genetics and health
TRANSCRIPT
Human genome project - 5min
Gene therapy -10min
Population genetics - 5min
Preventive and social measures in genetics – 15min
Apr 18, 2023 2Dept. Community Medicine
Attempt to systematize the research on mapping and isolating human genes
Aims at identifying and sequencing all the genes in the human genome
Apr 18, 2023 Dept. Community Medicine 3
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
Apr 18, 2023 4Dept. Community Medicine
•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.
Apr 18, 2023 5Dept. Community Medicine
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 crimesApr 18, 2023 6Dept. Community Medicine
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)
Apr 18, 2023 Dept. Community Medicine 7
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.
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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.
Apr 18, 2023 Dept. Community Medicine 10
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'
Apr 18, 2023 Dept. Community Medicine 11
• 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.
Apr 18, 2023 12Dept. Community Medicine
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
Apr 18, 2023 13Dept. Community Medicine
Single gene disorders:(best results) Cystic fibrosis, Hemophilia, Sickle cell
anemia, Thalassemia, Huntington’s disease, Familial hypercholesterolemia
Polygene disorders (with difficulty) CHD, Hypertension, Diabetes Mellitus,
Arthritis, Alzheimer’s disease Others: Melanoma, Myeloid leukemia,
SCID, Parkinson disease, Metabolic disorders, Muscular dystrophy
Apr 18, 2023 15Dept. Community Medicine
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.
Apr 18, 2023 16Dept. Community Medicine
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
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In vivo = intravenous or intramuscular or non-invasive (‘sniffable’)Ex vivo = hepatocytes, skin fibroblasts, haematopoietic cells (‘bioreactors’)
Apr 18, 2023 18Dept. Community Medicine
• Monogenic gene therapy -Cystic fibrosis, Muscular dystrophy,
Sickle cell disease, Haemophilia, SCID• Suicide gene therapy - Cancer• Antisense gene therapy -AIDS/HIV
Apr 18, 2023 19Dept. Community Medicine
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
Apr 18, 2023 20Dept. Community Medicine
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
Apr 18, 2023 22Dept. Community Medicine
Ex vivo manipulation techniques• Electroporation• Liposomes• Calcium phosphate• Gold bullets (fired within helium pressurized gun)• Retrotransposons (jumping gene)• Human artificial chromosomes
Apr 18, 2023 23Dept. Community Medicine
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)
Apr 18, 2023 24Dept. Community Medicine
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
Apr 18, 2023 25Dept. Community Medicine
Short Lived
Immune Response
Viral Vectors
Multigene Disorders
May induce a tumor if integrated in a tumor suppressor gene because insertional mutagenesis
Apr 18, 2023 26Dept. Community Medicine
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?
Apr 18, 2023 27Dept. Community Medicine
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?
Apr 18, 2023 28Dept. Community Medicine
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
Apr 18, 2023 29Dept. Community Medicine
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)
Apr 18, 2023 30Dept. Community Medicine
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
Apr 18, 2023 Dept. Community Medicine 31
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
Apr 18, 2023 Dept. Community Medicine 32
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
Apr 18, 2023 Dept. Community Medicine 33
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 =1Apr 18, 2023 Dept. Community Medicine 34
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
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1. Health promotional measures Eugenics: Positive and Negative Eugenics Euthenics Genetic counseling Nutritional genomics
2. Specific protection3. Early diagnosis and treatment4. Rehabilitation
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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)
Apr 18, 2023 37Dept. Community Medicine
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
Apr 18, 2023 38Dept. Community Medicine
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 Apr 18, 2023 39Dept. Community Medicine
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
Apr 18, 2023 40Dept. Community Medicine
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.
Apr 18, 2023 41Dept. Community Medicine
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
Apr 18, 2023 42Dept. Community Medicine
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.
Apr 18, 2023 43Dept. Community Medicine
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.
Apr 18, 2023 44Dept. Community Medicine
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.
Apr 18, 2023 45Dept. Community Medicine
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
Apr 18, 2023 46Dept. Community Medicine
1.Prospective
Identifying heterozygous individuals
Explaining them the risk of having affected children if they marry
another heterozygote.
eg: sickle cell anemia [AR] thalasemia
Apr 18, 2023 49Dept. Community Medicine
.2) Retrospective: Disorder has already occurred in familycontraceptionAbortion sterilization
Apr 18, 2023 50Dept. Community Medicine
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 problem
Apr 18, 2023 51Dept. Community Medicine
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,)
Apr 18, 2023 52Dept. Community Medicine
2. Treatable hereditary diseases
Phenylketonuria (low phenylalanine diet) Galactosemia (exclusion of milk) Hemophilia (X-linked, Factor VIII or IX replacement)
Apr 18, 2023 53Dept. Community Medicine
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)
Apr 18, 2023 54Dept. Community Medicine
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
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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.
Apr 18, 2023 56Dept. Community Medicine
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.
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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
Apr 18, 2023 58Dept. Community Medicine
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
Apr 18, 2023 59Dept. Community Medicine
Genetic relationshipGenetic relationship Proportion of Proportion of shared genesshared genes
Risk of abnormality Risk of abnormality in offspringin offspring
1.First degree1.First degree
Parent/ChildParent/Child1/21/2 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 cousins1/81/8 3-53-5
Apr 18, 2023 60Dept. Community Medicine
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
Apr 18, 2023 61Dept. Community Medicine
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.
Apr 18, 2023 62Dept. Community Medicine
1) Lowering of consanguineous marriage
2) Early marriage better than late marriages
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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)
Apr 18, 2023 64Dept. Community Medicine
Methods of genetic testing• Cytogenetic Testing- FISH, aCGHCytogenetics involves the examination of whole
chromosomes for abnormalities• Biochemical TestingUtilizes techniques that examine the protein instead of
the gene• Molecular Testing- PCR
Apr 18, 2023 Dept. Community Medicine 65
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 4.Screening for neural tube defects and Trisomydefects and Trisomy
Chorionic GonadotropinChorionic Gonadotropin
Apr 18, 2023 66Dept. Community Medicine
Screening new born: genetic abnormality hypothyroidism PKU
Recognizing preclinical cases phenyl alanine tolerance test - PKU urine sugar - DM
Apr 18, 2023 67Dept. Community Medicine
Disorder/Effect TestTarget
PopulationIntended Use
Diabetes, Type II TCF7L2 General populationRisk 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 CancerGene expression
profilesWomen diagnosed with breast cancer
Treatment and recurrence risk
Apr 18, 2023 Dept. Community Medicine 68
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.
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.
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/project/about.shtml
Diseases and Gene Therapy - ADA-SCID. Available from: www.bgmoedlingkeim.ac.at/fachbereiche/biologie/gentherapie/pages/krankheiten/krankheiten_6.html
Genetic Research in India. Available from: www.chillibreeze.com/articles_various/Genetic-Research.asp
Apr 18, 2023 72Dept. Community Medicine