Human genome
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The document discusses human genes and bioinformatics. It defines bioinformatics as the field that merges biology, computer science, and information technology to understand and organize molecular data on a large scale. It provides information on the human genome, including that it contains around 35,000-50,000 genes and has been sequenced. Genome projects have provided data that can be used in medicine, pharmacogenomics, and other areas to gain biological insights.
![MedicineMedicine
Diagnosis of disease and disease riskDiagnosis of disease and disease risk
(a) when a patient presents with symptoms(a) when a patient presents with symptoms
(b) in advance of apperance of symptoms(b) in advance of apperance of symptoms
[eg]Huntigton disease (an inherited[eg]Huntigton disease (an inherited
neurodegenerative disorder)neurodegenerative disorder)
• symptoms:uncontrollable dance-like (choreatic)symptoms:uncontrollable dance-like (choreatic)
movements,mental disturbance,personalitymovements,mental disturbance,personality
changes and intellectual impairmentchanges and intellectual impairment
• repeats of the trinucleotide CAG,correspondingrepeats of the trinucleotide CAG,corresponding
to polyglutamine blocks in the correspondingto polyglutamine blocks in the corresponding
protein,huntinginprotein,huntingin](https://image.slidesharecdn.com/humangenome-140329105054-phpapp02/85/Human-genome-23-320.jpg)
![Genetics of responses to therapy-Genetics of responses to therapy-
customized treatmentcustomized treatment
• sequence analysis permits selecting drugs andsequence analysis permits selecting drugs and
dosages optimal for individual patients, a fast-dosages optimal for individual patients, a fast-
growing field called pharmacogenomics [eg] 6-growing field called pharmacogenomics [eg] 6-
mercaptopurine used in the treatment ofmercaptopurine used in the treatment of
childhood leukaemiachildhood leukaemia](https://image.slidesharecdn.com/humangenome-140329105054-phpapp02/85/Human-genome-37-320.jpg)
![Identification of drug targetsIdentification of drug targets
(a) drug design process(a) drug design process
(b) drugs act on targets such as receptors, enzymes,(b) drugs act on targets such as receptors, enzymes,
harmones and some unknown targetsharmones and some unknown targets
(c) differential genomics [eg] tumour cells(c) differential genomics [eg] tumour cells
Gene theraphyGene theraphy
(a) direct supply of proteins [eg] insulin(a) direct supply of proteins [eg] insulin
(b) antisense therapy [eg] crohn disease(b) antisense therapy [eg] crohn disease](https://image.slidesharecdn.com/humangenome-140329105054-phpapp02/85/Human-genome-38-320.jpg)
![• Bioengineered foods [e.g. Flavr Savr tomato
(antisense – polygalacturonase) to delay rotting]
• “Pharm” animals](https://image.slidesharecdn.com/humangenome-140329105054-phpapp02/85/Human-genome-52-320.jpg)
Human genome
- 1. Human GenesHuman Genes • By A.Arputha SelvarajBy A.Arputha Selvaraj
- 2. • What is Bioinformatics?What is Bioinformatics? • Availability of information about the human genomeAvailability of information about the human genome and other genomesand other genomes • Human health related databasesHuman health related databases • Bioinformatics and Drug developmentBioinformatics and Drug development • Ethical, Legal and Social Issues (ELSI)Ethical, Legal and Social Issues (ELSI)
- 3. What is Bioinformatics?What is Bioinformatics? • One idea for a definition:One idea for a definition: • (Molecular)(Molecular) Bio - informaticsBio - informatics == • is conceptualizing biology in terms of moleculesis conceptualizing biology in terms of molecules (in the sense of physical-chemistry) and then(in the sense of physical-chemistry) and then applying "informatics" techniques (derived fromapplying "informatics" techniques (derived from disciplines such as applied math, CS, anddisciplines such as applied math, CS, and statistics) to understand and organize thestatistics) to understand and organize the information associated with these molecules, oninformation associated with these molecules, on a large-scale.a large-scale.
- 4. • Bioinformatics is the field of science in which biology, computer science, and information technology merge into a single discipline. The ultimate goal of the field is to enable the discovery of new biological insights as well as to create a global perspective from which unifying principles in biology can be discerned. There are three important sub-disciplines within bioinformatics:
- 5. • the development of new algorithms and statisticsthe development of new algorithms and statistics with which to assess relationships amongwith which to assess relationships among members of large data sets;members of large data sets; • the analysis and interpretation of various types ofthe analysis and interpretation of various types of data including nucleotide and amino aciddata including nucleotide and amino acid sequences, protein domains, and proteinsequences, protein domains, and protein structures;structures; • the development and implementation of tools thatthe development and implementation of tools that enable efficient access and management ofenable efficient access and management of different types of information.different types of information.
