news and views the risk of nephropathy from diabetes. It is certainly plausible that risk factors for one form of chronic renal injury (for example, that resulting from hypertension) would also be risk factors for others (diabetic kidney disease). However, this was not observed in either study. This is particularly interesting because hypertension and diabetes so often occur together in affected individuals. The fact that, despite this potential confounder, no association was observed in diabetic kidney disease is strong support that different genetic factors (and therefore different cellular mechanisms) underlie the susceptibility to kidney damage from these two common disorders. Clinical implications There are a number of notable clinical and pathophysiological questions that arise from these findings. High on the list is defining the precise variant(s) that alter disease susceptibility. Highly penetrant mutations in the MYH9 coding region cause forms of inherited disease leading to both kidney and hematologic abnormalities10. Other cytoskeletal proteins have been shown to be critical for normal podocyte function9,11. Nonmuscle myosins have been known for some time to be components of the podocyte cytoskeleton, contributing to its contractile functions (Fig. 1)12. Although podocytes have been the focus of much recent
research in inherited and secondary renal disease, it is premature to assume that altered myosin function in podocytes is responsible for modulating human disease. For example, nonmuscle myosin IIA is the only isoform of nonmuscle myosin II expressed in platelets, and one could imagine how genetic variants altering the regulated expression of MYH9 could alter platelet function in some subtle way that predisposes the glomerular endothelium to damage. Other mechanistic hypotheses are possible as well. Although it may be difficult to unravel the biology underlying these associations, there are some important and relatively straightforward clinical questions that arise and should be answerable. Immune-modulating therapies have widely variable success in treating FSGS. Does an individual’s MYH9 genotype predict the response to these forms of treatment? Are drugs that act on the renin-angiotensin system—the mainstay of treatment for proteinuric kidney diseases—more (or perhaps less) effective in individuals with a given haplotype? How does the MYH9 genotype in a kidney harvested for transplantation (or its recipient) alter the clinical outcome? In the meantime, clinicians should realize that the kidney damage seen in the context of two common disorders, hypertension and diabetes, may be distinct entities. On the other
hand, these results also suggest a shared etiology to many forms of nondiabetic kidney disease. The genetic relationship between hypertensive nephropathy and FSGS suggests that FSGS may be underdiagnosed. It also highlights the fact that use of the term FSGS, given the etiological complexity of this injury pattern, should be limited to histological description, rather than used as a clinical diagnosis. The success of these two studies further highlights the power of the admixture mapping approach. If we are to translate the genetic basis of human disease into improved patient care, understanding the broad implications of these important new studies will be critical. 1. Freedman, B.I. J. Am. Soc. Nephrol. 14, S192–S194 (2003). 2. Price, D.A. & Crook, E.D. J. Natl. Med. Assoc. 94, 16S–27S (2002). 3. Kopp, J.B. et al. Nat. Genet. 40, 1175–1184 (2008). 4. Kao, W.H.L. et al. Nat. Genet. 40, 1185–1192 (2008). 5. Patterson, N. et al. Am. J. Hum. Genet. 74, 979–1000 (2004). 6. Zhu, X., Tang, H. & Risch, N. Adv. Genet. 60, 547–569 (2008). 7. Winn, M.P. et al. Science 308, 1801–1804 (2005). 8. Boute, N. et al. Nat. Genet. 24, 349–354 (2000). 9. Kaplan, J.M. et al. Nat. Genet. 24, 251–256 (2000). 10. Heath, K.E. et al. Am. J. Hum. Genet. 69, 1033–1045 (2001). 11. Asanuma, K. et al. J. Clin. Invest. 115, 1188–1198 (2005). 12. Drenckhahn, D. & Franke, R.P. Lab. Invest. 59, 673– 682 (1988).
