Dissection of Genetic Pathways in C. elegans - Caenorhabditis Elegans: Molecular Genetics and Development - page 126

including human ADPKD ( Barr et al., 2001; Barr and Sternberg, 1999 ), muscular
dystrophy ( Kim et al., 2004 ), cancer ( Bergamaschi et al., 2003; Polanowska et al.,
2004 ), diabetes and obesity ( Pierce et al., 2001 ), and neurodegenerative diseases
( Lakso et al., 2003 ). The applications of C. elegans for various disease models have
been extensively reviewed ( Dimitriadi and Hart, 2010; Kaletta and Hengartner,
2006; Kirienko et al., 2010 ). With the unique genetic advantages of C. elegans,
large-scale screens that are impractical in vertebrates can be readily performed in
C. elegans to identify highly conserved genes that may modulate human diseases. To
identify those genes, suppressor screens are often performed on a transgenic strain
generated to resemble a pathological process of interest. For example, one hallmark
of some notable neurodegenerative diseases is the abnormal aggregation of proteins,
such as wild-type or mutated tau protein that normally functions to stabilize micro-
tubules and promote their polymerization. The aggregation of tau is seen in a group
of neurodegenerative diseases, including Alzheimer ' s disease and frontotemporal
dementia with parkinsonism chromosome 17 type (FTDP-17T) ( Lee et al., 2001 ). To
identify genes participating in tau neurotoxicity, Guthrie et al. (2009) carried out a
forward genetic screen for suppressors of the Unc (uncoordinated movement) phe-
notype caused by accumulation of exogenous mutated human tau in a transgenic
strain that was engineered to express this tau protein in all neurons. Using this
transgenic worm as a model of human taunopathy disorders, they revealed that loss
of function in a gene, sut-2, which encodes a highly conserved subtype of CCCH zinc
finger protein, was able to suppress tau neurotoxicity. The identification of this gene
suggested a novel neuroprotective strategy to interrupt

tau pathogenesis

( Guthrie et al., 2009 ).

Some Considerations Regarding Nature of Suppressors
There are two specialized types of suppression that can arise when performing a
suppressor screen, which may not provide insight into the biological processes of
interest. These are important to be aware of when interpreting results of suppressor
screens. One is informational suppression caused by mutations in genes involved in
the general machinery of transcription, RNA processing, and protein translation. This
suppression is allele-specific, gene-nonspecific. A large number of EMS-induced null
alleles are nonsense point mutations causing early stop codons. Suppressor screens
using these nonsense alleles can produce tRNA mutations that recognize stop codons
as sense codons so that the starting allele can be translated to the protein with
biological activity. As an informational suppressor is allele-specific, it may not
suppress the phenotype of other alleles of the gene of interest, which provides a good
way to test if a suppressor mutant is an informational mutation. Similarly, mutations of
components in the nonsense decay system that is responsible for degrading premature
mRNA can also suppress the phenotype of the starting mutation. Informational
mutations are valuable for studies on regulation of transcription, RNA processing,
and translation; however, they do not provide insights into the genetic networks
controlling the biological processes likely to be of interest in the screens.