- 6. Biological Data + Computer Calculations Bioinformatics
- 7. The Bioinformatics SpectrumThe Bioinformatics Spectrum
- 8. What is the Human Genome?What is the Human Genome? •The entire genetic makeup of the human cell nucleus. •Genes carry the information for making all of the proteins required by the body for growth and maintenance. •The genome also encodes rRNA and tRNA which are involved in protein synthesis.
- 9. • Made up of ~35,000-50,000 genes which code forMade up of ~35,000-50,000 genes which code for functional proteins in the bodyfunctional proteins in the body • Includes non-coding sequences located betweenIncludes non-coding sequences located between genes, which makes up the vast majority of the DNAgenes, which makes up the vast majority of the DNA in the genome (~95%)in the genome (~95%) • The particular order of nucleotide bases (As, Gs, Cs,The particular order of nucleotide bases (As, Gs, Cs, and Ts) determines the amino acid composition ofand Ts) determines the amino acid composition of proteinsproteins
- 10. • Information about DNA variations (polymorphisms)Information about DNA variations (polymorphisms) among individuals can lend insight into newamong individuals can lend insight into new technologies for diagnosing, treating, and preventingtechnologies for diagnosing, treating, and preventing diseases that afflict humankind.diseases that afflict humankind.
- 11. What Goals Were Established for the HumanWhat Goals Were Established for the Human Genome Project When it Began in 1990?Genome Project When it Began in 1990? •Identify all of the genes in human DNA. •Determine the sequence of the 3 billion chemical nucleotide bases that make up human DNA. •Store this information in data bases. •Develop faster, more efficient sequencing technologies. •Develop tools for data analysis. •Address the ethical, legal, and social issues (ELSI) that are arise form the project.
- 12. Two Different Groups Worked to Obtain theTwo Different Groups Worked to Obtain the DNA Sequence of the Human GenomeDNA Sequence of the Human Genome •The HGP is a multinational consortium established by government research agencies and funded publicly •Celera Genomics is a private company whose former CEO, J. Craig Venter, ran an independent sequencing project •Differences arose regarding who should receive the credit for this scientific milestone •June 6, 2000, the HGP and Celera Genomics held a joint press conference to announce that TOGETHER they had completed ~97% of the human genome
- 13. PublishedPublished •The International Human Genome Sequencing Consortium published their results in Nature, 409 (6822): 860-921, 2001.”Initial Sequencing and Analysis of the Human Genome” •Celera Genomics published their results in Science, Vol 291(5507): 1304-1351, 2001.“The Sequence of the Human Genome”
- 14. Banking on Genome dataBanking on Genome data • Britain is about embark on the world’s largestBritain is about embark on the world’s largest genome data project focussed on middle aged peoplegenome data project focussed on middle aged people which may shed light on the interaction betweenwhich may shed light on the interaction between genes, health and the environmentgenes, health and the environment • Studies of families affected by genetic diseaseStudies of families affected by genetic disease have proven useful for genetic linkage analyses (e.g.have proven useful for genetic linkage analyses (e.g. Huntington’s disease, neurofibramatosis, cysticHuntington’s disease, neurofibramatosis, cystic fibrosis, Duchenne’s muscular dystrophy).fibrosis, Duchenne’s muscular dystrophy).
