This document discusses genomics, proteomics, bioinformatics, pharmacogenomics, and the human genome project. It provides information on how genetic polymorphisms can influence drug disposition by affecting metabolizing enzymes and transporters. The human genome project mapped the entire human genome sequence to further the goals of personalized medicine based on an individual's genetic profile. Single nucleotide polymorphisms are particularly important for understanding how individuals respond differently to drugs.

1. GENOMICS AND PROTEOMICSBYRAJASHEKAR MANTHRIM.PHARMACY IISEMESTERDEPARTMENT OF PHARMACEUTICSVAAGDEVI COLLEGE OF PHARMACY

2. CONTENTSINTRODUCTION

3. Genomics and Proteomics

4. Bioinformatics

5. PHARMACOGENOMICS

6. SNPs

7. Personalized medicine

8. Benefits of pharmacogenomics

9. HUMAN GENOME PROJECT

10. Birth and activity of HGP

11. Mapping of HG

12. Approaches for genome sequence

13. GENETIC POLYMORPHISMS INFLUENCING DRUG DISPOSITION

14. Metabolizing enzymes

15. Transporters

16. GENETIC POLYMORPHISMS IN DRUG TARGETS

17. β2 – receptors

18. ApolipoproteinsGENE: An inherited factor that determines a biological characteristics of an organism is called gene.

19. GENOME: The total genetic information contained in an organism or cell is regarded as the genome. Genes carry the information for making the proteins required for the body growth and maintenance.GENOMICS: The study of the structure and function of the genome is genomics.Structural genomics: refers to the structural motifs and complete protein structure.Functional genomics: It focuses on genome wide patterns of gene expression, the mechanism by which gene expression is coordianted and the interrelation ships of gene expression when a cellular environmental change occurs.

20. PROTEOME: Proteome defines a complete protein entity encoded by a specific gene of an organism or cell.

21. Proteome plays a key role in intracellular signalling pathways of the immune system and intercellular metabolism as being the interface between the cell and the environment.

22. Proteins are important targets of drug discovery. In several disease states, the protein expression is altered. This is one of the reasons for the evolution of proteomic techniques. PROTEOMICS: Proteomics is the study of protein characteristics and functions to obtain a global integrated view of:• normal and abnormal cellular processes• protein-protein interactionsMining: Identification of all proteins in a sample.Protein Expression Profiling: Identification of protein in a sample as a function of a state of the organism or cell under certain condition.Protein Network Mapping: Approach to determine how proteins interact with each other in living systems.Mapping of protein modifications: Identification how and where proteins are modified.

23. BIOINFORMATICSBioinformatics is the combination of biology and information technology.

24. It broadly involves the computational tools and methods used to manage, analyze and manipulate volumes and volumes of biological data.

25. It requires advanced knowledge of computer science, mathematics and statistical methods for the understanding of biological phenomena at the molecular level.Components of Bioinformatics: It comprises three components1.Creation of databases:This involves the organizing, storage and management the biological data sets.Database: The collection of the biological data on a computer which can be manipulated to appear in varying arrangements and subsets is regarded as a database.The biological information can be stored in different databases.

26. Some of the examples of databases areProtein sequence database:

27. SWISS – PROT (www.expasy.ch/sport): it provides the description of the structure of a protein.

28. PIR (Protein Information Resource) is a database provided by the National Biomedical Research Foundation (NBRF) in USA

29. PROSITE: provides information on protein families and domains.

30. Nucleotide sequence database:

31. Gene bank: provides nucleotide sequence maintained by the National Center for Biotechnology Information (NCBI), USAEMBL: European Molecular Biology Laboratory maintained by European Bioinformatics Institute (EBI)2. Development of Algorithms and statistics:It involves the development of tools and resources to determine the relation ship among the members of large data sets.E.g. comparison of protein sequence data with the already existing protein sequences.3. Analysis of data and interpretation:Above said two components used to analyze the data and interpret the results.

