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The art and design of genetic screens: Caenorhabditis elegans

Key Points

  • The advantages of the nematode Caenorhabditis elegans for genetics studies are its short generation time, and that it is easy and inexpensive to maintain. Mutant strains can be frozen and maintained indefinitely.

  • Because strains can be propagated as self-fertilizing hermaphrodites, screens for recessive mutations are easy — the F2 generation of mutagenized animals can be inspected for interesting phenotypes. Labour-intensive crosses are not required.

  • Suppressor screens have been widely used to identify components of signal-transduction pathways.

  • The ease with which mutants can be obtained is useful for saturation screening and for the analysis of structure–function relationships of a protein.

  • Some screens are labour intensive, but are nevertheless fruitful if there are no other ways to generate mutants in a specific biological process. These have included screens for cell-death mutants, which have required screening on a compound microscope.

  • Lethal mutations can be identified and maintained in heterozygous animals that segregate 1 in 4 dead embryos. This led to the development of maternal-effect lethal screens, which identified proteins that are required for early cell-fate decisions in the developing embryo.

  • Sensitized screens can be used to identify genes that have a role in a process but are mutated to lethality. The advantage is that the screens can be carried out in the F1 generation and are identified as haploinsufficient loss-of-function loci.

  • Synthetic-lethal screens can identify loci that act redundantly in a process.

Abstract

The nematode Caenorhabditis elegans was chosen as a model genetic organism because its attributes, chiefly its hermaphroditic lifestyle and rapid generation time, make it suitable for the isolation and characterization of genetic mutants. The most important challenge for the geneticist is to design a genetic screen that will identify mutations that specifically disrupt the biological process of interest. Since 1974, when Sydney Brenner published his pioneering genetic screen, researchers have developed increasingly powerful methods for identifying genes and genetic pathways in C. elegans.

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Figure 1: Scanning electron micrograph of a Caenorhabditis elegans hermaphrodite.
Figure 2: A simple F2 screen.
Figure 3: Signalling cascades.
Figure 4: Green fluorescent protein screen.
Figure 5: Maternal-effect screen.
Figure 6: Non-allelic non-complementation screen.
Figure 7: Synthetic lethal screens.

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Acknowledgements

We thank A. Chisholm, R. Herman and M. Labouesse for comments on the manuscript. J. Srinivasan, R. Sommer, E. Troemel, C. Bargmann and L. Kaltenbach provided photographs. P. Anderson, L. Avery, B. Bowerman, S. Clark, M. Han, T. Harris, M. Hengartner, J. Hodgkin, M. Nonet, R. Korswagen, D. Pilgrim, N. Pujol and J. Priess made helpful contributions and suggestions.

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DATABASES

LocusLink

Bcl2

groucho

sevenless

<i>Schizosaccharomyces pombe</i> GeneDB

RAD1

Wormbase

ced-9

dif-1

dpy-21

end-1

end-3

glp-1

her-1

him-5

lag-1

lag-2

LET-23

lin-4

lin-8

lin-9

lin-12

lin-15

lin-35

lin-58

MEC-4

mec-8

mrt-2

npr-1

rpm-1

sad-1

SAX-3/Robo

sdc-2

SDC-3

SEM-5

skn-1

SOS-1

tam-1

TTX-1/OTD

UNC-4

UNC-6

unc-17

unc-24

UNC-30

unc-37

unc-52

vab-1

vab-2

XOL-1

FURTHER INFORMATION

Encyclopedia of Life Sciences

Caenorhabditis elegans as an experimental organism

AceDB

C.elegansWWW.server

Erik Jorgensen's lab

Searchable C. elegans literature index

Susan Mango's lab

Glossary

GABA NEURON

A neuron that releases the inhibitory neurotransmitter GABA (γ-aminobutyric acid).

FATE MAP

The description of the cell divisions from fertilized egg to adult, linked to the eventual anatomical position of the cell in the animal and the differentiated state, or fate, of the cell.

OPERON

A locus consisting of two or more genes that are transcribed as a unit and are expressed in a coordinated manner.

RNA INTERFERENCE

(RNAi). A process by which double-stranded RNA silences specifically the expression of homologous genes through degradation of their cognate mRNA. In worms, a gene can be selectively disabled and its phenotype determined simply by feeding wild-type animals double-stranded RNA.

ANCHOR CELL

A somatic cell in the gonad that induces vulval development in the underlying epidermal cells.

M4 MOTOR NEURON

A motor neuron in the pharynx that is required for the peristaltic movements of the muscle that move food into the grinder.

BALANCER CHROMOSOME

Balancer chromosomes are used in trans to a chromosome that carries a lethal mutation. Such chromosomes carry deleterious mutations, so that heterozygotes have a selective advantage and are easily maintained. They are used as genetic tools because they allow lethal mutations to be propagated indefinitely. In addition, balancer chromosomes frequently contain rearrangements or translocations that disrupt recombination between the homologues.

mRNA SURVEILLANCE PATHWAY

A pathway that recognizes and degrades mRNA molecules that bear nonsense mutations.

QUANTITATIVE TRAIT

A measurable trait that typically depends on the cumulative action of many genes and the environment. [ok?]

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Jorgensen, E., Mango, S. The art and design of genetic screens: Caenorhabditis elegans. Nat Rev Genet 3, 356–369 (2002). https://doi.org/10.1038/nrg794

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