- 15. Organism Genome size(basepairs)Organism Genome size(basepairs) • Epstein-Barr virusEpstein-Barr virus 0.172 *0.172 *106 • BacteriumBacterium (E.coli)(E.coli) 4.6 *4.6 *106 • YeastYeast (S.cerevisiae)(S.cerevisiae) 12.1 *12.1 * 106 • Nematode wormNematode worm (C.elegans)(C.elegans) 95.5 *95.5 * 106 • Thale cressThale cress (A.thaliana)(A.thaliana) 117 *117 * 106 • Fruit flyFruit fly (D.melanogaster)(D.melanogaster) 180 *180 * 106 • HumanHuman (H.sapiens)(H.sapiens) 3200 *3200 * 106
- 16. Gene Sequence Protein SequencesGene Sequence Protein Sequences • Supposed to be raw data .Supposed to be raw data . • One has to add layers of information to theOne has to add layers of information to the sequence datasequence data • Annotation of the data becomes very importantAnnotation of the data becomes very important • Annotation : Theoretical methodsAnnotation : Theoretical methods Experimental methodsExperimental methods • Bioinformatics / Statistics / MathematicsBioinformatics / Statistics / Mathematics
- 17. Complete Genome Sequences From SeveralComplete Genome Sequences From Several Organisms Are KnownOrganisms Are Known • Comparative GenomicsComparative Genomics • Structural GenomicsStructural Genomics • Functional GenomicsFunctional Genomics • Cellular GenomicsCellular Genomics • Network GenomicsNetwork Genomics • Ethical GenomicsEthical Genomics • Moral GenomicsMoral Genomics
- 18. Other Completed GenomesOther Completed Genomes • Haemophilus influenzaeHaemophilus influenzae • Escherichia coliEscherichia coli • Bacillus subtilusBacillus subtilus • Helicobacter pyloriHelicobacter pylori • Borrelia burgdorferiBorrelia burgdorferi • Streptococcus pneumoniaeStreptococcus pneumoniae • Saccharomyces cerevisiaeSaccharomyces cerevisiae
- 19. • Caenorhabditis elegansCaenorhabditis elegans • Arabidopsis thalianaArabidopsis thaliana • Archaeoglobus fulgidusArchaeoglobus fulgidus • Methanobacterium thermoautotrophicumMethanobacterium thermoautotrophicum • Methanococcus jannaschiiMethanococcus jannaschii • Mycoplasma pneumoniaeMycoplasma pneumoniae • Mycoplasm genitaliuMycoplasm genitaliu • Rickettsia prowazekiiRickettsia prowazekii • Mycobacterium tuberculosisMycobacterium tuberculosis
- 20. • Treponema pallidumTreponema pallidum • Staphylococcus aureusStaphylococcus aureus • And more!And more!
- 21. Completed Plant GenomesCompleted Plant Genomes • Arabidopsis thalianaArabidopsis thaliana Completed Insect GenomesCompleted Insect Genomes • Drosophila melanogasterDrosophila melanogaster Completed Rodent GenomesCompleted Rodent Genomes • Mus musculusMus musculus
- 22. Which Branches of Biology will Benefit from thisWhich Branches of Biology will Benefit from this Knowledge?Knowledge? •Medicine •PharmacogenomicsPharmacogenomics •Biotechnology •Bioinformatics •Proteomics
- 23. MedicineMedicine Diagnosis of disease and disease riskDiagnosis of disease and disease risk (a) when a patient presents with symptoms(a) when a patient presents with symptoms (b) in advance of apperance of symptoms(b) in advance of apperance of symptoms [eg]Huntigton disease (an inherited[eg]Huntigton disease (an inherited neurodegenerative disorder)neurodegenerative disorder) • symptoms:uncontrollable dance-like (choreatic)symptoms:uncontrollable dance-like (choreatic) movements,mental disturbance,personalitymovements,mental disturbance,personality changes and intellectual impairmentchanges and intellectual impairment • repeats of the trinucleotide CAG,correspondingrepeats of the trinucleotide CAG,corresponding to polyglutamine blocks in the correspondingto polyglutamine blocks in the corresponding protein,huntinginprotein,huntingin
- 24. • 11-28 CAG repeats -->normal11-28 CAG repeats -->normal • 29-34 CAG repeats---->likely to develop disease29-34 CAG repeats---->likely to develop disease • 35-41 CAG repeats develop mild symptoms35-41 CAG repeats develop mild symptoms • morethan 41 CAG repeats suffer full huntingtonmorethan 41 CAG repeats suffer full huntington diseasedisease (c) for in utero diagnosis of potential abnormalities(c) for in utero diagnosis of potential abnormalities such as cystic fibrosis, asthma etc.such as cystic fibrosis, asthma etc. (d) for genetic counselling of couples contemplating(d) for genetic counselling of couples contemplating having childrenhaving children
- 25. Online databases of disease-associatedOnline databases of disease-associated mutationsmutations
