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Comparative genomics

Two worms are better than one

The genome of the microscopic worm Caenorhabditis briggsae has been sequenced, and shows some remarkable differences from the genome of the better known — and physically similar — C. elegans.

In the early 1960s, when biologist Sydney Brenner was searching for a new model organism with which to study animal development and neurobiology, he screened a wide range of invertebrate species and chose the nematode Caenorhabditis elegans because it is easy to culture and transparent at all stages of its life cycle1. This small worm is now famous, not least for being the first animal to have its whole genome sequenced2. A close relative of C. elegans also passed by Brenner's microscope, and narrowly missed this accolade. This creature, C. briggsae, is physically very similar to C. elegans (it takes an expert to distinguish them), and the two have near-identical biology, even down to the minutiae of developmental processes. Surprisingly, however, their genomes are not so similar, as the sequencing of the C. briggsae genome to around 98% completion, reported in Public Library of Science Biology, now reveals3. Comparing the two species offers a new view of the patterns and processes that have shaped genomes, and raises many questions for the future.

From the first draft of the C. elegans genome2, it was predicted that this microscopic worm has more than 19,000 protein-coding genes and 1,000 RNA-encoding genes. With the completion of the sequence to the last base pair (all 100,258,171 of them4) in late 2002, these numbers have grown respectively to around 21,000 and 3,000. There is still vigorous debate as to how many of these genes are actually functional5, but what is clear is that the complexity of the C. elegans gene set contrasts markedly with the organism's morphological simplicity. For comparison, the more physically complicated fruitfly Drosophila melanogaster has only around 15,000 protein-coding genes6, and humans have some 40,000 (refs 7, 8).

The C. briggsae sequence reported by Stein et al.3, with its 19,500 protein-coding genes, provides comparative confirmation of most of the C. elegans gene set and, surprisingly, suggests that there may be another 1,300 C. elegans genes to add to the list. Stein et al. also propose more than 4,800 changes to current C. elegans gene predictions, such as the existence of new exons (the coding parts of genes, as opposed to their intervening, non-coding regions). These refinements will be crucial in exploiting this nematode as a model system. There are also some fascinating differences between the two species (why, for instance, does C. elegans have more than 700 chemoreceptor genes when C. briggsae gets by on just 430?), and many genes unique to each (about 800 per species).

Two other pairs of related genomes have been sequenced: humans7,8 and mice9 last shared a common ancestor about 85 million years ago, and mosquitoes10 and fruitflies6 diverged around 250 million years ago. When did C. briggsae and C. elegans split? Judging from their morphology, one might think it was relatively recently, but the sequences tell a different story. Using equivalent genes from mosquitoes, humans and the two nematodes, Stein et al. estimate that the worms diverged between 80 million and 110 million years ago.

Do patterns of genome change help to describe the range of physical disparity between these various species pairs? The answer is a resounding no: the physically most similar pair, the nematodes, shows the most differences in terms of rate of genome evolution (Fig. 1). For instance, there are about three times more synonymous substitutions ('silent' base-pair changes that do not affect encoded proteins) between the two nematodes than there are between mice and humans. And changes in genome organization have occurred around 50 times as often.

Figure 1: Rapid genome change and physical conservation in nematodes.
figure1

Stein et al.3 have sequenced the genome of Caenorhabditis briggsae, and their comparison of its genome with that of C. elegans reveals rates of genomic change that stand in stark contrast to the lack of major morphological change that has occurred since the two species shared a common ancestor, around 100 million years ago. Humans and mice have undergone much more morphological evolution since they parted 85 million years ago, but have relatively more stable genomes. Flies and mosquitoes, separated by 250 million years, have an intermediate rate of change. The units on the y-axis are rates relative to the human–mouse divergence rates. Stars represent the rate of loss and gain of introns (non-coding gene regions); squares, the rate of genome reorganization; circles, the rate of 'silent' base-pair changes (not calculated for the fly–mosquito pair); hexagons, the number of blocks of genes whose order is conserved. The scale on the x-axis is arbitrary.

Similarly, since the nematodes diverged, there have been about 0.5 changes in gene structure — that is, in the pattern and spacing of exons — per gene. Since the divergence of mice and humans, there have been fewer than 0.01 changes in gene structure per gene9. Given all these changes, one question for the future is why the nematodes still look so similar. Stein et al. give a hint of an answer: they identify 1.3 million base-pair-level sequence matches between the two genomes, only a third of which correspond to coding portions of genes. The remaining sequence matches may represent conserved control elements that coordinate gene expression to produce physically similar organisms.

Another interesting finding comes from a look at the pattern of gene evolution along chromosomes. In C. elegans, the 'arms' of the chromosomes were found to be rich in repeated sequences and genes that have no similarity to those of other organisms, and undergo frequent genetic exchange2. By contrast, the centres of the chromosomes had few repeats and contained more genes that are also found in other animals. Comparison with C. briggsae reinforces this model: genes on the arms are significantly more different to genes in other organisms than are those in the centres, and gene order is less likely to have been preserved on the arms. This is strikingly reminiscent of the linear chromosomes of streptomycete bacteria, where exotic functions, such as antibiotic synthesis, are encoded on the arms and housekeeping genes are encoded in the centre. In C. elegans, gene-knockout studies have identified blocks of genes from the same chromosome that are expressed in the same tissues or stages of the life cycle11. How these blocks are maintained in the face of randomizing genome reorganization remains unknown.

Rapid change is not the rule, however. Despite having undergone more than 4,000 chromosomal breakages since they parted3, C. briggsae and C. elegans have the same number of chromosomes: most rearrangements occur within chromosomes rather than between different ones. This pattern may be generally true of nematodes, as comparisons with the distantly related human parasite Brugia malayi also suggest a preponderance of intrachromosomal rearrangements12. Moreover, the nematode group to which C. elegans and C. briggsae belong, the Rhabditida, has a remarkable constancy of chromosome number, with six or seven chromosomes being the norm13. So another question for the future is how this set number of chromosomes is maintained.

The publication of the C. briggsae genome sequence will undoubtedly spur many workers to use this species in comparative work, and a programme of identifying 'true' genes (rather than 'predicted' ones) by mutating them is already under way14. A third nematode genome, that of B. malayi, should be added soon15, and plans are also afoot to fill out the caenorhabditid tree with genome sequences of related species, such as that of C. remanei, approximately equally related to the two with sequenced genomes. These additional genomes will nourish comparative genomics, and bolster C. elegans' position as an invaluable model organism.

References

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