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Genomics

Genomics. Vincent Nardone March 24, 2014. Overview. What is Genomics? How does it apply to chronic diseases? Background The human genome project Genetics 2000-2014 Ethical Concerns Recent Genomics articles. What is genomics?. Something to do with: Genes? The human genome project?

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Genomics

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  1. Genomics Vincent Nardone March 24, 2014

  2. Overview • What is Genomics? • How does it apply to chronic diseases? • Background • The human genome project • Genetics 2000-2014 • Ethical Concerns • Recent Genomics articles

  3. What is genomics? • Something to do with: • Genes? • The human genome project? • Health/Diseases? • DNA? • Science?

  4. Quiz 1 • When was the term genomics first coined? • A. In 1953 after Watson and Crick published a paper on the structure of DNA • B. In 1975 after DNA sequencing began with DNA polymerase • C. In 1986 over a beer following a genetics conference • D. In 2003 after the human genome project was complete

  5. Quiz 1 • When was the term genomics first coined? • A. In 1953 after Watson and Crick published a paper on the structure of DNA • B. In 1975 after DNA sequencing began with DNA polymerase • C. In 1986 over a beer following a genetics conference (geneticist Dr. Tom Roderick) • D. In 2003 after the human genome project was complete

  6. What is Genomics? • Merriam-Webster • Genomics (n)- a branch of biotechnology concerned with applying the techniques of genetics and molecular biology to the genetic mapping and DNA sequencing of sets of genes or the complete genomes of selected organisms using high-speed methods, with organizing the results in databases, and with applications of the data (as in medicine or biology)

  7. What is Genomics? • Wikipedia • Genomics is a discipline in genetics that applies recombinant DNA, DNA sequencing methods, and bioinformatics to sequence, assemble, and analyze the function and structure of genomes (the complete set of DNA within a single cell of an organism)

  8. What is Genomics? • World Health Organization • Genomics is defined as the study of genes and their functions, and related techniques. • The main difference between genomics and genetics is that genetics scrutinizes the functioning and composition of the single gene where as genomics addresses all genes and their inter relationships in order to identify their combined influence on the growth and development of the organism.

  9. Why Should I Care? • Genes have a large effect in susceptibility to chronic diseases • Sickle Cell disease • GAG replaced by GTG; valine replaces glutamine • Cystic Fibrosis • 66% of cases from CFTR-phenylalanine 508 deletion • Familial Dysbetalipoproteinemia • Chromosome 19 ApoE2 mutation

  10. Quiz 2 • What is the current life expectancy for people with sickle cell disease? • A. 25 • B. 35 • C. 45 • D. 55 • E. 65

  11. Quiz 2 • What is the current life expectancy for people with sickle cell disease? • A. 25 • B. 35 • C. 45 • D. 55 • E. 65

  12. https://www.nhlbi.nih.gov/news/spotlight/success/reducing-the-burden-of-sickle-cell-disease.htmlhttps://www.nhlbi.nih.gov/news/spotlight/success/reducing-the-burden-of-sickle-cell-disease.html

  13. Sickle Cell disease • Autosomal Recessive (2 HbS required) • 1 in 5000 Americans affected; 1 in 500 African Americans • $500 million per year cost to US in 2004 (CDC) • Causes RBCs to stick together and occlude arteries • Leads to pain, strokes, heart attacks • RBCs live shorter than normal • Heterozygotes thought to be resistant to malaria

  14. Sickle Cell and Malaria Sickle Cell Trait Distribution Historical Malaria Distribution http://www.understandingrace.org/humvar/sickle_01.html

  15. Quiz 3 • How many different genetic mutations have been shown to cause cystic fibrosis? • A. 1 • B. 10 • C. 100 • D. 1000 • E. >1000

  16. Quiz 3 • How many different genetic mutations have been shown to cause cystic fibrosis? • A. 1 • B. 10 • C. 100 • D. 1000 • E. >1000

