human genome project seminal achievement. scientific milestone. scientific implications. social...
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Human Genome Project
• Seminal achievement.• Scientific milestone.• Scientific implications.• Social implications.
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HGP: Background
• International Human Genome Sequencing Consortium: Proposed 1985, endorsed in
1988. 20 governmental groups. “Public project.”
Craig Venter & Celera Genomics:
Founded 1998. Sequence in 3 years. Technology: automation,
computers. Had access to public project’s data.
Race ends in tie Feb. 2001: both publish in Science and Nature.
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International Human Genome Sequencing
Consortium• Approach was conservative and methodical.• Had to wait for technology.• First produced a clone-based physical map of the genome that
would serve as a scaffold for the later sequence data:– Broke genome into chunks of DNA whose position on chromosome
was known from maps, clone into bacteria using BACs.
– Digest BAC-inserted clonal chunks of DNA into small fragments.
– Sequence small fragments.
– Stitch together BAC clones to assemble sequence.
– Assemble genome sequence from BAC clone sequences, using clone-based physical map.
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Celera
• Approach using "shotgun sequencing" (no organized map).
• Shreds genome randomly into small fragments with no idea of where they are physically located.
• Clones and sequences fragments.• Uses computer to stitch together genome by
matching overlapping ends of sequenced fragments.
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Timeline
• Genome sequencing driven by technology.– 1985: 500 base pairs per day
by hand.– 1985-86: PCR and automated
DNA sequencing.– 1992: BACs.– 2000: 1000 bases per second.
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Waiting for Technology
• Eyes on the human genome.
• While waiting for technology other genomes were sequenced.
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Current Status
• Human genome ~3.2 Gb.• “Rough draft” sequence of the human
genome.• Have sequenced 90% of the 2.5 Gb of gene-
rich (euchromatic) DNA.• What is considered finished?
– Fewer than 1 base in 10,000 is incorrectly assigned.
– More than 95% of the euchromatic regions are assigned.
– Each gap is smaller than 150 kb.
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Access to Information
• All public project data on the Internet.
• NCBI Website: www.ncbi.nlm.nih.gov.– Human genome database.– Sequence and mapping tools.
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Database Search Example
• The genome database has many tools to locate a gene of interest or search for potential traits of the gene.
• Example–chromosomal map search result for the "breast cancer–causing gene" BRCA2:
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Early Statistics
• Only 28% is transcribed into RNA.
• Only 1.1%-1.4% of genome actually encodes protein (=5% of transcribed RNA).
• Surprises:– More junk DNA.– Fewer genes.
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Junk DNA• No apparent direct biological function.• Long stretches of repeated sequence.• Hot area of investigation.• Human genome has far more repeat DNA
than any other sequenced organism (over half).
• Parasitic elements–45% of this repeat DNA is from selfish, parasitic DNA:– Transposable elements.– May play role in evolution.
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Gene Count
• Many fewer genes than expected (half):– Only 35,000-45,000 genes vs. previously
predicted 100,000.– Only twice the amount of a nematode or a fruit fly.– Does not correlate to twice as complex.– Alternative splicing: Invertebrate genes are more
innovative in their assembly of genes. – Protein domains are mixed more creatively and in
larger numbers by invertebrates.
• Genes elusive.
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Genetic Variation
• The International Single Nucleotide Polymorphism (SNP) Map. – Compiled 1.4 million SNPs (single-base pair
differences between individuals).
• Investigate:– Disease resistance.– Response to therapeutics.– Evolution.– Natural selection.– Individual traits.
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Gene Variation Example• Mutations in "breast cancer gene” BRCA2. • Chromosomal location and beginning sequence with
one of the mapped variations.
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Future Directions
• Fill gaps (refinement).• Bioinformatics.• Sequence additional
genomes.– For comparison.– Upcoming: mouse, fish,
dogs, kangaroo, chimpanzee (most valuable).
• Proteomics.• Gene and Protein Chips
(Microarrays).