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GENETIC VARIATIONS AND ITS ROLE IN HEALTH /
PHARMACOLOGY
Department of pharmacology
Under the guidance of
Vivek Kumar Tiwari
(M.Pharm)
Submitted by,
M.Srivani
(Regd No: 1702-18-887-014)
GOKARAJU RANGARAJU COLLEGE OF PHARMACY
(Affiliated to Osmania University)
Bachupally, Nizampet Road
Hyderabad -500090.
CONTENTS
• What are genetic variations?
• Why genetic variation is important?
• Examples
• Mechanisms of genetic variations
• Causes
• Sources
• Factors affecting
• Role in health/ pharmacology
• Advances in genetic variations
DNA
Gene
Chromosome
Allele
Genome
Genotype
Phenotype
Genetics
variations
WHY GENETIC VARIATION IS IMPORTANT?
• Adaptability
• Survival
• Evolution
• Reproduction
• Genomic combinations
• Natural selection can occur
EXAMPLES
• Skin color, hair color, multi-colored eyes, dimples
• Modified leaves of carnivorous plants
• Cheetahs with stripes, snakes that fly, animals that play dead
MECHANISMS OF GENETIC VARIATION
• Mutations
• Genetic drift
• Gene flow or migration
• Non- random mating
• Natural selection
Mutations
Genetic drift
Gene flow/ Migration Non-random mating
Natural selection
CAUSES OF GENETIC VARIATIONS
1. GENETIC FACTORS
A) SEXUAL REPRODUCTION
Crossing over
Random mating/ Independent assortment
Random fertilization
B) MUTATIONS
2. ENVIRONMENTAL FACTORS
SOURCES OF GENETIC VARIATION
1. MUTATIONS
- Causes
A) DNA fails to copy accurately
B) External influences can create mutations
- Types
2. MEIOTIC DIVISIONS 3. SEXUAL REPRODUCTION
Male + Female gametes (haploid cell)
46 chromosomes in haploid gametes
(23 in each)
Each gene has 2 alleles (223)
8 million possible chromosome
combinations (223)
Fertilization (ovum + sperm)
(223 * 223)
1 to 70 trillion possibilities
4. ERRORS IN CHROMOSOME
SEGREGATION
5. HORIZONTAL ACQUISITION OF
GENES
Replication of genetic material (no equal
chromosome segregation)
No equal distribution in daughter cells
Abnormal number of chromosomes in
daughter cell (ploidy changes)
Example: Down syndrome is caused due
to trisomy of chromosome21.
FACTORS AFFECTING GENETIC VARIATION
1. Mating partners are important
2. Random forces lead to genetic drift
3. Distribution
4. Migration
ROLE IN HEALTH/ PHARMACOLOGY
1. Gene replacement and gene addition
2. DNA and RNA targeting and delivery methods
3. Gene therapy
4. Genetic testing
5. Gene repair therapies
6. Viral vectors or vehicles used to transfer DNA and RNA
1. Gene replacement and gene addition
Apolipoprotein E (ApoE) is a blood
circulating protein with pleiotropic
(many effects) atheroprotective
properties that has emerged as a strong
candidate for treating
hypercholesterolemia and
cardiovascular disease.
2. DNA and RNA targeting and delivery
methods
• Receptors are proteins located on the
surface of the cell DNA
• Ex-vivo insulin production
• Catheterization of organ surgical
methods
• Antigens are proteins located on the
surface of the cell DNA
3. Gene therapy
• Replacing mutated genes
• Fixing mutated genes
• Making diseased cells more
evident to the immune system
4. Gene testing
• Molecular genetic tests
• Chromosomal genetic tests
• Biochemical genetic tests
5. Gene repair therapies
• DNA repair is a collection of
processes by which a cell identifies and
corrects damage to the DNA molecules
that encode its genome.
• CRISPR–Cas9, parts of a genome can
be edited by scientists by removing,
adding, or altering parts in a DNA
sequence.
