DISEASE MAP FUNCTION MAP FUNCTION GENE … · FUNCTIONAL CLONING POSITIONAL CLONING. 2 Figure 9.31 TD Gelehrter, FS Collins, D Ginsburg. ... highly penetrant Mendelian disorder is

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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

2

Figure 9.31 TD Gelehrter, FS Collins, D Ginsburg.Principles of Medical Genetics. 1997.

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…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

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5

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http://www.genome.gov

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8

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http://genome.ucsc.edu

PowerTo ThePeople!

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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

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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

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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…

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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

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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

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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.

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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

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Ethical, Legal, and Social Implications

An integral component of the

Human Genome Project

Will effective legislative

solutions to genetic

discrimination be found?

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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?

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Will knowledge of human variation

reduce prejudice, or increase it?

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Will we arrive at consensus about

the limits of genetic technology for

trait enhancement?

Will we succumb to geneticdeterminism, neglecting the role ofthe environment, and undervaluingthe power of the human spirit andour need for God?