future

3. Introduction
Charles Darwin (1809 - 1882)
1859: Theory of natural selection- members of
a population who are better adapted to the
environment survive and pass on their traits.
Gregor Mendel (1822 – 1884)
1866: Gregor Mendel published his
work “Experiments in Plant
Hybridization”, which set out the
basic theory of genetics.

4. Introduction
Friedrich Miescher (1844 – 1895)
1871: Isolated “nucleic acid” from pus cells.
1902: Archibald Garrod discovered that alkaptonuria
has a genetic basis.
Archibald Garrod

5. Introduction
• 1953: James Watson and Francis
Crick determine the structure of
the DNA molecule.
• 1966: Marshall Nirenberg solves
Marshall Nirenberg
Watson and Crick the genetic code, showing that 3
DNA bases code for one amino
acid.
• 1990: First gene therapy was
performed, Ashanti DeSilva was
treated for SCID by Dr. W.French
Anderson.
Dr. W.French Anderson Ashanti DeSilva
and Ashanti DeSilva

6. Introduction
• 1993: Dr. Kary Mullis
discovers the PCR procedure
• 1997: Dolly the sheep - the
first adult animal clone.
Dr. Kary Mullis
• 2003: Sequence of the entire
human genome is announced

7. Classification
Classification of diseases based on their genetic basis as
• Monogenic (Mendelian) disorders
• Chromosomal aberrations
• Polygenic disorders

8. Mendelian disorders
6 general patterns of inheritance are observed:
• Autosomal recessive
• Autosomal dominant
• X-linked recessive
• X-linked dominant
• Co-dominant
• Mitochondrial

9. Mendelian disorders
Autosomal recessive
• The disease appears in male
and female children of
unaffected parents.
• e.g., Cystic
Fibrosis, Phenylketonuria

10. Mendelian disorders
Autosomal dominant
• Affected males and females
appear in each generation of
the pedigree.
• Affected mothers and fathers
transmit the phenotype to
both sons and daughters.
• e.g., Neurofibromatosis, Adul
t polycystic kidney disease

11. Mendelian disorders
X-linked recessive
• Many more males than
females show the disorder.
• All the daughters of an
affected male are
“carriers”.
• None of the sons of an
affected male show the
disorder or are carriers.
• e.g., Hemophilia A and
B, Colour blindness

12. Mendelian disorders
X-linked dominant
• Affected males pass the
disorder to all daughters but
to none of their sons.
• Affected heterozygous
females married to
unaffected males pass the
condition to half their sons
and daughters
• e.g. Vitamin D resistant
rickets, Familial
hypophosphatemia

13. Mendelian disorders
Co-dominant inheritance
• Two different versions
(alleles) of a gene can be
expressed, and each
version makes a slightly
different protein
• Both alleles influence the
genetic trait or determine
the characteristics of the
genetic condition.
• E.g. ABO locus

14. Mendelian disorders
Mitochondrial inheritance
• 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)

15. Chromosomal aberrations
• Alternations in the number or structure of chromosomes
• Autosomes or sex chromosomes
• Numerical abnormalities –
– Polyploidy (3n or 4n),
– Trisomy (2n+1): Klienfelter’s syndrome
– Monosomy (2n-1): Turner’s syndrome
• Structural abnormalities - breakage followed by loss or
rearrangement deletion, translocation. E.g. t(9;22) in CML

16. multifactorial inheritance
(polygenic)
• Influence of multiple genes and environmental factors
• These include mainly the non-communicable diseases
– Diabetes mellitus
– Hypertension
– Cardiovascular diseases
– Cancers

17. Burden of genetic diseases
• Each year more than 3 million children born with a serious
genetic defect die; most of these deaths (90%) occur in
developing countries.
• In the western world, there is 1% chance of having an
inherited disease at birth.
• Approximately 5% of the world‟s population carries trait genes
for haemoglobin disorders, mainly sickle-cell disease and
thalassemia.
• Over 300 000 babies with severe haemoglobin disorders are
born each year.

18. Burden of genetic diseases
• The estimated incidence of Down Syndrome is 1 in 1,000 live
births worldwide.
• Each year approximately 3,000 to 5,000 children are born with
this chromosome disorder and it is believed there are about
250,000 families in the United States of America who are
affected by Down Syndrome.
• The incidence of Cystic Fibrosis varies across the globe.
Although it is severely underdiagnosed in Asia, existing
evidence indicates that the prevelance of CF is rare. In the
United States of America the incidence of CF is reported to be
1 in every 3500 births.