Pristionchus pacificus: an appropriate fondness for beetles Jagan Srinivasan and Paul W Sternberg The nematode Pristionchus pacificus associates with one particular beetle and eats its rotting corpse. The report of the genome sequence of P. pacificus, the fifth nematode to be sequenced and a useful secondary nematode genetic model system, highlights genes that may have influenced the route to parasitism. J.B.S. Haldane saw the divine in the diversity of beetle species. Nematodes (roundworms), however, greatly outnumber beetles, comprising about a million species, including many parasites of humans, livestock and plants. One nematode, Caenorhabditis elegans, is a laboratory model for a wide
Jagan Srinivasan and Paul W. Sternberg are in the Howard Hughes Medical Institute and Biology Division, California Institute of Technology, 156-29 1200 E. California Blvd, Pasadena, California 91125, USA. e-mail:
[email protected] or
[email protected]
1146
range of biological processes including signal transduction and longevity, and it was one of the first animals to have its complete genome sequenced1. Although C. elegans has proven invaluable for studies of human genes and pathways, it has had far less of an impact on research of parasitic nematodes. Now, Ralf J. Sommer and colleagues2 report a draft genome sequence of the nematode Pristionchus pacificus, which might help bridge the gap between the model C. elegans and the diversity of nematode species. P. pacificus (Fig. 1a), with its 3-day generation time3, is highly amenable to genetic analysis, as it has similar genetics as C.
elegans: both have self-fertilizing hermaphrodites, allowing rapid homozygosis of recessive alleles, and males, allowing crosses for genetic analysis. A SNP and physical map exists and allows positional cloning of genes4. The other three nematodes whose genomes are sequenced and published are C. briggsae5, a close relative of C. elegans, Meloidogyne incognita, a plant parasite 6, and Brugia malayi, the causative agent of filariasis and elephantiasis7. P. pacificus is of interest not only because of its ease of manipulation in the laboratory but also because of its genetic distance from C. elegans and its different lifestyle.
volume 40 | number 10 | october 2008 | nature genetics
news and views
Figure 1 The worm, the beetle, the consequence. (a) Scanning electron micrograph of the adult hermaphrodite. (b) Pristionchus pacificus associates with the oriental beetle Exomala orientalis. (c) Beetles are caught using insect pheromone traps and cut open to isolate Pristionchus. Photographs courtesy of J. Berger (top) and M. Herrmann (bottom two) (Max Planck Institute, Tuebingen).
The beetle connection The differences in lifestyle between P. pacificus and C. elegans make the former a model of interest for understanding the evolution toward nematode parasitism. P. pacificus was first isolated in Arcadia, California8 and subsequently found worldwide, associated with the oriental beetle Exomala orientalis9 (Fig. 1b,c). By contrast, C. elegans is a soil nematode often associated with rotting fruit and vegetables. In general, nematodes of the genus Pristionchus live on the outside of the beetles, using the beetle as mode of transportation and, after the beetle’s death, eating them to develop to adulthood9. What does this peculiar ‘necromenic’ lifestyle reveal about the genome of Pristionchus pacificus, and, more importantly, how can this genome be used for mechanistic studies? The genome of Pristionchus Dieterich et al.2 have now sequenced the standard reference strain of P. pacificus (at ninefold coverage) and three other relatives of P. pacificus to a lesser extent (at approximately onefold coverage). The genome size of Pristionchus has been estimated to be 169 Mb, substantially higher than that of C. elegans (http://www.wormbase.org/). By contrast,
parasitic nematodes have a more compact genome compared to that of C. elegans6,7. Although C. elegans has about 22,000 proteincoding genes, Pristionchus is estimated to have about 23,500; however, this is very much an estimate, as the genome sequence is not yet complete and there is less experimental validation of gene structure than for C. elegans for which there has been a decade’s experience of using the genome. One particularly notable feature of the P. pacificus genome is that it has nearly double the number of coding exons per gene compared to that of C. elegans. As a result, the average size of the exons seems reduced compared to that of C. elegans. Also, the exons of novel genes in P. pacificus are shorter than genes having orthologs