6. Viral vectors or vehicles used to
transfer DNA and RNA
Retroviruses, adenovirus, adeno-
associated virus, herpesvirus and
poxvirus are employed in more than
70% of clinical gene therapy trials
ADVANCES IN GENETIC VARIATIONS
1. Genetics of congenital heart defects
Homocystein (hyperhomocysteinemia)
Excitation causes due to release of glutamate, aspartate
That leads to trauma, stroke, stress
Also leads to atherosclerosis
De novo mutations causes nearly 10% CHD
Genome scanning methods for studying CHD
2. Disease-related genes play a role in pain responding
Pain may increase with disease severity or disease induced pain
2 genes responsible arte CASP-9, encodes for caspase 9 involved in programmed cell death
Place major role in lumbar discogenic disease
3. Delivery of RNA therapeutics
CRISPR-Cas9 (stretococcus pyogenes)
In-vitro delivery Ex-vivo editing
Correct mutations in DMD, heriditary
Tyrosynemia type 1, liver diseases, decrease
Blood cholesterol levels.
(PCSK9 knockout)
Editing with spcas9 trigger
haemopoietic stem cells to correct
sickle cell anemia
This is due to mutation in gene coding
β-globin
Deplete CCR5 to trigger anti HIV or to
deplete PD-1 to boost anti cancer
therapy
Limitations:
a) Inperfect DNA targeting
b) Low efficiency of genome editing
4. Gene editing technology
Gene finger nucleases + Cas/CRISPRs + TALENS
Destroy and repair without genotoxicity
Used in hematological diseases and to destroy malignant cell and to achieve proliferating
cells activity
CART Gene therapy is applied to B cell malignancies
5. Genetic Testing and Treatment of Neonatal Diabetes Mellitus
Sulphonylurea treatment to decrease NDM before genetic diagnosis is available
Genetic diagnosis detects single-nucleotide, testing of all NDM genes that alters treatment
method
6. Herpes vector gene delivery - two strategies useful
Sterotactic inoculation Peripheral inoculation
into neural parenchyma
Parkinsons and spinal root trauma
Peripheral inoculation to transduce
sensory neurons to treat neuropathy/ pain
Created BCL-2 or GDNF vectors
Florogold beads injected into CNS,
then translocated & injected into
substantia nigra
Vectors injected with 6-OH dopamine
and activity is studied
7. Mutations in CCR5 gene protects against AIDS
C-C chemokine receptor type 5 (CCR5) is a key player in HIV infection
binding to the virus and leading to the entry and spread of HIV
scientists targetted CCR5 molecule to prevent HIV infection in-vivo
anti-HIV humoral responses through CCR5 targeting
REFERENCES
1. Types of mutations- frameshift, chromosomal and point mutation.
https://www.biotecharticles.com/Genetics-Article/Types-of-Mutations-Frameshift-
2. Understanding evolution.
https://evolution.berkeley.edu/evolibrary/article/0_0_0/evo_16
3. The Genetic Variation in a Population Is Caused by Multiple Factors.
https://www.nature.com/scitable/topicpage/the-genetic-variation-in-a-population-is-
6526354
4. Recent advances in understanding the genetics of congenital heart defects, Bruce D.
Gelb, M.D. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4049978/
5. Genetic Basis of Pain Variability: Recent Advances. Erin E. Young, William R.
Lariviere, and Inna Belferhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3821734/.
6. Viruses as gene delivery vectors: Application to gene function, target validation, and
assay development. Michael T Lotze & Thomas A Kost.
https://www.nature.com/articles/7700493
7. Current status and recent advances of gene therapy in hematological diseases.
Masato Yamamoto, Kenzaburo Tani
8. Recent Advances in Genetic Testing and Treatment of Neonatal Diabetes Mellitus.
Banu Küçükemre Aydın Feyza Darendeliler.
https://academic.oup.com/jcem/article/100/1/L13/2835564
9. Gene therapy progress and prospects: targeted gene repair. H Parekh-Olmedo, L Ferrara,
E Brachman & E B Kmiec. https://www.nature.com/articles/3302511
10. Therapies targeting DNA and RNA in Huntington's disease.
Wild EJ1, Tabrizi SJ2.
