The Human Genome Project:

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The Human Genome Project Applications and
Implications
Evan Eichler Case Western Reserve University
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I. How was it done?
II. What were the major findings?
III. What are the future applications and
implications?
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Human Genome Project Goal

• Understand the hereditary instructions of
  humankind by
• Identification of the 100,000 human genes
• To read the entire script of our sequence (all 3
  billion bits
• of information) in their correct order by spring
  2003.

Purpose of HGP To revolutionize Medicine AND
Biology.
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Public
Hierarchial Shotgun Sequencing
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Private
Whole-Genome Shotgun Sequencing
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Human Genome Project Timeline
Announcement
Celera begins large-scale
Draft sequence target
WDS Publication Celera Publication
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(No Transcript)
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Magnitude of the Task

• 15 months time in which 90 of the human genome
• was generated.
• 2) 1000 bp/second (24 hours per day, 7 days a
  week)
• 9 monthstime for Celera to generate its data
• 3000 individuals working in 16 major centers to
  generate
• Data (249 listed on the publication)
• 5) 48 individuals working for 8 months to
  analyze data
• 6) 274 individuals on the Celera publications

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One Page of Text from the Human Genome
CCATCCAGCTTTGTTCCATTGCTCGCAAGGAGCTGCAATCCTTTGGAGGA
GAAGCGGCGCTCTGGTTTTT TGAATTTTCAGCTTGTCTGCTCTGGTTTC
CCCCCATATTTGTGGTTTTATCTACCTTTGGTCTTTAATGA TGGTGACC
TACAGATGTGGTTTTGGTGTGGATGTCCTTTTTGTTGATGCTGTTCCTTT
CTGTTTGCTAGT TTTCCTTCTAACAATCAGGACCCTCAGCTGCAGGTCT
GTTGGAGTTTGTTGGAGGTCCACTCCAGACCCT GTTTGCCTGAGTGTCA
CCAGTGGAGGCTGCAGAACAGCAAATATTGCTGCCTGATCCTTCTTCTGG
AAGC TTTCCTTCTAACAATCAGGACCCTCAGCTGCAGGTCTGTTGGAGT
TTGTTGGAGGTCCACTCCAGACCCT GTTTGCCTGAGTGTCACCAGTGGA
GGCTGCAGAACAGCAAATATTGCTGCCTGATCCTTCTTCTGGAAGC TTC
ATCTCAGAGGGACACCTGGCTGTATGAGGTGTCAGTAAATCCCTACGGGC
AGCTCTGTCTATTCTCA GAGTTCAAACTCCATGCTGGAGAATGACTGCT
CTCTTCAGAGCTGTCAGACAGGGATGTTTAAGTCTGCA GAAGTTTCTGC
TGCCTTTTATTCAGCTATACCCTGCCCCTAGAGGTGGAGTCTACAGAGGC
TTCCAGGGC TCCTTGAGCTGCAGTGAGCTCCACCCAGTTCAGGCTTCCC
AGCTGCTTTGTTTAACTATTCAAGCCTCAG CAATGGTGGACGCCCCTCC
CCCAGCCCAGGCTGCCACCTTGCAGTTCGATCTCGGACTGCTGCACTAGC
A GTAAGCAAGGCTGTGTGGGCATGGGACCCGCCAAGCCATGCAAGGGAT
ATAATCTCCTGGTGTGCCGCTT GCTAAGACCATTGGAAAAGCACAGTAT
TAGGGTGGGAATGTCTGGATTTTCCAGGTGCCGTCTGTCACGG CTTCCC
TTGGCTAGGAAAGGGAAATCCCCCGACCACTTGTGCTGCTTCCCAGATGA
GGTGACACCCTGCC CTGCTTCGGCTCACCCTCTGTGGGCTGCACCCACT
