C. Elegans Genetic Portait

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The nematode Caenorhabditis elegans, one of the simplest

multicellular organisms, lives in soils worldwide and feeds on

soil bacteria. Adults are about 1 mm in length and contain an

invariant number of somatic cells (Fig. C.1). The maturefemale, which is actually a hermaphrodite able to produce

both eggs and sperm, has precisely 959 somatic cells that arose

from progenitor cells by a reproducible pattern of cell division.

The mature male, which produces sperm and has genitalia thatenable it to mate with the hermaphrodite, includes precisely1031 somatic cells that also arose by a reproducible pattern of

cell division. C. elegans has a short life cycle and an enormous

reproductive capacity, progressing in just three days from the

fertilized egg of one generation to between 250 and 1000 fer-

tilized eggs of the next generation. It is transparent at all stages,

so that investigators can use the light microscope to trackdevelopment at the cellular level throughout the life cycle. Its

small size and small cell number, precisely reproducible and

viewable cellular composition, short life cycle, and capacity for prolific reproduction

make C. elegans an ideal subject for the genetic analysis of development. The fact

that the genome for C. elegans was sequenced in 1998 makes it an even more appeal-

ing organism to study.Although C. elegans and most other free-living species of nematodes are gen-

erally beneficial, they are related to nematodes that parasitize animals and plants,

causing human disease and agricultural damage. Knowledge gained from the study

of C. elegans will help combat these problems.

Three unifying themes surface in our discussion of C. elegans. First, the invari-ance of cell number and fates forms the basis of many experimental protocols used

to study nematode development. Second, the invariant specification of cellular

divisions and fates depends on a varied palette of developmental strategies. These

include the segregation of particular molecules to particular daughter cells at divi-

sion, inductive signals sent from one cell to influence the development of an adja-cent cell, signal transduction pathways within each cell that respond to the arrival of

an inductive signal, and a genetically determined program that causes the death of

specific cells. Third, genetic studies on the development of C. elegans reveal the

simultaneous conservation and innovation of evolution. Because the nematode

exhibits many features of development, physiology, and behavior found in other com-

plex animals such as Drosophila and humans, studies of C. elegans can help eluci-date developmental pathways and genes conserved throughout animal evolution. But

because other features of C. elegans development, such as the invariant spatial and

temporal pattern of cell positions, divisions, and fates, are quite different from those

found in more complex animals, studies of C. elegans provide a comparative coun-

terpoint that deepens our understanding of the full range of genetic controls overdevelopment in multicellular eukaryotes.

Caenorhabditis elegans:Genetic Portrait of a Simple

Multicellular Animal

ReferenceC

49

An adult C. elegans hermaphrodite

surrounded by larvae of various

stages.

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Aligning the Physical and Genetic Maps

Researchers have constructed a detailed physical map of the

C. elegans genome showing the order of cosmid and YAC

clones covering each of the six chromosomes. The physical

map has been useful not only for genomic sequencing butalso for the positional cloning of genes important in

development.

Ongoing mapping and molecular identification of

genes and DNA markers are providing an increasingly

accurate alignment of the genetic and physical maps.

Interestingly, the relationship between recombination fre-quency and physical distance varies in different parts of the

C. elegans genome. Recombination on the arms is 310 X

higher than in the central region of the chromosomes. The

depression of recombination in the central region meanthat the genetic map is not an accurate reflection of the

physical distribution of C. elegans genes. One symptom o

this anomaly is that genetic maps based on linkage analysishow a marked clustering of genes near the centers of the

autosomes (Fig. C.2), although the genomic sequence ha

shown that the average gene density is no greater in theseregions.

Genome Sequence and Organization

The sequencing of the C. elegans genome, completed in

1998, provided researchers with the first complete DNA se

quence of a multicellular organism. The results establisheda genome size of 97 Mb, and computer analysis predicted

C.1 An Overview of C. elegans as an Experimental Organism 51

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I II III IV V X

Figure C.2 Skeleton genetic maps of the six C. elegans chromosomes. Only a small subset of the approximately 19,000 C. elegangenes is shown. Distances on these maps represent recombination frequencies in centimorgans. The zero position on each chromosome

was chosen arbitrarily, as these chromosomes do not have defined centromeres. Each of the five autosomes has a central cluster (darker

blue) in which the gene density appears to be unusually high, reflecting a lower rate of recombination per kilobase of DNA.

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that there were about 19,000 genes in the genome, making

the average gene density about 1 gene per 5 kb of DNA.

Compared with the gene densities seen in larger animals,

C. elegans genes are closely packed, in part because its in-trons are smaller on average than those of most other animals.

Annotation of the complete genome sequence, that is,

the confirmation and cataloging of all the predicted genes,will take many years. Already, however, the completed

sequence has enabled researchers to make some general-izations about the C. elegans proteome: the complete set

of proteins encoded by the 19,000 known and predicted

C. elegans genes. The majority of these proteins match

homologous proteins in current databases derived from

sequencing the genomes of other organisms. Based on the

known functions of these homologs, most of the C. elegansproteins can be assigned to a functional class such as tran-

scription factor, protein kinase, membrane-bound receptor,

and so on.

About 20% of the predicted C. elegans proteins carry

out core biological functions that are common to all liv-ing cells. The enzymes of intermediary metabolism; the

machinery for DNA, RNA, and protein synthesis; and com-

ponents of the cytoskeleton are all in this category. These

proteins have functional homologs, in about the same pro-

portions, in yeast as well as in other metazoans. Interest-

ingly, genes for the core-function proteins are foundpreferentially in the central regions of the chromosomes,

where recombination frequencies are lower.

The remainder of the C. elegans proteins whose func-

tions can be surmised are involved in processes required

only in multicellular organisms; such processes includespecialized signal transduction pathways and programmed

cell death. These multicellular-based proteins have ho-mologs in other animals, but not in yeast. Almost all the

signaling pathways found in other animals are represented

in C. elegans.

In addition to the 19,000 known and predicted genes,

there are several kinds of repetitive DNA sequences dis-persed throughout the C. elegans genome. The best charac-

terized of these sequences are seven kinds of transposable

elements, named Tc1 through Tc7. Different strains ofC. elegans carry different numbers