La Genetica Medica è basata sullo studio di malattiegenetiche rare, ereditate in modo “mendeliano”

La Medicina Genetica implica il fatto che la geneticapervade tutta la medicina, incluse le malattie comuni

come l’ipertensione, il cancro, le malattiecardiovascolari, etc.

(= malattie genetiche complesse)

Medicina Genetica versusGenetica Medica

1985 1985 -- ProposedProposed

1986 1986 -- 89 89 -- Discussed, Discussed, debated, and planneddebated, and planned

Oct. 1, 1990 Oct. 1, 1990 -- Official start Official start datedate

Sept. 30, 2005 Sept. 30, 2005 -- Projected Projected completion datecompletion date

The Human Genome ProjectThe Human Genome Project

DefinitionsDefinitionsGeneGene: Introduced by Johansson in : Introduced by Johansson in Copenhagen for MendelCopenhagen for Mendel’’s unit of inheritance s unit of inheritance (1909).(1909).

GeneticsGenetics: Introduced by : Introduced by BatesonBateson in England in England for the science of inheritance (1905).for the science of inheritance (1905).

GenomeGenome: First used by Winkler in Germany : First used by Winkler in Germany (1920) for (1920) for GENesGENes and and chromosOMEschromosOMEs, i.e. the , i.e. the complete set of chromosomes and the genes complete set of chromosomes and the genes they contain.they contain.

GenomicsGenomics: Structural and functional study : Structural and functional study of genomes (Roderick, Bar Harbor, Me. of genomes (Roderick, Bar Harbor, Me. 1986).1986).

Methods in Human Genetics1960 1970 1980 1990 2000

‘Chromosomology’

1956Somatic Cell Genetics

•Gene mapping

•Inborn errors of metabolism•Somatic mutations in cancer

Molecular Genetics

Transgenic, KO, etc, mice

Database searching‘In silico cloning’

“ DNA chips ”Microarray technology

2010

MENDELIAN INHERITANCE IN MANMENDELIAN INHERITANCE IN MAN( MIM )( MIM )

CATALOG OF AUTOSOMAL DOMINANT,CATALOG OF AUTOSOMAL DOMINANT,

AUTOSOMAL RECESSIVE, ANDAUTOSOMAL RECESSIVE, AND

XX--LINKED PHENOTYPESLINKED PHENOTYPES

1^ 1^ edizioneedizione 1966: 1500 1966: 1500 vocivoci –– oggioggi: >14000: >14000

DalDal 1998: solo in forma 1998: solo in forma elettronica:Onelettronica:On--lineMIMlineMIM

http://http://www.ncbi.nlm.nih.gov/entrezwww.ncbi.nlm.nih.gov/entrez//

Gene DensityGene DensityMicrobesMicrobes 1 gene / kb1 gene / kb 90% 90% CodingCoding

S. S. cerevisiaecerevisiae 1 gene / 2 kb1 gene / 2 kb 70%70%

C.elegansC.elegans 1 gene / 5 kb1 gene / 5 kb 40%40%

A. thalianaA. thaliana 1 gene / 5 kb1 gene / 5 kb 20%20%

D. D. melanogastermelanogaster 1 gene / 13 kb1 gene / 13 kb 20%20%

H. sapiensH. sapiens 1 gene / 40 kb1 gene / 40 kb 3%3%

Comparative Genomicsdisease models

biochemistry

crop yield

behavior

development

medicine

infectious disease

genetics

microbes

Arabidopsis

C. elegans

Drosophila

human

mouse

yeast

physiology

rat

Power of Comparative GenomicsPower of Comparative Genomics

•• Understanding the Understanding the human genome through human genome through comparative genomics comparative genomics

•• Evolution preserves Evolution preserves function between function between speciesspecies

•• Genome comparisons Genome comparisons increase the increase the interpretative capabilityinterpretative capability

Mutations in the Pax-6 gene of Drosophila cause an eyeless phenotype

Mutations in the Pax-6 gene of humanscauses Aniridia “no iris” phenotype

The The child is child is blindblind

The fly is blindThe fly is blind

Genetic Medicine ParadigmGenetic Medicine Paradigm

Information: Critical to Understanding Disease Mechanisms

Y

YRNA Proteins

Modified ProteinsDNA Biological

Function

Transcription Translation Post-TranslationModification

50,000 Genes > 1,000,000 Proteins

Cloned human genes Genes with mutations causing human disorders

Total ~ 35,000 genesSEA 3017

23Sep03

16773 1493

Caratteri Quantitativi o “continui”

Caratteri Semiquantitativi o “discontinui”

Caratteri Autosomici Dominanti

Caratteri Autosomici Recessivi

Caratteri legati al Cromosoma X

Caratteri Monofattoriali o “mendeliani”

Caratteri Multifattoriali

1/20001/2000

Le malattie monogenicheLe malattie monogeniche

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

MALATTIE POLIGENICHE

100% AMBIENTE 100% GENI

Paraparesi spastica

Fibrosi cistica

Distrofia Muscolare di Duchenne

Raffreddore

TBC

Traumi

Autismo Asma ObesitàDiabete Cancro

(malattie poligeniche o complesse)

Siamo entrati nellSiamo entrati nell’’era era postpost--genomicagenomica

• Finora le tecnologie disponibili permettevano l’analisi di singoli geni

• Oggi possiamo analizzare il funzionamento di migliaia di geni

Geni e malattie: una nuova dimensioneGeni e malattie: una nuova dimensione

normalenormale

Variazione 1:Variazione 1:MutazioneMutazione

Variazione 2: polimorfismoVariazione 2: polimorfismo

sanosano

Malattia Malattia monofattorialemonofattorialeSano, ma Sano, ma con una con una proteinaproteinache funziona di che funziona di pipiùù o di meno: o di meno: suscettibilitsuscettibilitàà

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