Fx chpter 4 p2

• Functional Genomics


  Transcriptomic and Pharmacogenomics
• Comparative Genomics


  1. Microarray Analysis

  2. Drug Discovery
• Gene Mutation


  International HapMap Project

  
• Goal of International HapMap Project

  • Develop a haplotype map of the human genome
  • Describe the common patterns of human genetic variation

  
• Importance of studying genetic variation


  • Most common diseases are affected by many genes and environmental factors
  • 0.1% of DNA sequence differences contain genetic variants that influence disease risk and drug response
• Single nucleotide variations (SNPs)


  Sites in the genome where DNA sequences vary by a single base

  
• Alleles


  The two copies of a gene that a person has

  
• Genotype


  The set of alleles that a person has
• Haplotype


  A set of associated SNP alleles in a region of a chromosome

  
• The Human Genome Project and related technologies has generated thousands of novel potential drug targets
• Pharmacogenomics


  Genetic differences between individuals (SNP) can cause large differences in drug effects both agonist and antagonist and toxic
• Genes do not cause disease


  Defective genes cause disease
• Gene is missing or defective


  Replace protein or replace activity
• Gene is overexpressed


  Develop inhibitors of synthesis or activity
• Using functional genomics to guide drug discovery


  • Improve identification and selection of potential targets
  • Provide information on relationship between potential targets and associated disease at DNA, RNA and protein level

  
• Open Targets


  An open access and user friendly web-based tool for identifying novel associations between targets and diseases
• Open Targets combines expertise in

  • Gene editing (CRISPR)
  • Induced pluripotent stem cells
  • Single cell genomics
  • Organoid and tissue culture
  • Large-scale genomics and epigenomics
  • Genome wide association studies
  • Next-generation sequencing
  • Bioinformatics
  • High performance computing
• Drug Discovery: Analgesic Drug

  • Computational Functional Genomics used for drug discovery and repurposing for analgesic indications
• Drug Discovery: Breast Cancer

  • Functional genomics used to discover HER2 overexpression and develop Herceptin drug
  • High throughput analyses and meta-analyses uncovered additional targets for drug repurposing
• Tools for Forward and Reverse Genetics

  • Insertional mutagenesis
  • Transposon tagging
  • T-DNA tagging
  • Sequence mutagenesis
  • Radiation mutagenesis
  • Chemical mutagenesis
  • Targeted gene mutagenesis
  • Sense or anti-sense expression
  • Homologous recombination
  • Virus induced gene silencing (VIGS)
  • RNA interference (RNAi)
• CRISPR/Cas9


  • Efficient and reliable tool for making precise, targeted changes to the genome of living cells
  • Simplicity, high efficiency and versatility of the system
  • Potential reaches beyond DNA cleavage for genome locus-specific recruitment of proteins

  
• In 2015, the journal Science chose CRISPR-Cas9 technology as one of the most important technological advances in science in the last few years
• A Japanese research group has succeeded in blocking the production of HIV-1 by infected cells using the CRISPR/Cas9 genome editing system