Genomics

Vincent NardoneMarch 24, 2014Genomics

OverviewWhat is Genomics?How does it apply to chronic diseases?BackgroundThe human genome projectGenetics 2000-2014Ethical ConcernsRecent Genomics articles

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

Quiz 1When was the term genomics first coined?A. In 1953 after Watson and Crick published a paper on the structure of DNAB. In 1975 after DNA sequencing began with DNA polymeraseC. In 1986 over a beer following a genetics conferenceD. In 2003 after the human genome project was complete

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

What is Genomics?Merriam-WebsterGenomics (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 thecompletegenomes of selected organisms using high-speed methods, with organizing the results in databases, and with applications of the data (as in medicine or biology)

What is Genomics?WikipediaGenomicsis a discipline ingeneticsthat appliesrecombinant DNA,DNA sequencingmethods, andbioinformaticsto sequence, assemble, and analyze the function and structure ofgenomes(thecompleteset of DNA within a single cell of an organism)What is Genomics?World Health OrganizationGenomicsis defined as the study of genes and their functions, and related techniques.Themain differencebetween 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.

Why Should I Care?Genes have a large effect in susceptibility to chronic diseasesSickle Cell diseaseGAG replaced by GTG; valine replaces glutamineCystic Fibrosis66% of cases from CFTR-phenylalanine 508 deletionFamilial DysbetalipoproteinemiaChromosome 19 ApoE2 mutation

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

https://www.nhlbi.nih.gov/news/spotlight/success/reducing-the-burden-of-sickle-cell-disease.htmlSickle Cell diseaseAutosomal 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 arteriesLeads to pain, strokes, heart attacksRBCs live shorter than normalHeterozygotes thought to be resistant to malaria

Sickle Cell and MalariaSickle Cell Trait DistributionHistorical Malaria Distribution

http://www.understandingrace.org/humvar/sickle_01.htmlQuiz 3How many different genetic mutations have been shown to cause cystic fibrosis?A. 1B. 10C. 100D. 1000E. >1000Quiz 3How many different genetic mutations have been shown to cause cystic fibrosis?A. 1B. 10C. 100D. 1000E. >1000Cystic FibrosisDue to homozygous defect in cystic fibrosis transmembrane conductance regulator (7)Diagnosed by sweat testLife expectancy: 1959: 6 months; 2007: 37 yrs1 in 3500 children born with CF 1 in 30 Caucasians carrier mutation1 in 65 AfricansCosts US $450 million per year

Familial DysbetalipoproteinemiaAutosomal RecessiveOnly 10% of apoE2 homozygotes develop dz.Is essential but not sufficientCharacterized by:Increased LDLIncreased TriglyceridesDecreased HDLLeads to heart attacks and strokes in 30s and 40shttp://ghr.nlm.nih.gov/gene/APOEQuiz 4If 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%Quiz 4If 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%Background1953- James D. Watson and Francis Crick Publish an article on the structure and composition of deoxyribose nucleic acid (DNA)

Background1955- Fred Sanger publishes the amino acid sequence of insulin1964- Robert Holley publishes the ribonucleotide sequence of alanine tRNA1976- Walter Fiers and team publish the complete nucleotide sequence of bacteriophage MS2-RNA (3569 base pairs)

Background-DNA sequencing1980- Frederick Sanger and Walter Gilbert share the Nobel Prize for developing independent methods to sequence DNA

www.nobelprize.orgBackground DNA sequencing1981- The human mitochondrion was completely sequenced (16,568 bp)1983- First Genetic Disease Mapped (Huntingtons Disease)1989- Cystic Fibrosis gene mutation recognized1992- Chromosome III of brewers yeast was completely sequenced (315,000 bp)1995- Haemophilus influenza completely sequenced (1,800,000 bp)

Disease gene sequencing

http://www.genome.gov/Pages/Education/AllAbouttheHumanGenomeProject/CumulativePaceofGeneDiscovery1981-2005.pdfCost changes over time

http://upload.wikimedia.org/wikipedia/commons/7/73/Number_of_prokaryotic_genomes_and_sequencing_costs.svgCost changes over time

