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Figure 9.15 TD Gelehrter, FS Collins, D Ginsburg.Principles of Medical Genetics. 1997.
DISEASE
FUNCTION
GENE
MAP
DISEASE
FUNCTION
GENE
MAP
FUNCTIONAL CLONING POSITIONAL CLONING
3
…GAA AAT ATC ATC TTT GGT GTT TCC…
Glu Asn Ile Ile Phe Gly Val Ser
504 505 506 507 508 509 510 511
DNA
PROTEIN
POSITION
NORMAL
…GAA AAT ATC AT - - - T GGT GTT TCC…
Glu Asn Ile Ile Gly Val Ser
DNA
PROTEIN
CYSTIC FIBROSIS
10
A SAMPLING OF COOL THINGS ABOUTTHE GENOME
Humans have fewer genes than expected
Human genes make more proteins than those ofother critters
Male mutation rate is twice that of females
“Junk” DNA contains the remnants andraw materials for evolution
Big Events in April 2003
• 50th Anniversary of Watson andCrick
• Completion of the sequence of all thehuman chromosomes
• Announcement of bold new researchplan for genomics
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Comparative Genomics
Proteomics
Functional Genomics
Fulfilling the Promise of Genomics for Better Health
Medical Genomics
Positional cloning of a gene for ahighly penetrant Mendeliandisorder is now straightforward –
but tracking genetic susceptibilityfactors for non-Mendeliandisorders continues to be vexing
12
Finding genetic variants thatcontribute to common disease is
critically important. Hereassociation (case control) studieshave greater power than family
linkage studies.
N. Risch and K. Merikangas,Science 273: 1516-1517, 1996
Sequence from chromosome 7
GAAATAATTAATGTTTTCCTTCCTTCTCCTATTTTGTCCTTTACTTCAATTTATTTATTTATTATTAATATTATTATTTTTTGAGACGGAGTTTCACTCTTGTTGCCAACCTGGAGTGCAGTGGCGTGATCTCAGCTCACTGCACACTCCGCTTTCC/TGGTTTCAAGCGATTCTCCTGCCTCAGCCTCCTGAGTAGCTGGGACTACAGTCACACACCACCACGCCCGGCTAATTTTTGTATTTTTAGTAGAGTTGGGGTTTCACCATGTTGGCCAGACTGGTCTCGAACTCCTGACCTTGTGATCCGCCAGCCTCTGCCTCCCAAAGAGCTGGGATTACAGGCGTGAGCCACCGCGCTCGGCCCTTTGCATCAATTTCTACAGCTTGTTTTCTTTGCCTGGACTTTACAAGTCTTACCTTGTTCTGCCTTCAGATATTTGTGTGGTCTCATTCTGGTGTGCCAGTAGCTAAAAATCCATGATTTGCTCTCATCCCACTCCTGTTGTTCATCTCCTCTTATCTGGGGTCACA/CTATCTCTTCGTGATTGCATTCTGATCCCCAGTACTTAGCATGTGCGTAACAACTCTGCCTCTGCTTTCCCAGGCTGTTGATGGGGTGCTGTTCATGCCTCAGAAAAATGCATTGTAAGTTAAATTATTAAAGATTTTAAATATAGGAAAAAAGTAAGCAAACATAAGGAACAAAAAGGAAAGAACATGTATTCTAATCCATTATTTATTATACAATTAAGAAATTTGGAAACTTTAGATTACACTGCTTTTAGAGATGGAGATGTAGTAAGTCTTTTACTCTTTACAAAATACATGTGTTAGCAATTTTGGGAAGAATAGTAACTCACCCGAACAGTGTAATGTGAATATGTCACTTACTAGAGGAAAGAAGGCACTTGAAAAACATCTCTAAACCGTATAAAAACAATTACATCATAATGATGAAAACCCAAGGAATTTTTTTAGAAAACATTACCAGGGCTAATAACAAAGTAGAGCCACATGTCATTTATCTTCCCTTTGTGTCTGTGTGAGAATTCTAGAGTTATATTTGTACATAGCATGGAAAAATGAGAGGCTAGTTTATCAACTAGTTCATTTTTAAAAGTCTAACACATCCTAGGTATAGGTGAACTGTCCTCCTGCCAATGTATTGCACATTTGTGCCCAGATCCAGCATAGGGTATGTTTGCCATTTACAAACGTTTATGTCTTAAGAGAGGAAATATGAAGAGCAAAACAGTGCATGCTGGAGAGAGAAAGCTGATACAAATATAAATGAAACAATAATTGGAAAAATTGAGAAACTACTCATTTTCTAAATTACTCATGTATTTTCCTAGAATTTAAGTCTTTTAATTTTTGATAAATCCCAATGTGAGACAAGATAAGTATTAGTGATGGTATGAGTAATTAATATCTGTTATATAATATTCATTTTCATAGTGGAAGAAATAAAATAAAGGTTGTGATGATTGTTGATTATTTTTTCTAGAGGGGTTGTCAGGGAAAGAAATTGCTTTTTTTCATTCTCTCTTTCCACTAAGAAAGTTCAACTATTAATTTAGGCACATACAATAATTACTCCATTCTAAAATGCCAAAAAGGTAATTTAAGAGACTTAAAACTGAAAAGTTTAAGATAGTCACACTGAACTATATTAAAAAATCCACAGGGTGGTTGGAACTAGGCCTTATATTAAAGAGGCTAAAAATTGCAATAAGACCACAGGCTTTAAATATGGCTTTAAACTGTGAAAGGTGAAACTAGAATGAATAAAATCCTATAAATTTAAATCAAAAGAAAGAAACAAACTA/GAAATTAAAGTTAATATACAAGAATATGGTGGCCTGGATCTAGTGAACATATAGTAAAGATAAAACAGAATATTTCTGAAAAATCCTGGAAAATCTTTTGGGCTAACCTGAAAACAGTATATTTGAAACTATTTTTAAA
Three variants are present
13
These three variants could theoreticallyoccur in 8 different haplotypes
…C…A…A…
…C…A…G…
…C…C…A…
…C…C…G…
…T…A…A…
…T…A…G…
…T…C…A…
…T…C…G…
But in practice,only two are observed
…C…A…A…
…C…A…G…
…C…C…A…
…C…C…G…
…T…A…A…
…T…A…G…
…T…C…A…
…T…C…G…
14
These three variants are said tobe in linkage disequilibrium
…C…A…A…
…C…A…G…
…C…C…A…
…C…C…G…
…T…A…A…
…T…A…G…
…T…C…A…
…T…C…G…
~ 30 kb
15
A Haplotype Map of Human Variation
• Goal is to define all common haplotypes inthe human genome
• Genome-wide association studies can thenbe done with 30 – 50 times less work
• Project was initiated in October 2002, usingsamples of African, Asian, and Europeanorigin
16
Nature, Vol. 418, 426-430, July 25, 2002
With these resources, it is likely that manyof the major contributing genes for
diabetes, heart disease, cancer, mentalillness, Alzheimer’s disease, Parkinson’s
disease, asthma, etc. will be identifiedwithin the next 5 – 10 years.
17
Gleevec™ – Specifically TargetsAn Abnormal Protein, BlockingIts Ability To Cause Chronic Myeloid Leukemia
Chromosome 9;22 translocation
CML
Bcr-Abl fusion protein
Gleevec™
Bcr-Abl fusion protein
Normal
18
Ethical, Legal, and Social Implications
An integral component of the
Human Genome Project
Will effective legislative
solutions to genetic
discrimination be found?
19
Can health care providers and
the public become genetically
literate in time?
Will the benefits of the advances in
genetics only be available to a
privileged few?