Genotype-phenotype linkages

In vivo methods for creating genotype-phenotype linkages are well established and exploit the cellular machinery necessary to process some proteins. Cell surface display of proteins coupled with fast cell-sorting systems can increase the size of the library that can be displayed and selected or screened. 

Leemhuis, H. et al (2005) New genotype—phenotype linkages for directed evolution of functional proteins. Curr. Opin. Struct. Biol, 15 (4), 472 -478. 

The second approach, directed evolution, attempts to mimic natural evolution on a laboratory timescale. The basis of directed evolution is repeated rounds of mutagenesis or recombination followed by a screening or selection step (while maintaining a genotype-phenotype linkage) to identify proteins with improved properties. This process requires no structural or functional information and is widely applicable. Currently, the main drawback of directed evolution is the lack... 

Once genotypes have been derived from genome-wide scans, the data can be analyzed so as to determine whether any markers cosegregate with the disease/phenotype. Segregation of alleles is evaluated using linkage... 

The key is to link phenotype to genotype. Linkage studies can indicate the correlation between disease state and changes in the drug targets concentration or activity. Transcriptional and proteomic analysis, where one can show changes in the expression of mRNA levels or protein gene product in a disease or disease model, has been most successful if you have a chronic disease, so that there is time for both transcriptional and... 

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