32. Applications of Bioinformatics:Identification of nucleotide sequence of functional genes.

33. Finding of sites that can be cut by restriction enzymes.

34. Prediction of functional gene products.

35. Prediction of 3 – dimensional structure of proteins.

36. Designing of drugs for medical treatment.

37. Molecular modeling of biomolecules.PHARAMACOGENOMICSPharmacogenomics is the study of how an individuals genetic differences effects the body’s response to drugs.

38. Pharmacogenomic studies explain the inherited nature of these differences in drug disposition and effects.

39. It is the branch of pharmacology which deals with studying the influence of genetic variation on drug response in patients.

40. Study of pharmacogenomics helps to study how different drugs interact with multiple genes and biological molecules they encode.

41. Pharmacogenomic analysis promises to identify disease susceptibility genes thus discovering new drug targets.Promises of Pharmacogenomics:Pharmacogenomics hold the promise that drug might one day be tailor made for individuals that is to say as the tailor stitches the dress of an individual by taking the size in the same way the dose of drug will be decided by the individual genetic make up.The promise of pharmacogneomics is that both the choice of the drug and its dose will be determined by the individual genetic make up leading to the personalized, more efficacious and less harmful drug therapy.

42. The emerging discipline of pharmacogenomics attempts to apply the innovative technologies of genome sequencing in order to better understand drug response to produce more effective drugs with fewer side effects on the basis of individual patients genetic makeup and making personalized medicine an economically viable possibility.Human genetic variation in DNA:Single nucleotide polymorphisms (SNPs)

43. Insertions

44. Deletions

45. Short Tandem Repeats (STRs)

46. TranslocationsCommon SequenceVariationsPolymorphismDeletionsInsertionsTranslocations

47. What are SNPs and How are They Found? A Single Nucleotide Polymorphism, or SNP (pronounced "snip") is a small genetic change, or variation, that can occur within a person's DNA sequence. One-letter variations in the DNA sequence.

48. SNPs contribute to differences among individuals. Most SNPs are found outside of "coding sequences." SNPs found within a coding sequence are alter the biological function of a protein.

49. SNPs represent as much as 90% of all human genetic variation. More than 1.4 million single nucleotide polymorphisms were identified in the initial sequencing of the human genome.

50. The majority have no effect, others cause differences in characteristics, including risk for certain diseases and influence their response to a drug.Role of SNPs in Pharmacogenomics:For pharmacogenomics to be effective, it is essential to identify the markers that can correlate drug response and genetic make up.

51. SNPs are believed to underlie susceptibility to such common diseases as cancer, diabetes, cardio vascular and inflammatory diseases and to contribute to the traits that make individuals unique.

52. Mapping of these SNPs in an individual helps in understanding which genetic factors will influence drug action in an individual. SNPs also helps to explain why different people respond differently to same drug.SNPs are most common and most technically accessible class of genetic variants. These are much more frequent than other variations and spread through out the genome, so SNPs are turning into useful markers of drug response. Pharmacogenomics has become a key to develop personalized drugs.PERSONALISED MEDICINEGenetic markers such as single-nucleotide polymorphisms may lead to personalized medicines for a wide variety of diseasesWhat is it?Developing drugs on the basis of individual genetic differencesHow does it work? Tailoring therapies to genetically similar subpopulations results in improved efficacy and less toxicityWhat is it based upon?Pharmacogenomics = Pharmacology + Genomics

53. Personalized medicineis the use of detailed information about a patient’s genotype or level of gene expression and a patient’s clinical data in order to select a medication, therapy or preventive measure that is particularly suited to that patient at the time of administration. Certain drugs work differently in different individuals. In some individuals they produce therapeutic effects and in some other individuals, they produce severe toxic effects at the same dose.Inter individual variability can be seen in drug absorption, distribution, elimination and excretion. This inter individual variation in drug efficacy and toxicity is related to inherited differences in the genes that encode drug metabolizing enzymes drug transporters or drug receptors.

55. Inter individual variability in drug response and ADRs are major public health problems.

56. The ADRs are the major cause on non - compliance and failure of treatment, particularly for chronic pathologies.

57. Many of these deaths can be avoided, if the physician has prior knowledge of patient’s genetic profile of drug metabolizing enzymes and receptors, which determine drug responses.