GTCCGACCCGTCTCAGTGTGATGAACTAAGTACCT CAGATGGAAATACA
GAAATCACCTGTCTTCTACGTCAATTATGCTGAGAGCTGCAGACAGGAGC
TGTTCC TATTCGGCCATCTTGGAAAAATCCTCTCTTTTCATTTATTTAA
GAAATATTTGAAAAGCAAAGATTTCAT CATTTTGGTGCAGTCCAATTTA
TCTGTTTTTCTTTTATGGAACATGTTTTTGATATTATATCTAAGAAAA C
TTTTCTTAGTCCAAGGTCATAAATATTTTCTCCTATTTTTTTTCCTAGAA
GTTTTACAGTTTTAGCTCA TACAATTAGGTCTATGATCCATTTTAGTTA
ATTTTCGTATATGACCTAAGGATCTAGGCTTAGTTTTTGT
1page3000 characters
1chapter50 pages
20,000 chapters
CCATCCAGCTTTGTTCCATTGCTCGCAAGGAGCTGCAATCCTTTGGAGGA
GAAGCGGCGCTCTGGTTTTT TGAATTTTCAGCTTGTCTGCTCTGGTTTC
CCCCCATATTTGTGGTTTTATCTACCTTTGGTCTTTAATGA TGGTGACC
TACAGATGTGGTTTTGGTGTGGATGTCCTTTTTGTTGATGCTGTTCCTTT
CTGTTTGCTAGT TTTCCTTCTAACAATCAGGACCCTCAGCTGCAGGTCT
GTTGGAGTTTGTTGGAGGTCCACTCCAGACCCT GTTTGCCTGAGTGTCA
CCAGTGGAGGCTGCAGAACAGCAAATATTGCTGCCTGATCCTTCTTCTGG
AAGC TTCATCTCAGAGGGACACCTGGCTGTATGAGGTGTCAGTAAATCC
CTACGGGCAGCTCTGTCTATTCTCA GAGTTCAAACTCCATGCTGGAGAA
TGACTGCTCTCTTCAGAGCTGTCAGACAGGGATGTTTAAGTCTGCA GAA
GTTTCTGCTGCCTTTTATTCAGCTATACCCTGCCCCTAGAGGTGGAGTCT
ACAGAGGCTTCCAGGGC TCCTTGAGCTGCAGTGAGCTCCACCCAGTTCA
GGCTTCCCAGCTGCTTTGTTTAACTATTCAAGCCTCAG CAATGGTGGAC
GCCCCTCCCCCAGCCCAGGCTGCCACCTTGCAGTTCGATCTCGGACTGCT
GCACTAGCA GTAAGCAAGGCTGTGTGGGCATGGGACCCGCCAAGCCATG
CAAGGGATATAATCTCCTGGTGTGCCGCTT GCTAAGACCATTGGAAAAG
CACAGTATTAGGGTGGGAATGTCTGGATTTTCCAGGTGCCGTCTGTCACG
G CTTCCCTTGGCTAGGAAAGGGAAATCCCCCGACCACTTGTGCTGCTTC
CCAGATGAGGTGACACCCTGCC CTGCTTCGGCTCACCCTCTGTGGGCTG
CACCCACTGTCCGACCCGTCTCAGTGTGATGAACTAAGTACCT CAGATG
GAAATACAGAAATCACCTGTCTTCTACGTCAATTATGCTGAGAGCTGCAG
ACAGGAGCTGTTCC TATTCGGCCATCTTGGAAAAATCCTCTCTTTTCAT
TTATTTAAGAAATATTTGAAAAGCAAAGATTTCAT CATTTTGGTGCAGT
CCAATTTATCTGTTTTTCTTTTATGGAACATGTTTTTGATATTATATCTA
AGAAAA CTTTTCTTAGTCCAAGGTCATAAATATTTTCTCCTATTTTTTT
TCCTAGAAGTTTTACAGTTTTAGCTCA TACAATTAGGTCTATGATCCAT
TTTAGTTAATTTTCGTATATGACCTAAGGATCTAGGCTTAGTTTTTG
1,000,000 pages
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Robotics and Technology Development
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Computational Capacity

• 32 processors
• P3 (450 MHz)

• 0.5 Terrabyte
• RAID Server

• JBS software
• Manage system

• Price 35,000

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Results
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I. Human Genome Sequence Organization
GENE
LINES
SINES
RPTS
GC
0.5

• 1.5 of the genome encodes genes
• 45 -50 repeat DNA

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II. Gene Density (1 per 100, 000 bp)
Human 33,000 genes Fly 14,000
genes Worm 18,000 genes
Human has fewer genes than anticipated
(60-120,000 genes)
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III. Cross-species homology gt95 of our genes
share homology with other species.
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IV. Human genes are more complex

• Two-fold more more domain accretion than fly or
  worm.