- 26. Online database of Mendelian Inheritance inOnline database of Mendelian Inheritance in Man (OMIM)Man (OMIM)
- 27. Human Gene Mutation Database (HGMD)Human Gene Mutation Database (HGMD)
- 28. IARC p53 databaseIARC p53 database
- 29. Haemophilia B databaseHaemophilia B database
- 30. Von Willebrand factor databaseVon Willebrand factor database
- 31. Amyotrophic lateral sclerosis databaseAmyotrophic lateral sclerosis database
- 32. Bioinformatics and Drug developmentBioinformatics and Drug development
- 33. CompoundCompound Target enzymeTarget enzyme Clinical useClinical use AcetazolamideAcetazolamide Carbonic anhydraseCarbonic anhydrase GlaucomaGlaucoma AspirinAspirin CylooxygenasesCylooxygenases InflammationInflammation Amoxicillin Pencillin binding proteinsAmoxicillin Pencillin binding proteins Bacterial infectionsBacterial infections DigoxinDigoxin Sodium,potassium ATPaseSodium,potassium ATPase Heart diseaseHeart disease OmeprazoleOmeprazole HH++ ,K,K++ -ATPase-ATPase Peptic ulcersPeptic ulcers SorbinolSorbinol Aldose reductaseAldose reductase CancerCancer VIAGRAVIAGRA PhosphodiesterasePhosphodiesterase Erectile DysfunctionErectile Dysfunction
- 34. RECEPTORSRECEPTORS • G-protein coupled receptorsG-protein coupled receptors • Ligand-gated ion channelsLigand-gated ion channels • Tyrosine kinase receptorsTyrosine kinase receptors • Nuclear receptorsNuclear receptors
- 36. Workflow of a virtual screening run against a specific target
- 37. Genetics of responses to therapy-Genetics of responses to therapy- customized treatmentcustomized treatment • sequence analysis permits selecting drugs andsequence analysis permits selecting drugs and dosages optimal for individual patients, a fast-dosages optimal for individual patients, a fast- growing field called pharmacogenomics [eg] 6-growing field called pharmacogenomics [eg] 6- mercaptopurine used in the treatment ofmercaptopurine used in the treatment of childhood leukaemiachildhood leukaemia
- 38. Identification of drug targetsIdentification of drug targets (a) drug design process(a) drug design process (b) drugs act on targets such as receptors, enzymes,(b) drugs act on targets such as receptors, enzymes, harmones and some unknown targetsharmones and some unknown targets (c) differential genomics [eg] tumour cells(c) differential genomics [eg] tumour cells Gene theraphyGene theraphy (a) direct supply of proteins [eg] insulin(a) direct supply of proteins [eg] insulin (b) antisense therapy [eg] crohn disease(b) antisense therapy [eg] crohn disease
- 39. Eliminating side effectsEliminating side effects Developing revolutionary new drugs and treatmentsDeveloping revolutionary new drugs and treatments for illness that previously couldn't befor illness that previously couldn't be treated/preventing or avoiding serious diseasestreated/preventing or avoiding serious diseases It is believed that we are approaching a new era ofIt is believed that we are approaching a new era of ‘personalized medicines’ medicine that understands‘personalized medicines’ medicine that understands as individual patient at the genetic level and offers theas individual patient at the genetic level and offers the optimum treatmentoptimum treatment
- 40. Rationales for Drug DesignRationales for Drug Design Tuberculosis is a global threat affecting 1/3 of world population with latent infections. 50% of HIV patients develop TB. TB cases are on the rise and approximately 2 million people each year die from the infection. The spread of HIV/AIDS and the emergence of multidrug-resistant TB are contributing to the worsening impact of this disease. It is estimated that between now and 2020, approximately 1000 million people will be newly infected, over 150 million people will get sick, and 36 million will die of TB - if control is not further strengthened. 2002
- 41. Drug Design CycleDrug Design Cycle
- 42. Realistic Design CycleRealistic Design Cycle
- 43. Blockbuster DrugsBlockbuster Drugs Claritin an anti-allergy drug with sales reaching $3 billion in 2000 (nearly 1/3 of Schering Plough’s revenues . Prilosec an ulcer drug produced by Astra Zeneca, sold over $6.2 billion worth globally in 2000 alone. Zantac also an ulcer drug. Glaxo sold $9 billion worth of globally, but lost patent protection in 1997. Drug sales in the US in 1997 totaled more than $69.4 billion. HIV drugs In 1998 in the US, NRTIs accounted for $885 million in sales, PIs $865 million and NNRTIs for $100 million. The market in the rest of the world is about $2 billion (1998).