58. In the near future, the present prescription model of “one dose for all” (based on age, sex, gender, weight, drug interactions) will be replaced by “individualized prescription” (i.e. individualized / personalized therapy) – that is the right drug in right dose for right person.

59. The whole purpose of the study of genetic variations in drug responses is to identify patients who may benefit from a particular medicine and avoid dangerous prescription to others.Anticipated benefits of pharmacogenomicsFacilitated drug discovery:Based on genetic makeup, most appropriate drugs can be designed which are more targeted to specific diseases. Thus maximum therapeutic effects can be obtained.Screening for disease:Genetic profile helps in prevention of diseases at early stages. It can also help to determine individual’s susceptibility to a particular disease.Better vaccines:Vaccines made of genetic material, either DNA or RNA activate the immune system but will be unable to cause infections. They will be inexpensive, stable, easy to store and capable of being engineered to carry several strains of a pathogen at once.

60. Facilitate drug approvals:Pharmaceutical companies can discover new drugs by targeting genomes. Risk of adverse effects in clinical trials can be minimized by targeting only those who will respond to drug.Accuracy in dosing:By knowing a person’s genetic makeup, it becomes easier to determine, how the body processes the medicine. Thus instead of using conventional method of calculating dosage based on age and weight, dosage can be calculated based on person’s genetic profile. This reduces chances of overdose and under dose thereby optimizing drug therapy

61. The Human Genome ProjectUntil the early 1970’s, DNA was the most difficult cellular molecule for biochemists to analyze.DNA is now the easiest molecule to analyze – we can now isolate a specific region of the genome, produce a virtually unlimited number of copies of it, and determine its nucleotide sequence overnight.

62. Aims of the project: To identify the approximate 100,000 genes in the human DNA.Determine the sequences of the 3 billion bases that make up human DNA. Store this information in databases. Develop tools for data analysis. Address the ethical, legal, and social issues that arise from genome research.

63. THE BIRTH AND ACTIVITY OF HUMAN GENOME PROJECTThe human genome project (HGP) was conceived in 1984 and officially begun in earnest in October 1990.

64. The primary objective of HGP was to determine the nucleotide sequence of the entire human nuclear genome.

65. First director of HGP was James Watson (who elucidated DNA structure).

66. In 1997, united states established the national human genome research institute (NHGRI).

67. The HGP was an international venture involving research groups from six countries USA,UK,FRANCE,GERMANY,JAPAN, CHINA and several individual laboratories and a large number of scientists and technicians from various disciplines.This collaborative venture was named as international human genome sequencing consortium (IHGSC), and was headed by Francis Collins.

68. Total expenditure of $ 3 billion and a time period of 10 to 15 years for the completion of HGP was expected and it was completed in June 2000.

69. A second human genome project was setup by a private company —Celera genomics of Maryland USA in 1998. This team was led by Craig Venter. ANNOUNCEMENT OF THE DRAFT SEQUENCE OF HUMAN GENOME:Working drafts of human genome sequence was announced in the year of 2000 on June 26th by the leaders of the two HGPs, Francis Collins and Venter.

70. Mapping of the Human Genome:-The most important objective of human genome project was to construct a series of maps for each chromosomes.Cytogenetic map: This is a map of the chromosome in which the active genes respond to a chemical dye and display themselves as bands on the chromosomes.Gene linkage map: A chromosome map in which the active genes are identified by locating closely associated marker genes. The most commonly used DNA markers are restriction fragment length polymorphism (RFLP), variable tandem repeats(VNTRs) and short tandem repeats (STRs). VNTRs are also called as minisatellites while STRs are microsatellites.

71. Restriction fragment map: This consists of the random DNA fragments that have been sequenced.Physical map: This is the ultimate map of the chromosome with highest resolution base sequence. Cytogenetic mapGene linkage mapGene Gene Restriction fragment mapRestriction fragmentsPhysical mapBase sequence