1Figure 9.15 TD Gelehrter, FS Collins, D Ginsburg.Principles of Medical Genetics. 1997.DISEASEFUNCTIONGENEMAPDISEASEFUNCTIONGENEMAPFUNCTIONAL CLONING POSITIONAL CLONING2Figure 9.31 TD Gelehrter, FS Collins, D Ginsburg.Principles of Medical Genetics. 1997.3…GAA AAT ATC ATC TTT GGT GTT TCC… Glu Asn Ile Ile Phe Gly Val Ser 504 505 506 507 508 509 510 511DNAPROTEINPOSITIONNORMAL…GAA AAT ATC AT - - - T GGT GTT TCC… Glu Asn Ile Ile Gly Val SerDNAPROTEINCYSTIC FIBROSIS456http://www.genome.gov789http://genome.ucsc.eduPowerTo ThePeople!10A SAMPLING OF COOL THINGS ABOUTTHE GENOMEHumans have fewer genes than expectedHuman genes make more proteins than those ofother crittersMale mutation rate is twice that of females“Junk” DNA contains the remnants andraw materials for evolutionBig Events in April 2003• 50th Anniversary of Watson andCrick• Completion of the sequence of all thehuman chromosomes• Announcement of bold new researchplan for genomics11Comparative GenomicsProteomicsFunctional GenomicsFulfilling the Promise of Genomics for Better HealthMedical GenomicsPositional cloning of a gene for ahighly penetrant Mendeliandisorder is now straightforward –but tracking genetic susceptibilityfactors for non-Mendeliandisorders continues to be vexing12Finding genetic variants thatcontribute to common disease iscritically important. Hereassociation (case control) studieshave greater power than familylinkage studies.N. Risch and K. Merikangas,Science 273: 1516-1517, 1996Sequence from chromosome 7GAAATAATTAATGTTTTCCTTCCTTCTCCTATTTTGTCCTTTACTTCAATTTATTTATTTATTATTAATATTATTATTTTTTGAGACGGAGTTTCACTCTTGTTGCCAACCTGGAGTGCAGTGGCGTGATCTCAGCTCACTGCACACTCCGCTTTCC/TGGTTTCAAGCGATTCTCCTGCCTCAGCCTCCTGAGTAGCTGGGACTACAGTCACACACCACCACGCCCGGCTAATTTTTGTATTTTTAGTAGAGTTGGGGTTTCACCATGTTGGCCAGACTGGTCTCGAACTCCTGACCTTGTGATCCGCCAGCCTCTGCCTCCCAAAGAGCTGGGATTACAGGCGTGAGCCACCGCGCTCGGCCCTTTGCATCAATTTCTACAGCTTGTTTTCTTTGCCTGGACTTTACAAGTCTTACCTTGTTCTGCCTTCAGATATTTGTGTGGTCTCATTCTGGTGTGCCAGTAGCTAAAAATCCATGATTTGCTCTCATCCCACTCCTGTTGTTCATCTCCTCTTATCTGGGGTCACA/CTATCTCTTCGTGATTGCATTCTGATCCCCAGTACTTAGCATGTGCGTAACAACTCTGCCTCTGCTTTCCCAGGCTGTTGATGGGGTGCTGTTCATGCCTCAGAAAAATGCATTGTAAGTTAAATTATTAAAGATTTTAAATATAGGAAAAAAGTAAGCAAACATAAGGAACAAAAAGGAAAGAACATGTATTCTAATCCATTATTTATTATACAATTAAGAAATTTGGAAACTTTAGATTACACTGCTTTTAGAGATGGAGATGTAGTAAGTCTTTTACTCTTTACAAAATACATGTGTTAGCAATTTTGGGAAGAATAGTAACTCACCCGAACAGTGTAATGTGAATATGTCACTTACTAGAGGAAAGAAGGCACTTGAAAAACATCTCTAAACCGTATAAAAACAATTACATCATAATGATGAAAACCCAAGGAATTTTTTTAGAAAACATTACCAGGGCTAATAACAAAGTAGAGCCACATGTCATTTATCTTCCCTTTGTGTCTGTGTGAGAATTCTAGAGTTATATTTGTACATAGCATGGAAAAATGAGAGGCTAGTTTATCAACTAGTTCATTTTTAAAAGTCTAACACATCCTAGGTATAGGTGAACTGTCCTCCTGCCAATGTATTGCACATTTGTGCCCAGATCCAGCATAGGGTATGTTTGCCATTTACAAACGTTTATGTCTTAAGAGAGGAAATATGAAGAGCAAAACAGTGCATGCTGGAGAGAGAAAGCTGATACAAATATAAATGAAACAATAATTGGAAAAATTGAGAAACTACTCATTTTCTAAATTACTCATGTATTTTCCTAGAATTTAAGTCTTTTAATTTTTGATAAATCCCAATGTGAGACAAGATAAGTATTAGTGATGGTATGAGTAATTAATATCTGTTATATAATATTCATTTTCATAGTGGAAGAAATAAAATAAAGGTTGTGATGATTGTTGATTATTTTTTCTAGAGGGGTTGTCAGGGAAAGAAATTGCTTTTTTTCATTCTCTCTTTCCACTAAGAAAGTTCAACTATTAATTTAGGCACATACAATAATTACTCCATTCTAAAATGCCAAAAAGGTAATTTAAGAGACTTAAAACTGAAAAGTTTAAGATAGTCACACTGAACTATATTAAAAAATCCACAGGGTGGTTGGAACTAGGCCTTATATTAAAGAGGCTAAAAATTGCAATAAGACCACAGGCTTTAAATATGGCTTTAAACTGTGAAAGGTGAAACTAGAATGAATAAAATCCTATAAATTTAAATCAAAAGAAAGAAACAAACTA/GAAATTAAAGTTAATATACAAGAATATGGTGGCCTGGATCTAGTGAACATATAGTAAAGATAAAACAGAATATTTCTGAAAAATCCTGGAAAATCTTTTGGGCTAACCTGAAAACAGTATATTTGAAACTATTTTTAAAThree variants are present13These 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…14These 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 kb15A 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 Europeanorigin16Nature, Vol. 418, 426-430, July 25, 2002With these resources, it is likely that manyof the major contributing genes fordiabetes, heart disease, cancer, mentalillness, Alzheimer’s disease, Parkinson’sdisease, asthma, etc. will be identifiedwithin the next 5 – 10 years.17Gleevec™ – Specifically TargetsAn Abnormal Protein, BlockingIts Ability To Cause Chronic Myeloid LeukemiaChromosome 9;22 translocationCMLBcr-Abl fusion proteinGleevec™Bcr-Abl fusion protein Normal18Ethical, Legal, and Social ImplicationsAn integral component of theHuman Genome ProjectWill effective legislativesolutions to geneticdiscrimination be found?19Can health care providers and the public become genetically literate in time?Will the benefits of the advances ingenetics only be available to aprivileged few?20Will knowledge of human variationreduce prejudice, or increase it?21Will we arrive at consensus aboutthe limits of genetic technology fortrait enhancement?Will we succumb to geneticdeterminism, neglecting the role ofthe environment, and undervaluingthe power of the human spirit andour need for