- 44. Cartoon representation ofCartoon representation of TATA xylanase along with thexylanase along with the active site Glu 131 and Glu 237, the salt bridge (Arg 124active site Glu 131 and Glu 237, the salt bridge (Arg 124 - Glu 232) and disulphide bridge- Glu 232) and disulphide bridge
- 45. The “salad bowl” view showing the substrate bindingThe “salad bowl” view showing the substrate binding cleft. The Active site is at the C-terminus of thecleft. The Active site is at the C-terminus of the ββ barrelbarrel and the salt bridge is at the N-terminus of theand the salt bridge is at the N-terminus of the ββ barrelbarrel
- 46. Figure shows an example for the competition for polarFigure shows an example for the competition for polar atoms by water molecules is more at low temperatureatoms by water molecules is more at low temperature
- 47. A Water dimer formed by Wat 533 (W1) and Wat 511 (W2) and itsA Water dimer formed by Wat 533 (W1) and Wat 511 (W2) and its interactions.Conserved residues are labeled in red. Interactionsinteractions.Conserved residues are labeled in red. Interactions involving water molecules appear to contribute to the stability ofinvolving water molecules appear to contribute to the stability of residues in the active site region.residues in the active site region.ββ-strands 1 and 8 are not shown.-strands 1 and 8 are not shown.
- 48. HIV protease & inhibitor
- 49. (HIV protease dimer complexed with protease inhibitor(red), GIF generated using RasMol)
- 50. HIV protease & inhibitor (red)
- 51. BiotechnologyBiotechnology – Production of useful protein products for use inProduction of useful protein products for use in medicine, agriculture, bioremediation andmedicine, agriculture, bioremediation and pharmaceutical industries.pharmaceutical industries. • AntibioticsAntibiotics • Protein replacement (factor VIII, TPA,Protein replacement (factor VIII, TPA, streptokinase, insulin, interferon…)streptokinase, insulin, interferon…) • BT insecticide toxin (fromBT insecticide toxin (from Bacillus thuringiensisBacillus thuringiensis)) • Herbicide resistance (glyphosate resistance)Herbicide resistance (glyphosate resistance)
- 52. • Bioengineered foods [e.g. Flavr Savr tomato (antisense – polygalacturonase) to delay rotting] • “Pharm” animals
- 53. ProteomicsProteomics – Investigates patterns and levels of geneInvestigates patterns and levels of gene expression in diseased cells that can be analyzedexpression in diseased cells that can be analyzed to build databases of expression profiles.to build databases of expression profiles.
- 54. Developmental BiologyDevelopmental Biology – Regulation of embryonic development.Regulation of embryonic development. – Regulation of the aging processRegulation of the aging process..
- 55. Evolutionary and Comparative BiologistsEvolutionary and Comparative Biologists – Because DNA mutates at a constant rate,Because DNA mutates at a constant rate, comparisons of DNA between different organismscomparisons of DNA between different organisms can provide evolutionary histories.can provide evolutionary histories.
- 56. Ethical, Legal and Social Issues (ELSI)Ethical, Legal and Social Issues (ELSI) •Privacy legislation •Gene testing •Patenting •Forensics •Behavioral Genetics •Genetics in the Courtroom
- 57. Philosophical ImplicationsPhilosophical Implications Human responsibility Free will versus genetic determinism
- 58. Psychological Impact and igmatizationPsychological Impact and igmatization – Affects on the individualAffects on the individual – Affects on society’s perceptions and expectationsAffects on society’s perceptions and expectations of the individualof the individual
- 59. Clinical IssuesClinical Issues – Growing demand to educate health care workers toGrowing demand to educate health care workers to accurately evaluate genetic tests.accurately evaluate genetic tests. – Public needs to gain scientific literacy andPublic needs to gain scientific literacy and understand the capabilities, limitations and risks.understand the capabilities, limitations and risks. – Standards need to be established including qualityStandards need to be established including quality controls to ensure accuracy and reliability.controls to ensure accuracy and reliability. – Federal regulation?Federal regulation?
- 60. Genetic CounselingGenetic Counseling – Informed consent for complex proceduresInformed consent for complex procedures – Counseling about the risks, limitations andCounseling about the risks, limitations and reliability of genetic screening techniquesreliability of genetic screening techniques – Reproductive decision making based on geneticReproductive decision making based on genetic informationinformation – Reproductive rightsReproductive rights
- 61. Multifactorial Diseases and EnvironmentalMultifactorial Diseases and Environmental FactorsFactors – Genetic predispositions do not mandate diseaseGenetic predispositions do not mandate disease developmentdevelopment – Caution must be exercised when correlatingCaution must be exercised when correlating genetic tests with predictionsgenetic tests with predictions
- 62. SummarySummary •The significance of the completion of the human genome project cannot be overstated. •With the dictionary of the genome available, the molecular mechanisms of human health and disease will be resolved. •Armed with this knowledge a transformation in medical diagnostics and therapy is underway and will continue into the next few decades. •The application of this knowledge needs to be regulated and restricted to practices deemed ethically sound.