Lecture 9: Human Genome and Its Applications

Learning Objectives

• Understand principles of human genome assembly
• Examine variability and similarity between human genomes
• Familiarize with functional and regulatory elements of human genome

Overview of the Human Genome

• Discussion on complexity of human genome
• How the human genome is assembled, annotated, and released
• Introduction to the Personal Genome Project (PGP) and its relevance
• Brief mention of mitochondrial genome and its differences from nuclear genome
• Applications of human genome knowledge in clinical practice and research

Historical Context

• Significant progress in molecular biology and genomics over the last 50-60 years
• Key milestones:
  • Watson and Crick's double helix prediction
  • Development of recombinant DNA techniques
  • Automated sequencing advancements (Sanger sequencing)
  • Publication of the human genome draft in 2001
• Sequencing costs have drastically decreased (from $3 billion to around $5,000)
• Rapid advancement in sequencing technologies: nearly 2,000% increase in 6 years (1995-2001)

Current Genome Sequencing Trends

• Annual sequencing of approximately 10,000 genomes with expected tenfold increase every two years
• Importance of understanding molecular processes through genome sequencing

Complexity of the Human Genome

• Known Knowns: Questions we can answer (e.g., number of genes)
• Known Unknowns: Questions we know exist but haven't answered yet
• Unknown Unknowns: Areas we haven't yet recognized as gaps in knowledge
• Misconceptions about the age of humanity: estimates revised to over 120,000 years
• Diversity of genes preserved through human evolution

Genome Reference Consortium (GRC)

• Responsible for maintaining and annotating the human genome
• Collaboration among major institutions (e.g., Wellcome Trust, NCBI)
• Genome Build Cycle:
  1. Submission of sequences
  2. Bioinformatics filtering and alignment
  3. Assembly of contigs
  4. Gene modeling and annotation
  5. Public release of annotated data
• Latest build (GRC38) released on December 24, 2013
• Current genome length: Over 3 billion base pairs

Human Genome Insights

• Total number of genes: Approximately 25,000 (less than 1% of the genome)
• Half of these genes have unknown functions
• Importance of non-coding RNA and microRNA for gene regulation
• Complexity of gene expression regulation and protein diversity

Next Generation Sequencing (NGS) Techniques

• NGS as a method for genome assembly and analysis
• Challenges regarding assembly accuracy and error acceptance
• Potential for multiple reference genomes based on diverse populations

Mitochondrial Genome Overview

• Contains 37 genes; distinct from nuclear DNA
• High mutation rate and maternal inheritance
• Variability causing certain hereditary diseases (e.g., MELAS)
• Mitochondrial DNA used for studying population migrations

Practical Applications of Genome Knowledge

Clinical Applications

• Primary diagnosis and biomarkers for diseases
• Personalized medicine and targeted therapies
• Increase in life expectancy and ongoing research in aging

Rare Diseases

• Defined differently across regions (US, EU, Japan)
• Approximately 80% of rare diseases have genetic factors
• Increased focus on rare diseases due to advancements in genomics

Polygenic Diseases

• Understanding chronic diseases through genomic changes
• Link between genomics and drug discovery processes
• Shift towards molecular targets in pharmaceutical development

Genome-Wide Association Studies (GWAS)

• Key in identifying SNPs associated with diseases
• Importance of sample size in confidence of findings
• Interactive maps of SNPs and their correlations with diseases

Resources and Databases

• Various databases maintaining genotype-phenotype relationships (e.g., Gene2Phen, HUGE)
• International efforts for cataloging genetic similarities (e.g., International HapMap Project)

Conclusion

• Practical applications of human genome research are expanding
• Ongoing research efforts to leverage genomic knowledge for clinical and therapeutic advancements
• Open floor for questions related to the lecture