  17. Cystic Fibrosis • Due to homozygous defect in cystic fibrosis transmembrane conductance regulator (7) • Diagnosed by sweat test • Life expectancy: 1959: 6 months; 2007: 37 yrs • 1 in 3500 children born with CF • 1 in 30 Caucasians carrier mutation • 1 in 65 Africans • Costs US $450 million per year

  18. Familial Dysbetalipoproteinemia • Autosomal Recessive • Only 10% of apoE2 homozygotes develop dz. • Is essential but not sufficient • Characterized by: • Increased LDL • Increased Triglycerides • Decreased HDL • Leads to heart attacks and strokes in 30s and 40s http://ghr.nlm.nih.gov/gene/APOE

  19. Quiz 4 • If a child is born to a mom with homozygous apoE2 and a dad with heterozygous apoE2/apoE (wt), what is the chance that this child develops familial dysbetalipoproteinemia? • A. 0% • B. 5% • C. 25% • D. 50% • E. 100%

  20. Quiz 4 • If a child is born to a mom with homozygous apoE2 and a dad with heterozygous apoE2/apoE (wt), what is the chance that this child develops familial dysbetalipoproteinemia? • A. 0% • B. 5% • C. 25% • D. 50% • E. 100%

  21. Background • 1953- James D. Watson and Francis Crick Publish an article on the structure and composition of deoxyribose nucleic acid (DNA)

  22. Background • 1955- Fred Sanger publishes the amino acid sequence of insulin • 1964- Robert Holley publishes the ribonucleotide sequence of alanine tRNA • 1976- Walter Fiers and team publish the complete nucleotide sequence of bacteriophage MS2-RNA (3569 base pairs)

  23. Background-DNA sequencing • 1980- Frederick Sanger and Walter Gilbert share the Nobel Prize for developing independent methods to sequence DNA www.nobelprize.org

  24. Background DNA sequencing • 1981- The human mitochondrion was completely sequenced (16,568 bp) • 1983- First Genetic Disease Mapped (Huntington’s Disease) • 1989- Cystic Fibrosis gene mutation recognized • 1992- Chromosome III of brewers yeast was completely sequenced (315,000 bp) • 1995- Haemophilus influenza completely sequenced (1,800,000 bp)

  25. Disease gene sequencing http://www.genome.gov/Pages/Education/AllAbouttheHumanGenomeProject/CumulativePaceofGeneDiscovery1981-2005.pdf

  26. Cost changes over time http://upload.wikimedia.org/wikipedia/commons/7/73/Number_of_prokaryotic_genomes_and_sequencing_costs.svg

  27. Cost changes over time http://upload.wikimedia.org/wikipedia/commons/7/73/Number_of_prokaryotic_genomes_and_sequencing_costs.svg

  28. Quiz 5 • How many base pairs are in the human genetic code? • A. 33,000,000 • B. 330,000,000 • C. 3,300,000,000 • D. 33,000,000,000

  29. Quiz 5 • How many base pairs are in the human genetic code? • A. 33,000,000 • B. 330,000,000 • C. 3,300,000,000 • D. 33,000,000,000

  30. Human Genome Project • Goal: To map all of the genes of the human genome • Timeline: • 1987- funding is submitted in budget to Congress • 1990- Project begins • 1999- Chromosome 22 first chromosome fully decoded • 2001- First draft released • 2003-Human genome project completed

  31. Facts: The Human Genome Project • Was completed under budget and 2 years ahead of schedule • Fueled the discovery of more than 1800 disease genes and 2000 genetic tests • 350 biotech products resulting from the Human Genome Project are currently in clinical trials http://report.nih.gov/NIHfactsheets/ViewFactSheet.aspx?csid=45&key=H#H

  32. Future: The Human Genome project • The Cancer Genome Atlas aims to identify genetic abnormalities in 50 major cancer types • Aims to target interventions and drugs that will be more effective and less side effects • Aim to cut the cost of sequencing an individual genome to less than $1,000 http://report.nih.gov/NIHfactsheets/ViewFactSheet.aspx?csid=45&key=H#H

