Genetic Screening
Personalized Medicine

Author: Monica Pradotto
Date: 10/06/2011


Drosophila is a powerful tool for genetic studies
• To investigate the basic biological questions common to flies and humans
• To carry out large-scale genetic screens for mutations that affect a given process
• To provide an unbiased way to identify genes involved in a particular process
• To provide mutants as a very valuable resource for dissecting the function of a gene
Advantages of the fly system
• Fast and cheap (little equipment and little space)
• Small and easy to grow
• Culturing flies is cost-effective (vs mice)
• A relatively short life cycle (10 days)
• High fecundity
• The mature larvae show giant chromosomes in the salivary gland (polytene chromosome)
• Only 4 pairs of chromosomes: 3 autosomes and 1 sex chromosome
• Complete genome sequence (13,500 genes) in 2000
Advantages of the fly system for studies of human diseases
• Large number of developmental processes are conserved btw flies and vertebrates
• Less redundant genome (13000 genes)
• High homology with human genes
• High homology with human genes involved in human diseases (197 out of 287)
Enhancer and suppressor screens
• To find out the missing components of a developmental pathway
• To find out components in the signal-transduction pathways
• In a sensitized genetic background (mutations partially disrupting a biological processes),mutations in genes involved in the pathway can be identified as dominant enhancer or suppressor
The enhancer trap: The GAL4-UAS system to have a transgenic fly
• The enhancer trap lines express Gal4 under the control of nearby genomic enhancers
• Gal4 insertions in random positions
• Transgene cloned into a P-element vector (EP) that carries UAS sites
• Genes insert next to UAS can be activated by GAL4

A wide modifier screening can be performed crossing the transgenic flies with commercially available stocks of Dm (Deficiences Kit, Bloomington stock center) carrying small and well characterized chromosome deletions within the whole fly genome. Analyzing the progeny phenotype, it’s possible identifying two different groups : a first group of flies with a more aggressive phenotype, suggesting the lack of one or more target gene negative regulators while a second group with an improvement of the phenotypes most likely due to the absence of genes sustaining the target signalling.

The genome sequence of Drosophila Melanogaster, 2000
Development of a Drosophila seizure model for in vivo high throughput drug screening,2006
A sensitized genetic screen to identify novel regulators and components of the Drosophila janus kinase/signal transducer and activator of transcription pathway,2003

To characterize the genes included in deletions is suitable the gene bank flybase
Indeed this site supplies many informations about gene position and gene functions with links to the literature.
After the identification of candidate genes as interactors of target gene, the human counterpart can be detected by using nbc/unigene or kegg
In this way the study moves to human.
The characterization of splicing isoforms is easy to perform with Alternative Splicing Prediction Data Base

A lot of organism may be use to perform a genetic screening:
- warm;
- yeast;
- mouse;
- weed.

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