to C. elegans genes. Operons, which are typical for prokaryotic genomes but an unusual feature of nematode genomes, are also found in P. pacificus. Approximately 15% of operons are conserved with C. elegans. Such low conservation is in sync with that shown by the parasitic nematode B. malayi, for which only 20% of operons are conserved with C. elegans7. In addition to looking at bulk numbers, it is informative to look at individual genes or gene families. Compared to C. elegans, protein domains involved in detoxification are found to be expanded in P. pacificus, suggesting evolution driven by ability to ward off xenobiotics. P. pacificus is known to be resistant to several pathogenic bacteria to which C. elegans is susceptible10. There is also an underrepresentation of genes required for oxidative phosphorylation and aminosugar metabolism genes, and C. elegans has expanded families of G protein–coupled receptors (GPCRs), F-box proteins and immunoglobulin I genes. The under-representation of the genes encoding GPCRs is intriguing, as these proteins act as chemoreceptors, and nematodes of the genus Pristionchus are known to show chemoattraction to its specific insect hosts11. Perhaps C. elegans utilizes its apparently greater chemosensory repertoire for its more cosmopolitan lifestyle. Another notable finding is the presence of seven genes encoding cellulases. In general, cellulases are associated with plant parasitic nematodes, as these enzymes degrade cellulose, a major component of plant cell walls. The marked similarity of the Pristionchus cellulase genes to those of bacteria is suggestive of lateral gene transfer. Finally, we can ask whether P. pacificus represents an intermediate between C. elegans and parasitic worms. For the genome to reflect an intermediate lifestyle, one would expect both the presence of genes required for
nature genetics | volume 40 | number 10 | october 2008
parasitism and the loss of genes required for a free-living lifestyle. The genome sequence has now revealed that Pristionchus does possess certain genetic features found in other parasitic nematodes, but a more detailed functional investigation of these genes is required before conclusions regarding their involvement in the route toward parasitism can be made. A satellite model system It has been argued that P. pacificus and C. elegans diverged 280–430 million years ago2. This number seems an overestimation, as nematodes have faster substitution rates than other organisms12. Because nematodes lack fossil records and divergence estimates rely on using nucleotide substitution rates as molecular clocks, it is more informative to use nucleotide substitutions as a metric. Nonetheless, P. pacificus has diverged from C. elegans and thus can serve as a distant satellite model system. Candidate gene approaches have been successfully used to positionally clone P. pacificus developmental control genes. However, important technologies such as DNA-mediated transformation and RNAi are still works in progress, putting a brake on the rapid stride of this satellite system. Although other strategies, such as the use of morpholinos, are efficient13, there is a sense of urgency to see these technologies work, especially because parasitic nematodes have been shown to be amenable to them. On the other hand, although the advent of reverse genetic approaches has put conventional chemical mutagenesis studies on the back burner in the last few years, the ability to use high-throughput sequencing to identify SNPs genome-wide14 may well bring classical genetic screens back to center stage, and P. pacificus is ripe for this approach. 1. The C. elegans Worm Community. Wormbook (2006). 2. Dieterich, C. et al. Nat. Genet. 40, 1193–1198 (2008). 3. Sommer, R.J. & Sternberg, P.W. Curr. Biol. 6, 52–59 (1996). 4. Srinivasan, J. et al. Mol. Genet. Genomics 269, 715– 722 (2003). 5. Stein, L.D. et al. PLoS Biol. 1, E45 (2003). 6. Abad, P. et al. Nat. Biotechnol. 26, 909–915 (2008). 7. Ghedin, E. et al. Science 317, 1756–1760 (2007). 8. Sommer, R.J., Carta, L.K., Kim, S.Y. & Sternberg, P.W. Fundam. Appl. Nematol. 19, 511–521 (1996). 9. Herrmann, M. et al. Zoolog. Sci. 24, 883–889 (2007). 10. Rae, R. et al. J. Exp. Biol. 211, 1927–1936 (2008). 11. Hong, R.L. & Sommer, R.J. Curr. Biol. 16, 2359–2365 (2006). 12. Kiontke, K. et al. Proc. Natl. Acad. Sci. USA 101, 9003–9008 (2004). 13. Pires-daSilva, A. & Sommer, R.J. Genes Dev. 18, 1198– 1208 (2004). 14. Sarin, S., Prabhu, S., O’Meara, M.M., Pe’er, I. & Hobert, O. Nat. Methods advance online publication, doi:10.1038/nmeth.1249 (1 August 2008).
1147
