M. Seri marco.seri@unibo.it Bologna 24 Gennaio 2009
Definitions Definitions Gene Gene : Introduced by Johansson in : Introduced by Johansson in Copenhagen for Mendel’s unit of inheritance Copenhagen for Mendel’s unit of inheritance (1909). (1909). Genetics Genetics : Introduced by Bateson in England : Introduced by Bateson in England for the science of inheritance (1905). for the science of inheritance (1905). Genome Genome : First used by Winkler in Germany : First used by Winkler in Germany (1920) for GENes and chromosOMEs, i.e. the (1920) for GENes and chromosOMEs, i.e. the complete set of chromosomes and the genes complete set of chromosomes and the genes they contain. they contain. Genomics Genomics : Structural and functional study of : Structural and functional study of genomes (Roderick, Bar Harbor, Me. 1986). genomes (Roderick, Bar Harbor, Me. 1986).
Medicina Genetica versus Genetica Medica La Genetica Medica è basata sullo studio di malattie genetiche rare, ereditate in modo “mendeliano” La Medicina Genetica implica il fatto che la genetica pervade tutta la medicina, incluse le malattie comuni come l’ipertensione, il cancro, le malattie cardiovascolari, etc. (= malattie genetiche complesse)
The Human Genome Project The Human Genome Project 1985 - Proposed 1985 - Proposed 1986 - 89 - Discussed, 1986 - 89 - Discussed, debated, and planned debated, and planned Oct. 1, 1990 - Official start Oct. 1, 1990 - Official start date date Sept. 30, 2005 - Projected Sept. 30, 2005 - Projected completion date completion date
Progetto Genoma Umano Progetto Genoma Umano tagagttgg ataagtcaga tgctctccaa ggctgatgct tgccctgaca cattgtgcgt tcgtgcatt gcgttcaata caagaggtgc tgacgaggca ggtccattct cttgtctaac ctaatgatc attctccctg agttgttggc agggggctgc tggcgtggaa ggaaaggaaa aagaggctt tgcttctctc tgccctcgga ggggaatggg gatgagctgg atgtttgaac cacatcctg cccagacaca caccctgaat gtcaacctgt aatcctaact gtgacaattt aggtcaggg atctaggctg tgagcaattt gaaaacaaaa caaaactgtg gcgttctgca agctcagct gcacataaag aaacactctg cgtgtgcctc ccagaactgt gtggtctgcc tggttccct gcctccgtga ctgatttcct gcaggatggc attcagatct tttgaagcgt ttttgaaat ctttctcaag gaaactctaa aagttgacct gggtctgtta ttaggcccta tgaaactgt aggagacgcc aggaccctgt gaagacagct gaggctcggt ggacactgct attgaagga tttagccttc tgagtcgttt ttgttgctgt gagttttctt tgttatgttt gaaagtgag actgtcactc gtgagctttc tcgccaggca gcatatcctt ctgtctcagc ttttgggag tcttgacttg ctgatccaag gagatttgct tttccttttc ccactggaaa ctgcaaagg ggtagttgtt ctccatggga ccacccgccc ccaccccccc caccgccccc cttccgtag ttgccagcct ggtcttcaat gagaagtatg gtctggaagc ttgaaacatc ttcataaac tctttcttga actgtgcctt actaactggt cagaagtctg ctcatcaacc aaacttcat ttaataaaag gaataaacct gctttcattt tgaaatgttt tcagctgata tataactca tccatttact cagaactcac cattgccgcc atgttcccct aacttcatga gcacagtaa acctctgaaa acttgcccct ctccaccacc cacagattaa tttcattgac acaggtgtt caaagacttc gcatggctgt aaccaggttc atctcattcc ccggctgtaa aatttgcta accaactgtc ctttaatcct tcaggagtct tggattcagt cttcaatttt gaccttttc ttttcagaca tggatcttac aaaaatctgc actgggaagg gagcggtgac ctccgggcc tcgtcttcct acagggaaac cccaagcagt agccctgcga gccctcagga acccggcaa cacgaaagca aaccaggtgc gcggaagcta gggaaagctg ttcaaagcca gtgggaagg gcgggaggag gctctggtgt ttttgctcag gagggtgtga gttcatcaga acctcttgg gggggggggg tgtgtgtgtg tgtgtgtgtg tctcttacgg tcccctggga agtcaaatc atttggatgg gtagtggtca aagcctcaaa ctgacagtca catgctgcag tgaaggcac agcaataacc acactttatg ttagctttga ctgagcaggt catcctgtga
Methods in Human Genetics 1960 1970 1980 1990 2000 2010 ‘Chromosomology’ 1956 Somatic Cell Genetics •Gene mapping •Somatic mutations in cancer •Inborn errors of metabolism Molecular Genetics Transgenic, KO, etc, mice Database searching ‘In silico cloning’ “ DNA chips ” Microarray technology
MENDELIAN INHERITANCE IN MAN MENDELIAN INHERITANCE IN MAN ( MIM ) ( MIM ) CATALOG OF AUTOSOMAL DOMINANT, CATALOG OF AUTOSOMAL DOMINANT, AUTOSOMAL RECESSIVE, AND AUTOSOMAL RECESSIVE, AND X-LINKED PHENOTYPES X-LINKED PHENOTYPES 1^ edizione 1966: 1500 voci – oggi: >14000 1^ edizione 1966: 1500 voci – oggi: >14000 Dal 1998: solo in forma elettronica:On-lineMIM Dal 1998: solo in forma elettronica:On-lineMIM http:// http://www.ncbi.nlm.nih.gov/entrez www.ncbi.nlm.nih.gov/entrez/ /
disease models Comparative Genomics medicine behavior human Drosophila mouse development physiology C. elegans rat crop yield genetics Arabidopsis yeast biochemistry infectious disease microbes
Power of Comparative Genomics Power of Comparative Genomics • Understanding the Understanding the human genome human genome through comparative through comparative genomics genomics The fly is blind The fly is blind • Evolution preserves Evolution preserves Mutations in the Pax-6 gene of Drosophila cause an eyeless phenotype function between function between species species The The child is child is • Genome comparisons Genome comparisons blind blind increase the increase the interpretative interpretative capability capability Mutations in the Pax-6 gene of humans causes Aniridia “no iris” phenotype
Genetic Medicine Paradigm Genetic Medicine Paradigm Modified DNA RNA Proteins Proteins Biological Function Y Y Transcription Translation Post-Translation Modification 30,000 Genes > 1,000,000 Proteins Information: Critical to Understanding Disease Mechanisms
Genes with mutations Cloned human genes causing human disorders About 4000 Total ~ 30,000 genes SEA 3017
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