  33. Quiz 6 • Which costs more, a full body CT scan or an individual genomic sequencing?

  34. Quiz 6 • Which costs more, a full body CT scan or an individual genomic sequencing? • Individual genomic sequencing- $5,000 • Full body CT- $3,000

  35. Genomics- 2000-2014 • EGAPP • OPHG • Epigenetics • Genomics Testing • Translational Applications

  36. EGAPP • Evaluation of Genomic Applications in Practice and Prevention • The EGAPP Working Group was established in 2005 to support the development of a systematic process for assessing the available evidence regarding the validity and utility of rapidly emerging genetic tests for clinical practice.  This independent, multidisciplinary panel prioritizes and selects tests, reviews CDC-commissioned evidence reports and other contextual factors, highlights critical knowledge gaps, and provides guidance on appropriate use of genetic tests in specific clinical scenarios. http://www.egappreviews.org/

  37. EGAPP • Founded from the CDC Public Health • CDC is interested because 2000 tests exists and many recent one have population-based applications • For diseases, this genetic screening needs to be evaluated if cost effective for entire populations • If genomics affects clinical practice, must be evidence based

  38. OPHG • Office of Public Health Genomics • Classifies which genetic tests if implemented properly • Developed, maintains and updates the Genomic Applications in Practice and Prevention Knowledge Base http://www.cdc.gov/genomics/about/AAG/index.htm

  39. OPGH Three-tiered Framework • Tier 1- recommended for clinical used based on systematic assessment and validity • Current 47 tier on genomic applications

  40. OPGH Three-tiered Framework • Tier 2- May be useful for informed decision making in clinical practice, based on synthesized evidence of validity and promising utility

  41. OPGH Three-tiered Framework • Tier 3- Not ready for clinical use due to validity or utility not established, or systematic assesment finding harms outweigh benefits • Might be candidates for population or clinical research

  42. What is Epigenetics? • Something to do with: • Genes? • Genetics? • Epidemiology? • Science?

  43. Epigenetics • All cells in your body have the same DNA • Why do these cells appear phenotypically different? • “Heritable changes in gene activity that are NOT caused by DNA sequence changes” • DNA methylation and histone modifications • Cellular differentiation • Methylation of mRNA http://www.commed.vcu.edu/Chronic_Disease/genetics/whatisepigenetics.pdf

  44. Quiz 7 • What is the chance that a woman with a BRCA1 mutation will develop breast cancer by age 70? • A. 0% • B. 20% • C. 40% • D. 60% • E. 80%

  45. Quiz 7 • What is the chance that a woman with a BRCA1 mutation will develop breast cancer by age 70? • A. 0% • B. 20% • C. 40% • D. 60% • E. 80%

  46. Quiz 8 • What is the relative risk that a woman with a BRCA1 mutation will develop breast cancer before age 40? • A. 0 • B. 1 • C. 5 • D. 10 • E. 20

  47. Quiz 8 • What is the relative risk that a woman with a BRCA1 mutation will develop breast cancer before age 40? • A. 0 • B. 1 • C. 5 • D. 10 • E. 20 cebp.aacrjournals.org/content/10/5/467.full

  48. Genetic Testing • Most Tests look at single genes and diagnose rare genetic disorders (all listed Tier 1) • BRCA1, BRCA2, HER2 in breast cancer • Fragile X Syndrome • Duchenne’s Muscular Dystrophy • Lynch Syndrome • Philadelphia Chromosome in leukemia • Familial Hypercholesterolemia

  49. Genetic Testing • For those that can change management and increase survival, there is obvious benefit • What about genetic tests that exists for slowly developing diseases with no cures? • Huntington’s disease • Neurodegenerative and psychiatric disease • Symptoms begin in 40s, die in 50s • 27% attempt suicide

  50. Quiz 9 • Which of the following are potential applications of genomics? • A. Individual genetic testing to identify diseases like Sickle Cell, CF • B. Individual genomic sequencing to identify predisposition to diseases • C. Individual genomic sequencing to identify predisposition to drug side effects • D. Individual genomic sequencing to identify better medication for individuals • E. All of the above

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