19. Burden of genetic diseases in
india
DISORDER INCIDENCE BIRTHS/YEAR
Congenital Malformations 1:50 678,000
Down syndrome 1:800 34,000
Metabolic disorders 1:1200 22,500
Β-thalassemia & sickle cell 1:1700 16,700
disease
Congenital hypothyroidism 1:2500 10,900
Duchenne muscular 1:10000 2,700
dystrophy
Spinal muscular atrophy 1:10000 2,700
Source: Center of Medical Genetics, New Delhi, 2011

20. High Prevalence in india is due to:
• Consanguineous marriages
• High birth rate
• Poor governmental support facilities
• Lack of expertise in genetic counseling
• Lack of improved diagnostic facilities

21. Burden of ncd in india
Diseases Prevalence (per Cases (in millions)/ Deaths (in
thousand) year millions)/ year
Diabetes mellitus 62.4 37.7 0.11
Ischemic heart 37 22.3 0.55
disease
Stroke 1.54 1.64 0.63
Hypertension 159.4 94.8

22. Most diseases have a genetic
component
Heart
disease
Cystic PKU Schizophrenia Motor
Cancer
fibrosis vehicle
Fragile X Multiple Alzheimers accident
TB
sclerosis
Diabetes Obesity
Duchenne Struck
Asthma Autism
muscular Rheumatoid by
dystrophy arthritis Meningococcus lightning
Totally Totally
Genetic Environmental

23. Gene-Environment Interaction
• Some vegetarians with
'acceptable' cholesterol
levels suffer myocardial
infarction in the 30's.
• Other individuals seem to
live forever despite
personal
stress, smoking, obesity
and sedentary lifestyle.

24. Genetics v/s genomics
• Genetics:
– Conditions caused by an extra or missing
chromosome or part of a chromosome, caused by a
mutation in a single gene in chromosome or in a
mitochondria.
– Are important to the individuals and families who have
them
• Genomics:
– refers to those conditions plus discoveries from the
Human Genome Project (HGP) which show that most
adult onset and chronic diseases can be partially
caused or prevented by genetic factors.
– Environmental factors also play a significant role
Genomics 101: An Introduction

25. The Human Genome Project
• 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 are published
• April 2003: Human Genomic Project sequencing is completed
and Project is declared finished two years ahead of schedule

26. The Human Genome Project
Results
• The human genome contains 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.
• The total number of genes is estimated at around 30,000--much
lower than previous estimates of 80,000 to 140,000.
• Almost all (99.9%) nucleotide bases are exactly the same in all
people.
• The functions are unknown for over 50% of discovered genes.
U.S. Department of Energy Genome Programs, Genomics and Its Impact on Science and Society, 2003

27. The Human Genome Project
 Benefits of Genome Project
• 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
U.S. Department of Energy Genome Programs, Genomics and Its Impact on Science and Society, 2003

28. Pharmacogenomics
 Pharmacogenomics
– The development of drugs tailored to specific
subpopulations based on genes
– Pharmacogenomics has the potential to:
• Decrease side effects of drugs
• Increase drug effectiveness
• Make drug development faster and less costly
• use of medications otherwise rejected because of side
effects
• new medications for specific genotypic disease subtypes
Genomics 101: An Introduction

29. Closing the Gap
HuGENet
Population Human
Studies
Genome
US Genome Profile
Epidemiology
Public Health Studies
Network
Gene Population
Closing the Gap
Discovery Health
EGAPP
Practice
Evaluation of
Family history
Genomic
State Capacity
Applications in
Genomics Centers
Practice &
Prevention

30. Human Genome Epidemiology
Network
• HuGENet: A global collaboration of individuals and
organizations committed to
– the assessment of the impact of human genome variation on
population health.
– how genetic information can be used to improve health and
prevent disease.

31. EGAPP
Evaluation of CDC-funded initiative intended to
Genomic establish and test a systematic, evidence-
Applications in based process for evaluating genetic tests
Practice and and other applications of genomic
Prevention technology in transition from research to
practice.