11. CCR5: From Natural Resistance to a New Anti-HIV Strategy, Lucia Lopalco.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3185609/
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genetic variations and its role in health/ pharmacology

  • 1. GENETIC VARIATIONS AND ITS ROLE IN HEALTH / PHARMACOLOGY Department of pharmacology Under the guidance of Vivek Kumar Tiwari (M.Pharm) Submitted by, M.Srivani (Regd No: 1702-18-887-014) GOKARAJU RANGARAJU COLLEGE OF PHARMACY (Affiliated to Osmania University) Bachupally, Nizampet Road Hyderabad -500090.
  • 2. CONTENTS • What are genetic variations? • Why genetic variation is important? • Examples • Mechanisms of genetic variations • Causes • Sources • Factors affecting • Role in health/ pharmacology • Advances in genetic variations
  • 4. WHY GENETIC VARIATION IS IMPORTANT? • Adaptability • Survival • Evolution • Reproduction • Genomic combinations • Natural selection can occur EXAMPLES • Skin color, hair color, multi-colored eyes, dimples • Modified leaves of carnivorous plants • Cheetahs with stripes, snakes that fly, animals that play dead
  • 5. MECHANISMS OF GENETIC VARIATION • Mutations • Genetic drift • Gene flow or migration • Non- random mating • Natural selection Mutations Genetic drift
  • 6. Gene flow/ Migration Non-random mating Natural selection
  • 7. CAUSES OF GENETIC VARIATIONS
  • 8. 1. GENETIC FACTORS A) SEXUAL REPRODUCTION Crossing over Random mating/ Independent assortment Random fertilization B) MUTATIONS 2. ENVIRONMENTAL FACTORS
  • 9. SOURCES OF GENETIC VARIATION 1. MUTATIONS - Causes A) DNA fails to copy accurately B) External influences can create mutations - Types
  • 10. 2. MEIOTIC DIVISIONS 3. SEXUAL REPRODUCTION Male + Female gametes (haploid cell) 46 chromosomes in haploid gametes (23 in each) Each gene has 2 alleles (223) 8 million possible chromosome combinations (223) Fertilization (ovum + sperm) (223 * 223) 1 to 70 trillion possibilities
  • 11. 4. ERRORS IN CHROMOSOME SEGREGATION 5. HORIZONTAL ACQUISITION OF GENES Replication of genetic material (no equal chromosome segregation) No equal distribution in daughter cells Abnormal number of chromosomes in daughter cell (ploidy changes) Example: Down syndrome is caused due to trisomy of chromosome21.
  • 12. FACTORS AFFECTING GENETIC VARIATION 1. Mating partners are important 2. Random forces lead to genetic drift 3. Distribution 4. Migration ROLE IN HEALTH/ PHARMACOLOGY 1. Gene replacement and gene addition 2. DNA and RNA targeting and delivery methods 3. Gene therapy 4. Genetic testing 5. Gene repair therapies 6. Viral vectors or vehicles used to transfer DNA and RNA
  • 13. 1. Gene replacement and gene addition Apolipoprotein E (ApoE) is a blood circulating protein with pleiotropic (many effects) atheroprotective properties that has emerged as a strong candidate for treating hypercholesterolemia and cardiovascular disease. 2. DNA and RNA targeting and delivery methods • Receptors are proteins located on the surface of the cell DNA • Ex-vivo insulin production • Catheterization of organ surgical methods • Antigens are proteins located on the surface of the cell DNA
  • 14. 3. Gene therapy • Replacing mutated genes • Fixing mutated genes • Making diseased cells more evident to the immune system 4. Gene testing • Molecular genetic tests • Chromosomal genetic tests • Biochemical genetic tests
  • 15. 5. Gene repair therapies • DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. • CRISPR–Cas9, parts of a genome can be edited by scientists by removing, adding, or altering parts in a DNA sequence. 6. Viral vectors or vehicles used to transfer DNA and RNA Retroviruses, adenovirus, adeno- associated virus, herpesvirus and poxvirus are employed in more than 70% of clinical gene therapy trials
