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 1985 - Proposed 1986 - 89 - Discussed, debated, and planned Oct. 1, 1990 - Official start date Sept. 30, 2005 - Projected completion date Cb,jdqfmljdql,c

Definitions Gene: Introduced by Johansson in Copenhagen for Mendel’s unit of inheritance (1909). Genetics: Introduced by Bateson in England for the science of inheritance (1905). Genome: First used by Winkler in Germany (1920) for GENes and chromosOMEs, i.e. the complete set of chromosomes and the genes they contain. Genomics: Structural and functional study of genomes (Roderick, Bar Harbor, Me. 1986).

Microarray technology 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 ( MIM ) CATALOG OF AUTOSOMAL DOMINANT, AUTOSOMAL RECESSIVE, AND X-LINKED PHENOTYPES 1^ edizione 1966: 1500 voci – oggi: >14000 Dal 1998: solo in forma elettronica:On-lineMIM http://www.ncbi.nlm.nih.gov/entrez/

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Gene Density Microbes 1 gene / kb 90% Coding S. cerevisiae 1 gene / 2 kb 70% C.elegans 1 gene / 5 kb 40% A. thaliana 1 gene / 5 kb 20% D. melanogaster 1 gene / 13 kb 20% H. sapiens 1 gene / 40 kb 3%

Comparative Genomics disease models medicine behavior development human Drosophila mouse development physiology rat C. elegans genetics crop yield Arabidopsis yeast biochemistry infectious disease microbes

Power of Comparative Genomics Mutations in the Pax-6 gene of Drosophila cause an eyeless phenotype Mutations in the Pax-6 gene of humans causes Aniridia “no iris” phenotype The child is blind The fly is blind Understanding the human genome through comparative genomics Evolution preserves function between species Genome comparisons increase the interpretative capability As an example of the power of comparative genomics, the mutation of Pax-6 gene of Drosophila leads to an eyeless phenotype that obviously leads to the fruitfly being blind. Mutations in the Pax-6 gene of humans usually results in blindness in children.

Genetic Medicine Paradigm Modified Proteins DNA RNA Proteins Biological Function Y Transcription Translation Post-Translation Modification This slide depicts the building blocks of life increasing in complexity from a DNA strand to human life as you move from left to right across this slide. What isn’t depicted are the biological processes and molecular pathways that make life possible. The more we are able to uncover about these processes and pathways, the more we will understand about the complex logic of biology. We provide (and are continuing to develop) technologies that address the needs of researchers in examining and understanding different parts of the pathway. The breadth of our technology (and of the knowledge underlying the technology) is critical to our understanding of the logic of biology overall and to the development of technologies and products to help further that knowledge. 50,000 Genes > 1,000,000 Proteins Information: Critical to Understanding Disease Mechanisms

causing human disorders Cloned human genes Genes with mutations causing human disorders Cloned human genes 16773 1493 Total ~ 35,000 genes 23Sep03 SEA 3017

Caratteri Monofattoriali o “mendeliani” Caratteri Autosomici Dominanti Caratteri Autosomici Recessivi Caratteri legati al Cromosoma X Caratteri Multifattoriali Caratteri Quantitativi o “continui” Caratteri Semiquantitativi o “discontinui”

Le malattie monogeniche 1/2000

MALATTIE POLIGENICHE Sono causate dall’azione di due o più geni e dalla loro interazione con l’ambiente Hanno frequenza superiore ad un’affetto ogni mille individui

Distrofia Muscolare di Duchenne Interazione fra geni e ambiente Raffreddore TBC Traumi Autismo Asma Obesità Diabete Cancro (malattie poligeniche o complesse) Paraparesi spastica Fibrosi cistica Distrofia Muscolare di Duchenne 100% AMBIENTE 100% GENI

Siamo entrati nell’era post-genomica Finora le tecnologie disponibili permettevano l’analisi di singoli geni Oggi possiamo analizzare il funzionamento di migliaia di geni

Geni e malattie: una nuova dimensione normale sano Malattia monofattoriale Variazione 1: Mutazione Sano, ma con una proteina che funziona di più o di meno: suscettibilità Variazione 2: polimorfismo