32. Approach to Genomics Translation:
Application to Cancer
Promising Evidence based
Application Guideline/
(e.g. genetic test) Policy
Cancer
Discoveries Population Practice &
(e.g. genetic
risk factor)
Sciences Control
Programs
Reducing the
Burden of
Cancer

33. gene therapy
• Gene Therapy: Introduction of normal genes into cells that
contain defective genes to reconstitute a missing protein
product.
• Gene therapy is used to correct a deficient phenotype so that
sufficient amounts of a normal gene product are synthesized to
improve a genetic disorder
• Modification of cells by transferring desired gene sequences
into the genome.
• Delivery systems available:
– In vivo: delivery of genes takes place in the body
– Ex vivo: delivery takes place out of the body, and then
cells are placed back into the body

34. gene therapy
• 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

35. gene therapy
• Ex vivo manipulation techniques
– Electroporation
– Liposomes
– Calcium phosphate
– Gold bullets (fired within helium pressurized gun)
– Retrotransposons (jumping gene)
– Human artificial chromosomes

36. gene therapy
Somatic Cell Nuclear Transfer (SCNT)

37. Successful Gene Therapy for
Severe Combine Immunodeficiency
• Infants with severe combined immunodeficiency are unable to
mount an adaptive immune response, because they have a
profound deficiency of lymphocytes due to a deficiency of
adenosine deaminase.
• In these patients, peripheral T cells were transduced with a
vector bearing the gene for adenosine deaminase.
• The experiment was extremely labor intensive, because mature
peripheral-blood T cells were modified rather than stem
cells, and the procedure therefore had to be repeated many
times to achieve success.

38. Unsuccessful Gene therapy
• Jesse Gelsinger, a gene therapy patient who lacked ornithine
transcarbamylase activity, died in 1999 due to multi-organ
failure following gene therapy.
• One problem with gene therapy is that one does not have
control over where the gene will be inserted into the genome.
The location of a gene in the genome is of importance for the
degree of expression of the gene and for the regulation of the
gene (the so-called "position effect"), and thus the gene
regulatory aspects are always uncertain after gene therapy

39. Problems with Gene Therapy
• Short Lived
– Hard to rapidly integrate therapeutic DNA into genome and
rapidly dividing nature of cells prevent gene therapy from
long time
– Would have to have multiple rounds of therapy
• Immune Response
– new things introduced leads to immune response
– increased response when a repeat offender enters
• Viral Vectors
– patient could have toxic, immune, inflammatory response
– also may cause disease once inside
• Multigene Disorders
– Heart disease, high blood pressure, Alzheimer‟s, arthritis
and diabetes are hard to treat because you need to introduce
more than one gene
• May induce a tumor if integrated in a tumor suppressor gene
because insertional mutagenesis

40. Preventive and social
measures in genetics
1. Health promotional measures
– Eugenics: Positive and Negative Eugenics
– Euthenics
– Genetic counseling
– Nutritional genomics
2. Specific protection
3. Early diagnosis and treatment
4. Rehabilitation

41. eugenics
• 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)

42. eugenics
• Negative eugenics • Positive eugenics

43. Negative eugenics
• Negative eugenics: improving the quality of the human race by
eliminating or excluding biologically inferior people from the
population.
• This goal required severe restrictions on reproductive rights,
for those with "defects" had to be kept from reproducing, if
necessary through the forceful sterilization.
• Elderly and sick people killed under Hitler's policy of
eugenics.

44. Positive eugenics
• Positive eugenics: promotes marriage and breeding between people
considered "desirable", and though a positive Eugenist may view
certain persons as "undesirable", they will not initiate in such
practices as non-voluntary sterilization, genocide, active
euthanasia, or any other forms of violence.
• In fact, as these eugenists say that, “the defective will always be
with us, since people with hereditary defects come from the general
population and not strictly, from other defectives there is no logical
way to get rid of them. By promoting marriage and unions between
Desirables, it may be possible to increase the national even universal
average in the course of four or so generations”

45. Euthenics
• 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, which will enable the gene to express
themselves readily.
– E.g. Children with mild mental retardation when
placed in an encouraging environment showed
improvement in their IQ.