http://upload.wikimedia.org/wikipedia/commons/7/73/Number_of_prokaryotic_genomes_and_sequencing_costs.svgQuiz 5How many base pairs are in the human genetic code?A. 33,000,000B. 330,000,000C. 3,300,000,000D. 33,000,000,000Quiz 5How many base pairs are in the human genetic code?A. 33,000,000B. 330,000,000C. 3,300,000,000D. 33,000,000,000Human Genome ProjectGoal: To map all of the genes of the human genomeTimeline:1987- funding is submitted in budget to Congress1990- Project begins1999- Chromosome 22 first chromosome fully decoded2001- First draft released2003-Human genome project completedFacts: The Human Genome ProjectWas completed under budget and 2 years ahead of scheduleFueled the discovery of more than 1800 disease genes and 2000 genetic tests350 biotech products resulting from the Human Genome Project are currently in clinical trials

http://report.nih.gov/NIHfactsheets/ViewFactSheet.aspx?csid=45&key=H#HFuture: The Human Genome projectThe Cancer Genome Atlas aims to identify genetic abnormalities in 50 major cancer typesAims to target interventions and drugs that will be more effective and less side effectsAim to cut the cost of sequencing an individual genome to less than $1,000http://report.nih.gov/NIHfactsheets/ViewFactSheet.aspx?csid=45&key=H#HQuiz 6Which costs more, a full body CT scan or an individual genomic sequencing?

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

Genomics- 2000-2014EGAPPOPHGEpigeneticsGenomics TestingTranslational ApplicationsEGAPPEvaluation of Genomic Applications in Practice and PreventionThe 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/EGAPPFounded from the CDC Public HealthCDC is interested because 2000 tests exists and many recent one have population-based applicationsFor diseases, this genetic screening needs to be evaluated if cost effective for entire populationsIf genomics affects clinical practice, must be evidence basedOPHGOffice of Public Health GenomicsClassifies which genetic tests if implemented properlyDeveloped, maintains and updates the Genomic Applications in Practice and Prevention Knowledge Basehttp://www.cdc.gov/genomics/about/AAG/index.htmOPGH Three-tiered FrameworkTier 1- recommended for clinical used based on systematic assessment and validityCurrent 47 tier on genomic applications

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

OPGH Three-tiered FrameworkTier 3- Not ready for clinical use due to validity or utility not established, or systematic assesment finding harms outweigh benefitsMight be candidates for population or clinical research

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

EpigeneticsAll cells in your body have the same DNAWhy do these cells appear phenotypically different?Heritable changes in gene activity that are NOT caused by DNA sequence changesDNA methylation and histone modificationsCellular differentiationMethylation of mRNAhttp://www.commed.vcu.edu/Chronic_Disease/genetics/whatisepigenetics.pdfQuiz 7What 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%Quiz 7What 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%Quiz 8What is the relative risk that a woman with a BRCA1 mutation will develop breast cancer before age 40?A. 0B. 1C. 5D. 10E. 20Quiz 8What is the relative risk that a woman with a BRCA1 mutation will develop breast cancer before age 40?A. 0B. 1C. 5D. 10E. 20cebp.aacrjournals.org/content/10/5/467.fullGenetic TestingMost Tests look at single genes and diagnose rare genetic disorders (all listed Tier 1)BRCA1, BRCA2, HER2 in breast cancerFragile X SyndromeDuchennes Muscular DystrophyLynch SyndromePhiladelphia Chromosome in leukemiaFamilial Hypercholesterolemia

Genetic TestingFor those that can change management and increase survival, there is obvious benefitWhat about genetic tests that exists for slowly developing diseases with no cures?Huntingtons diseaseNeurodegenerative and psychiatric diseaseSymptoms begin in 40s, die in 50s27% attempt suicideQuiz 9Which 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 diseasesC. Individual genomic sequencing to identify predisposition to drug side effectsD. Individual genomic sequencing to identify better medication for individualsE. All of the above

Quiz 9Which 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 diseasesC. Individual genomic sequencing to identify predisposition to drug side effectsD. Individual genomic sequencing to identify better medication for individualsE. All of the above

Translational Applicationshttp://www.commed.vcu.edu/Chronic_Disease/genetics/BMJ_Clinical_Review_2010.pdf

Translational Applicationshttp://www.commed.vcu.edu/Chronic_Disease/genetics/BMJ_Clinical_Review_2010.pdf

Translational Applicationshttp://www.commed.vcu.edu/Chronic_Disease/genetics/BMJ_Clinical_Review_2010.pdf

Translational Applications

http://www.ncbi.nlm.nih.gov/pubmed/21406285Translational Applications-Gene TherapyMutated gene causes expression of some diseasesReplacing mutated gene with wild type gene would cure diseaseCould potentially impact 1000s of diseasesTargeted gene replacement has been difficult with little progress over the last 20 yearsTranslation Applications-Gene Therapy

http://photos.the-scientist.com/legacyArticleImages/2012/06/06_12_Delivery-New-Genes.jpgGene Therapy-Cautionary Tales1999- Gene therapy trial participant with mild liver disease caused by x-linked mutation died 4 days after gene therapy injection from massive immune response to adenovirus carrier2002- Gene therapy for SCID patients inserted improperly close to proto-oncogene for WBCs causing leukemia in 5 of 20 patientsGene therapy curing AIDS?

http://photos.the-scientist.com/legacyArticleImages/2012/06/06_12_MessingWithHIV.jpgQuiz 10In US law, which of the following is patentable?A. Naturally occurring human DNAB. Artificially occurring DNA sequencesC. BothD. NeitherQuiz 10In US law, which of the following is patentable?A. Naturally occurring human DNAB. Artificially occurring DNA sequencesC. BothD. NeitherQuiz 11How much does a BRCA1 and BRCA2 test approximately cost?A. $100B. $300C. $1000D. $3000E. $10000Quiz 11How much does a BRCA1 and BRCA2 test approximately cost?A. $100B. $300C. $1000D. $3000E. $10000Ethics of GenomicsHuntingtons Disease testingBRCA testing and impact on decision to have complete bilateral mastectomyGenetic links to other diseases discoveredIncreased health insurance premiums?Patients give up trying to be healthy?Obesity as a disease5 Recent Genomics ArticlesIs Evidence Based Medicine the enemy of Genomic Medicine? (Feb 13, 2014)Susceptibility to type 2 diabetes mellitus-from genes to prevention (Feb 18, 2014)Innovation, Risk, and Patient Empowerment: The FDA-Mandated Withdrawal of 23andMes Personal Genome Service (Feb 26, 2014)NCCN Updates Guidelines for Hereditary Colon Cancer Testing (Mar 4, 2014)Clinical Application of Whole-Genome Sequencing: Proceed with Care (Mar 12, 2014)Is Evidence Based Medicine the enemy of Genomic Medicine?Fear about many genomics discoveries being statistically significant but not clinically significantTough to put a clinical significance on genomics researchMany results of genomics research are personalized and do not apply to the population as a wholehttp://blogs.cdc.gov/genomics/2014/02/13/is-evidence-based/Susceptibility to type 2 diabetes mellitus-from genes to prevention65 loci credibly associated with T2DMIntensive lifestyle modifications can prevent T2DM even with individuals having the highest genetic susceptibilityCounseling patients to inform them of their genetics had no significant impact on lifestyle changeshttp://www.nature.com/nrendo/journal/v10/n4/full/nrendo.2014.11.htmlQuiz 12Discussion- Should individual people be able to receive copies of their genomic sequence even if this information may not be presented in the clearest way and cause them to make questionable decisions about their health?Innovation, Risk, and Patient Empowerment: The FDA-Mandated Withdrawal of 23andMes Personal Genome Service23andMe helps individuals and their doctors identify health areas that they need to keep an eye onEstimates the risk 250 diseases through SNPsFDA asked 23andMe to cease marketing and 23andMe eventually compliedNCCN Updates Guidelines for Hereditary Colon Cancer TestingUpdated guidelines:A recommendation that all patients who meet a five percent or greater risk threshold for Lynch syndrome are appropriate for testing;A recommendation against sequential testing for the five Lynch syndrome genes in lieu of panel testing; andAn acknowledgement that patients with cancer can proceed directly to sequencing tests without a complicated tissue screening algorithm.Myriad estimates that approximately 30 percent of newly diagnosed colorectal cancer patients, 100 percent of newly diagnosed endometrial cancer patients, and three percent of asymptomatic patients will now qualify for Lynch syndrome testing under the new medical guidelines.

http://finance.yahoo.com/news/nccn-updates-guidelines-hereditary-colon-120500779.htmlClinical Application of Whole-Genome Sequencing: Proceed with CareNeed sufficient power to determine clinical implications for rarer genetic conditionsMillions of different variations of individual genes, daunting task to find out which are clinically significant or notAccuracy of making sure all 3.3 billion base pairs are sequenced correctlyjama.jamanetwork.com/article.aspx?articleID=1840218Future DirectionsGene TherapyGenomics impact on primary care and disease susceptibilityGenomics impact on drug prescribing Genomics and health data privacyThank YouQuestions?!?