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IV. Genome Sequence Divergence agrees
with Paleontological and Evolutionary Record.
98.7
98.3
97.0
94.5
91.0
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V. Human Genome Sequence Organization
Total 3.43 (97.5 Mb) Inter 1.77 (47.7
Mb) Intra 2.29 (61.6 Mb)

• Large duplications cluster near centromeres and
  telomeres
• Architecture predisposes to rearrangements

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Segmental Duplication A Unique property of
Human Genome Architecture

• Genome structure of humans differs by an order of
  magnitude or more in terms of large duplications
• Important Biological and Practical Implications

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Model of Genomic Disease
A
B
C
TEL
A
B
C
TEL
Aberrant Recombination
GAMETES
Human Disease and Genetic Variation
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Genome Evolution

• Single base-pair changes and sequence duplication
• Fundamental process of evolution of species
• Key to the increase in vertebrate complexity

a) Polyploidization
b) Tandem duplication
c) Segmental Duplication
A
A
A
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Implications Medical Research

• Identification and characterization of a variety
  of
• rare single mendelian genetic disorders

• Identification of genetic susceptibility factors
  for
• complex traits that afflict majority of the
  population
• Eg . Asthma, heart disease, diabetes

• Diagnostic Testing technology development to
  allow
• the identification of 1000s of susceptibilities
  at birth.

• Pharmacogenomicsdevelopment of tailor made drugs
• By recognizing the heterogeneity of genetic
  disease

5) Gene Therapy?
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Implications Ethical and Social

• Preimplantation Testing
• a) selection of embryos without genetic
  disease
• b) discard genetically inferior embryos
• c) selection of embryos with sibling
  compatibility

• Disease vs. Variation (Eugenics revisited)
• Eg. achondroplastic individuals
• prefer to have children of similar heightselect
  against normal
• height embryos.

3) Genetic Elitism (who will have access to
genetic tests) a) Cost of a single diagnostic
test 2,000 b) Cost of preimplantation testing
40,000 Who will pay?
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Implications Ethical and Social
4) Genetic Information a) who will want this
information? b) who will have access to the
information? eg. Government, insurance
agencies c) who will safeguard this
information? Unlike other forms of personal
information, this information is transmitted to
our children, grandchildren, etc. Impact future
generations
5) Genetic Discrimination concept of race will
begin to dissolve (majority of genetic Differences
are shared across ethnic groups) -concept of
genetic races (groups) emerges -Insurance denies
access to certain individuals --jobs are denied
based on genetic predispositions Eg. narcoleptic
susceptibility and aviation Predisposition to
criminal behaviour.
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Implications Ethical and Social
6) Genetic Determinism --predispositions to
criminal behaviour --my genes made me do
it --genetic defenseshomicidal proclivity, how
will this impact the legal system a license to
kill, abolition of the death penalty
7) Religion vs. Science --blueprint of the book
of lifeas other organisms are sequenced we have
a defined genetic hierarchy Eg. Human vs. Human
99.9 genetic identity Human vs.
Chimpanzee 98.7 genetic identity Human vs.
Gorilla 98.0 genetic identity Human vs.
Orangutan 96.4 genetic identity --Identify the
genetic components that contribute to our
creativity, artistic ability and our
humanity --What impact on faith/religion? Eg.
Intelligent Design.
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Conclusions
Genomic Revolution 1) Biologyblueprint of
life 2) Healthdiagnostic, disease and
therapy 3) Scientific methodwork as groups,
International 3) Industrybiomedical research,
important to develop therapies and the
drugs 4) Legalgenetic evidence and genetic
defense 5) Socialsusceptibility, religion vs.
science 6) Ethicalselect offspring Major
achievement for mankind. --potential for
tremendous good or evil