46. Genetic Counseling
• The genetic is done by a genetic counselor who is a health
professional who is academically and clinically prepared to
provide genetic services to individuals and families seeking
information about the occurrence, of risk of occurrence, of a
genetic condition or birth defect.
• The counselor provides client-centered, supportive counseling
regarding the issues, concerns, and experiences meaningful to
the client‟s circumstances.
American Board of Genetic Counseling

47. Genetic Counseling
• The genetic counselor communicates
– Genetic,
– Medical and
– Technical information
in a comprehensive, understandable manner with
knowledge of psychosocial and cultural background of each
client and their family.
American Board of Genetic Counseling

48. Prenatal Genetic Counseling
• Preconception Counseling: if learned prior to conception that
female and/or her partner are at high risk for having a child
with a severe or fatal defect.
• Options will be:
– Pre-implantation diagnosis - when eggs that have been
fertilized in vitro (in a laboratory, outside of the womb) are
tested for defects at the 8-cell (blastocyst) stage, and only
non-affected blastocysts are implanted in the uterus to
establish a pregnancy
– Using donor sperm or donor eggs
– Adoption

49. Indications for Prenatal Diagnosis
• Advanced maternal age • Family history of other
• Previous child with a congenital structural
chromosome abnormality abnormalities
• Family history of a • Abnormalities identified in
chromosome abnormality pregnancy
• Family history of single • Other high risk factors
gene disorder (consanguinity, poor
• Family history of neural obstetric history, maternal
tube defect (NTD) illnesses)

50. Prenatal screening for genetic
disorders
• Invasive testing: • Non-invasive testing:
− Amniocentesis − Ultrasonography
− Chorionic villus sampling − Maternal serum AFP
(CVS) − Isolation of foetal cells from
− Cordocentesis maternal circulation
− Preimplatation genetic
diagnosis
− Fetoscopy

51. Prenatal screening techniques
• Preimplantation Genetic Diagnosis
(PGD) uses in vitro fertilisation
(IVF) to create embryos.
• Test one or two cells from each
embryo for a specific genetic
abnormality.
• Identify unaffected embryos for
transfer to the uterus.
• Assists couples at risk of an inherited
disorder to avoid the birth of an
affected child.

52. Nutritional Genomics
• 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.

53. Nutritional Genomics
• Potential Benefits:
– Increased focus on a healthy diet and lifestyle
– Motivate positive behavior change
– Improved health and quality of life
– Focus on prevention
– Decreased morbidity and premature mortality
– Reduced health care costs
– Identify subgroups who might be particularly
responsive or resistant to environmental (dietary)
intervention
– Better understanding of the mechanisms involved in

54. Nutritional Genomics
• Potential Harms:
– Focus on specific nutrients/foods
– Attention is drawn away from other modifiable risk
factors
– Decreased use of other services
– False sense of security
– Misleading claims
– Increased costs associated with personalized diets
and designer foods

55. Specific protection
• Specific protection:
– 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

56. Early diagnosis and
treatment
• Post-implantation: Received a diagnosis of a severe or fatal defect
after conception.
• Options might include : -
– Preparing family for the challenges they will face when they
have a baby
– Fetal surgery to repair the defect before birth (surgery can only
be used to treat some defects, such as spina bifida or congenital
diaphragmatic hernia. Most defects cannot be surgically
repaired.)
– Ending the pregnancy: For some families, knowing that they'll
have an infant with a severe or fatal genetic condition seems too
much to bear.
– Referral to cardiologist to discuss heart surgery, and a
neonatologist to discuss the care of a post-operative newborn.

57. screening for thalassemia
and hemoglobinopathies
• Carrier screening for thalassemia and hemoglobinopathies
should be offered to a woman if she and/or her partner are
having a positive family history.
• Ideally, this screening should be done pre-conceptionally or as
early as possible in the pregnancy.
• Screening should consist of a complete blood count, as well as
hemoglobin electrophoresis include quantitation of HbA2 and
HbF.
• If a woman‟s initial screening is abnormal (e.g., showing
microcytosis or hypochromia with or without an elevated
HbA2, or a variant Hb on electrophoresis or high performance
liquid chromatography) then screening of the partner should be
performed.

58. screening for thalassemia
and hemoglobinopathies
• If both partners are found to be carriers of thalassemia or an
Hb variant, or of a combination of thalassemia and a
hemoglobin variant, they should be referred for genetic
counselling. Ideally, this should be prior to conception, or as
early as possible in the pregnancy.
• Prenatal diagnosis should be offered to the pregnant
woman/couple at risk for having a fetus affected with a
clinically significant thalassemia or hemoglobinopathy.
• Prenatal diagnosis by DNA analysis can be performed using
cells obtained by chorionic villus sampling or amniocentesis.

59. Average treatment cost
• Blood transfusion therapy in a
government setup - Rs 250-350
• Average annual expenditure -
around Rs 5000/-
• Bone marrow transplantation -
Rs10 lakh

60. Rehabilitation
• Rehabilitation: Early referral of children with genetic disorders
which are known to cause physical or mental disability.

