Genetics and health

MODERATOR: DR. SHIVASWAMY M. S.PRESENTER: DR. SUHASINI K.

Apr 18, 2023 1Dept. Community Medicine

Human genome project - 5min

Gene therapy -10min

Population genetics - 5min

Preventive and social measures in genetics – 15min


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


•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.


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)


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.



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.


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'


• 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.


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



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


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.


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


In vivo = intravenous or intramuscular or non-invasive (‘sniffable’)Ex vivo = hepatocytes, skin fibroblasts, haematopoietic cells (‘bioreactors’)


• Monogenic gene therapy -Cystic fibrosis, Muscular dystrophy,

Sickle cell disease, Haemophilia, SCID• Suicide gene therapy - Cancer• Antisense gene therapy -AIDS/HIV


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



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


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


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)


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


Short Lived

Immune Response

Viral Vectors

Multigene Disorders

May induce a tumor if integrated in a tumor suppressor gene because insertional mutagenesis


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?


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?


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


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)


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


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


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


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


1. Health promotional measures Eugenics: Positive and Negative Eugenics Euthenics Genetic counseling Nutritional genomics

2. Specific protection3. Early diagnosis and treatment4. Rehabilitation


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)


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


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


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.


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


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.


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.


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.


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




1.Prospective

Identifying heterozygous individuals

Explaining them the risk of having affected children if they marry

another heterozygote.

eg: sickle cell anemia [AR] thalasemia


.2) Retrospective: Disorder has already occurred in familycontraceptionAbortion sterilization


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


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,)


2. Treatable hereditary diseases

Phenylketonuria (low phenylalanine diet) Galactosemia (exclusion of milk) Hemophilia (X-linked, Factor VIII or IX replacement)


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)


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


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.


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.


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


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


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


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


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.


1) Lowering of consanguineous marriage

2) Early marriage better than late marriages


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)


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


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


Screening new born: genetic abnormality hypothyroidism PKU

Recognizing preclinical cases phenyl alanine tolerance test - PKU urine sugar - DM


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



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



Genetics and health

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