Lecture Notes on the Human Genome Project

Overview of the Human Genome Project

• Completion Date: April 2003
• Duration: 13 years
• Objective: To sequence and map all genes of Homo sapiens
• Initiated in 1990 under James Watson at U.S. National Institutes of Health
  • Watson resigned in 1992 due to disagreements over patenting genes
  • Francis Collins took over in 1993
• Milestones:
  • Working draft released in 2000
  • Complete genome released in 2003
  • Last chromosome sequence published in 2006 in Nature

Human Genome Sequencing

• Representative Sequence: Composite from several anonymous donors
• Unfinished Regions: Approximately 1% of the genome remains unfinished, mainly centromeres and telomeres

Sequencing Methods

• Hierarchical Shotgun Sequencing

  • Used by publicly funded HGP
  • DNA cut into pieces, inserted into bacterial artificial chromosome (BAC) vectors
  • Constructs a "Golden Tiling Path"
  • Advantage: Reduced error in assembly
  • Disadvantage: Time-consuming and expensive

• Whole Genome Shotgun Sequencing

  • Used by Celera Genomics
  • Random shearing of DNA into small pieces
  • Advantage: Faster and cheaper
  • Disadvantage: More prone to assembly errors

• Hybrid Approach

  • Combined strengths of both methods
  • Both HGP and Celera achieved goals more efficiently

Details of the Human Genome

• Total Size: 3.2 gigabases

• Coding vs. Non-Coding DNA:

  • Non-coding: Majority; includes introns, intergenic regions, and repetitive sequences
  • Coding: 1.25% codes for proteins

• Genes: Around 25,000 genes

  • Comparison: Nematode worm (18,000 genes), Mouse (similar number of genes)
  • Biological complexity not directly related to genome size

• Repetitive Sequences: 45% transposons, 3% microsatellite repeats, 5% large segment duplications

Biological Implications

• Gene Function and Complexity
  • Alternative splicing and post-translational modifications contribute to diversity
  • Protein-protein interactions are crucial for cellular processes

Challenges and Future Directions

• Unsequenced Areas: 1% heterochromatin region
• Regulatory Signals: Epigenetic modifications still unclear
• Single Nucleotide Polymorphisms (SNPs): Over 1.4 million identified
• Gene Function Exploration: Ongoing efforts to understand gene products

Impact on Medicine

• Genetic Research: Facilitates discovery of genetic components of complex disorders like diabetes, asthma, cancer
• Gene Expression Techniques: Enable investigation of gene expression related to disease and drug responses

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These notes provide a comprehensive overview of the Human Genome Project, its methods, challenges, and implications for biology and medicine.