61. Disorder/Effect Test Target Population Intended Use
Risk assessment;
Diabetes, Type II TCF7L2 General population nutritional/lifestyle
management
Risk assessment; drug or
Multigene
Cardiovascular Disease General population nutritional/lifestyle
panels
management
Management of individuals
Individuals diagnosed with
Hereditary Nonpolyposis Mismatch repair and prevention/early
CRC and their family
Colorectal Cancer (HNPCC) gene mutations detection for family
members
members
Individuals with family
Prevention and
Thrombophilia F5, F2 history or clinical suspicion
management
of thrombophilia
Gene expression Women diagnosed with Treatment and recurrence
Breast Cancer
profiles breast cancer risk
Source: National office of Public Health Genomics, CDC

62. Research in india
• 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.

63. Research in india
• CURRENT RESEARCH ACTIVITY:
1. Genetic Susceptibility to Infectious Diseases:
Leprosy, Liver Failure.
2. Genetic Susceptibility to Cancer : In-Vitro and In-Vivo
models and Cancer Patient studies.
3. Molecular Characterization of Pyruvate kinase-M2
and its inhibitor in Bloom syndrome cells.
4. Structural and Functional Genomic studies and
offering molecular diagnostic services for common
and rare genetic diseases

64. Research in india
• 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.
• These institutions are equipped with world-class instrumentation
and have been provided with highly competent human resources.

65. Research in haryana
• Haryana: Department of Genetics and Department of
Biotechnology, MDU, Rohtak
• Current projects:
1. Evaluation of mental retardation cases in Haryana
population by cytogenetic analysis. (ICMR)
2. Molecular cytogenetic characterization of X-linked
mental retardation patients.
• Other research topics :
– Cytogenetic and pathological analysis of AML and its
significance as prognostic indicators
– Hematological and molecular genetic analysis of β-
thalassemia patients in Haryana

66. Future
"I am convinced that within five years every
college-educated person in America is going to
have a profile like this. You cannot afford not
having this.“
Kari Stefansson, 2009
neurologist, President and co-founder of deCODE
Genetics

67. Future
“The Year of perfect vision 2020”
JAMA March 20, 2008
"I predict that comprehensive, genomics-
based health care will become
the norm with individualized preventive
medicine and
early detection of illnesses”
Elias Zerhouni
NIH Director (2002-06)
Predictive, Preventive and
Personalized Medicine

68. references
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http://cbhidghs.nic.in/writereaddata/mainlinkFile/File1012.pdf
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http://www.abgc.net/docs/gcbrochure%20final.pdf
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on Science and Society, 2003. available from:
http://www.ornl.gov/sci/techresources/Human_Genome/publicat/primer200
1/index.shtml
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http://www.genetics.edu.au
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www.indiahospitaltour.com/ivf/genetic-counseling-india.html
• Maharshi Dayanand University, Rohtak. Department of Genetics. Available
from: www.mduonline.net
• Genetic Disorders & Gene Therapy. Available from:
http://genmed.yolasite.com/basics-of-gene-therapy.php

69. references
• K. Park. Textbook of Preventive and Social Medicine. Genetics and health:
2011: 21:760-770
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70. references
• Gregor Mendel. Available from: http://en.wikipedia.org/wiki/Gregor_Mendel
• Archibald Garrod. Available from:
http://en.wikipedia.org/wiki/Archibald_Garrod
• Elias Zerhouni. Available from: http://en.wikipedia.org/wiki/Elias_Zerhouni
• Friedrich Miescher. Available from:
http://en.wikipedia.org/wiki/Friedrich_Miescher
• Genetic Research in India. Available from:
www.chillibreeze.com/articles_various/Genetic-Research.asp
• The Basics of Gene Therapy. Available from:
http://genmed.yolasite.com/basics-of-gene-therapy.php
• Thalassemia Prevention: Screening and Prenatal Diagnostic Approaches.
http://www.gfmer.ch/SRH-Course-2011/community-genetics/Thalassemia-
Kleanthous-2011.html
• S Mallik, C Chatterjee, Pankaj K Mandal, Jadab C Sardar, P Ghosh, N Manna.
Expenditure to Treat Thalassaemia: An Experience at a Tertiary Care Hospital
in India. Iranian J Publ Health 2010: 39(1); 2010:78-84

71. HOPE INDIA TOO WILL HAVE SUCH DREAMS
AND MAKE IT A REALITY
THANK YOU