Wednesday, August 24, 2005

Alternative splicing and host defense in flies and plants

In an article appearing online in Science this week, and discussed in The Scientist, Watson et al. (PubMed) implicate the Drosophila Dscam gene in host defense. They detect secreted forms of the protein in hemolymph and show that the gene enhances phagocytosis of bacteria by hemocytes. They also demonstrate conservation of the potential for extreme isoform diversity across insect taxa, an extension of earlier work from the Graveley lab (Graveley et al. 2004; PubMed, RNA journal). Isoform diversity due to alternative splicing is therefore implicated in the generation of adaptive variation in host defense molecules. It is interesting that isoform diversity due to alternative splicing of Toll-like proteins has likewise been implicated in plant defense (reviewed by Kazan 2003 and Jordan et al. 2002; an example is Zhang & Gassmann 2003).

What kind of adaptation does this make possible? Certainly, extreme variability allows rapid adaptation on a population level. Furthermore, the presence of membrane bound and secreted forms of the same molecule presents the possibility of adaptive immunity through clonal selection of hemocytes that see antigen. Louisa Wu pointed me to an article in Nature Immunity (Little, Hultmark and Read 2005) making the point that neither memory nor specificity has been ruled out in invertebrate immunity. True adaptive immunity in insects would be very exciting, but we're a long way from that. How could variation in isoform production among hemocytes in Dscam isoforms be heritable? Through epigenetic silencing of splicing factors? We're just at the beginning of this story.

The authors say this:

broad conservation of receptor diversity strongly suggests important
functions and future studies will have to further address
whether the presence of diverse immune receptors in
invertebrates increases the effectiveness of immune responses
of individual animals. Alternatively, given the relative short
life span of many invertebrates, it may be that immune
receptor diversity is less important ontogenetically but rather
enhances the adaptive potential of animal populations to
changing environmental and pathogenic threats.


Greg Tyrelle said...

Hello Steve,

This is extremely fascinating work, implicating alternative splicing in insect adaptive immunity, thank you for pointing it out (one great benefit of weblogs).

I recently, today in fact, had the pleasure of listen to a talk by Eric Lander. One of the surprising comments (to me anyway) he made was the suggestion that many estimates of alternative splicing based on ESTs would be dramatically revised down in the near future.

In addition he seem to dismiss the importance of alternative splicing's role in regulation of cellular process, in stead he emphasized non-coding regions of the genome would have a more important role.

Do you have any thoughts on this ?

Greg Tyrelle (

Steve said...

Thanks Greg,

The latest research suggest that alternative splicing is working orthogonally to transcriptional regulation (as in, for example, the Nova story, but also results from Blencowe's grup), but these are early days. As to why Eric Lander thinks that estimates will be revised downward, I can only guess. Bogus cDNAs or ESTs, splicing errors, nonfunctional transcripts, etc. all contribute to current estimates. The question of what constitutes true alternative splicing is worth another post and you will probably see one soon.

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