  • 16. ADVANCES IN GENETIC VARIATIONS 1. Genetics of congenital heart defects Homocystein (hyperhomocysteinemia) Excitation causes due to release of glutamate, aspartate That leads to trauma, stroke, stress Also leads to atherosclerosis De novo mutations causes nearly 10% CHD Genome scanning methods for studying CHD 2. Disease-related genes play a role in pain responding Pain may increase with disease severity or disease induced pain 2 genes responsible arte CASP-9, encodes for caspase 9 involved in programmed cell death Place major role in lumbar discogenic disease
  • 17. 3. Delivery of RNA therapeutics CRISPR-Cas9 (stretococcus pyogenes) In-vitro delivery Ex-vivo editing Correct mutations in DMD, heriditary Tyrosynemia type 1, liver diseases, decrease Blood cholesterol levels. (PCSK9 knockout) Editing with spcas9 trigger haemopoietic stem cells to correct sickle cell anemia This is due to mutation in gene coding β-globin Deplete CCR5 to trigger anti HIV or to deplete PD-1 to boost anti cancer therapy Limitations: a) Inperfect DNA targeting b) Low efficiency of genome editing
  • 18. 4. Gene editing technology Gene finger nucleases + Cas/CRISPRs + TALENS Destroy and repair without genotoxicity Used in hematological diseases and to destroy malignant cell and to achieve proliferating cells activity CART Gene therapy is applied to B cell malignancies 5. Genetic Testing and Treatment of Neonatal Diabetes Mellitus Sulphonylurea treatment to decrease NDM before genetic diagnosis is available Genetic diagnosis detects single-nucleotide, testing of all NDM genes that alters treatment method
  • 19. 6. Herpes vector gene delivery - two strategies useful Sterotactic inoculation Peripheral inoculation into neural parenchyma Parkinsons and spinal root trauma Peripheral inoculation to transduce sensory neurons to treat neuropathy/ pain Created BCL-2 or GDNF vectors Florogold beads injected into CNS, then translocated & injected into substantia nigra Vectors injected with 6-OH dopamine and activity is studied
  • 20. 7. Mutations in CCR5 gene protects against AIDS C-C chemokine receptor type 5 (CCR5) is a key player in HIV infection binding to the virus and leading to the entry and spread of HIV scientists targetted CCR5 molecule to prevent HIV infection in-vivo anti-HIV humoral responses through CCR5 targeting
  • 21. REFERENCES 1. Types of mutations- frameshift, chromosomal and point mutation. https://www.biotecharticles.com/Genetics-Article/Types-of-Mutations-Frameshift- 2. Understanding evolution. https://evolution.berkeley.edu/evolibrary/article/0_0_0/evo_16 3. The Genetic Variation in a Population Is Caused by Multiple Factors. https://www.nature.com/scitable/topicpage/the-genetic-variation-in-a-population-is- 6526354 4. Recent advances in understanding the genetics of congenital heart defects, Bruce D. Gelb, M.D. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4049978/ 5. Genetic Basis of Pain Variability: Recent Advances. Erin E. Young, William R. Lariviere, and Inna Belferhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3821734/. 6. Viruses as gene delivery vectors: Application to gene function, target validation, and assay development. Michael T Lotze & Thomas A Kost. https://www.nature.com/articles/7700493 7. Current status and recent advances of gene therapy in hematological diseases. Masato Yamamoto, Kenzaburo Tani 8. Recent Advances in Genetic Testing and Treatment of Neonatal Diabetes Mellitus. Banu Küçükemre Aydın Feyza Darendeliler. https://academic.oup.com/jcem/article/100/1/L13/2835564
  • 22. 9. Gene therapy progress and prospects: targeted gene repair. H Parekh-Olmedo, L Ferrara, E Brachman & E B Kmiec. https://www.nature.com/articles/3302511 10. Therapies targeting DNA and RNA in Huntington's disease. Wild EJ1, Tabrizi SJ2. 11. CCR5: From Natural Resistance to a New Anti-HIV Strategy, Lucia Lopalco. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3185609/