Last March, Susan Lolle and colleagues reported in Nature about a high reversion rate in a particular Arabidopsis mutant, HOTHEAD (HTH) (Lolle SJ et al. 2005). This paper is notable because it hypothesized that the cause of the reversion was due non-Mendelian inheritance of an RNA cache. The media jumped on this paper and promoted it as if Lolle and colleagues had demonstrated the existence of non-Mendelian inheritance. They hadn’t; they only proposed a non-Mendelian inheritance to explain their data. Many of the scientists that I have spoken to did not like their hypothesis.
In the latest Plant Cell, Luca Comai and I have published a paper detailing an alternative hypothesis for the observations of Lolle and colleagues. This hypothesis is more attractive than the one proposed by Lolle and colleagues because it relies on the already established mechanisms of mutation and selection. This hypothesis also relies on knowledge about the structure of the HTH gene product, which is information not considered in the Nature paper.
My regular readers may remember that last March, right after the Nature paper came out, I discussed it on my blog (here and here). Those of you that remember the discussion will be familiar with our hypothesis already since I blogged it back then. That’s correct; this paper derived from a blog post that I did. Blogging does pay off.
Before I detail the paper, a little more background is in order.
Luca Comai is a Professor of Biology at the University of Washington. Soon after the Lolle et al.’s paper came out, he was asked to cover it in a journal club with grad students. From that discussion he came up with an alternative hypothesis to explain the data presented in the paper. He shared his hypothesis with colleague Steve “Number 22” Henikoff at the Fred Hutchinson Cancer Research Center, who also took an interest in the hypothesis. Luca submitted his hypothesis to Plant Cell, and it went through several rounds of review but was eventually accepted for publication. However, the slow progress of Luca’s paper was impacting Steve who was trying to publish an elaboration of Comai’s hypothesis, but was unable to cite Luca’s yet-to-be published hypothesis.
So in early September, Steve googled the RNA Cache hypothesis and discovered my blog sitting on the first page and upon reading my blog he realized that I had totally scooped Luca. Given the slow progress of the people at Plant Cell, Steve considered citing my blog for the toxic-mutator hypothesis. However, on September 6th, I got a surprising email:
A friend of mine just brought to my attention your blog on hothead. I have developed an explanation for the described phenomenon that is nearly identical to the one you posted in March in your blog. In April I submitted it to Nature, which promptly rejected it. Soon after I submitted to the Plant Cell where it has undergone considerable criticism (and skepticism). After three review cycles, it has been accepted. I enclose the latest version, which is not too far from the original one. I was not aware of your contribution until today. I copy Nan Eckhardt, the editor of the Plant Cell in charge of this commentary so that we can hear her opinion on this matter. I think that I should acknowledge your work in some way. One way would for you to be a coauthor. The other would be for me to quote your blog. Just in case you have not dealt with this matter recently, I should clarify that our religion (I call it the toxic mutator hypothesis) has very few acolytes. So, I do not know whether I am inviting you to step up on the chariot, or on the railroad tie. Read the commentary at your convenience and let me know what you think.
Regards, Luca Comai
So needless to say, as a graduate student looking to increase a C.V., I jumped at Luca’s charitable offer for a coauthorship, especially on an already accepted paper. There are maybe three sentences in the published paper that I had anything to do with, but I did produce the same hypothesis as Luca and scooped him to boot. I never really expected that my blog would lead to any publications.
Now in our paper, Luca and I propose that null mutations in the hothead gene may result in the accumulation of a toxic mutator that leads to an increased mutation rate across the entire genome (Comai and Cartwright 2005). We point out that in a previous paper HTH was shown to be related to a group of enzymes responsible for breaking down aromatic compounds (Krolikowski et al. 2003). (Many aromatic compounds have been shown to cause mutations.) Furthermore, we argue that selection during pollen competition for hth revertants may explain the large number of revertants. There’s more to it than that, but I’ve kept it simple for this blog. You can check out the paper for more.
In an invited paper that appears along side ours, Steve beautifully elaborates on this “toxic-mutator” hypothesis in his paper. Steve proposes that the substrate of the hothead gene is a inhibitor of DNA polymerase λ, which is the enzyme that plants use for base excision repair (BER), the major pathway of endogenous DNA damage repair (Henikoff 2005). As Steve says, “an excellent candidate for a toxic mutator is a glycosylated mandelonatrile inhibitor of DNA polymerase λ.” Steve further points out that the inhibition of BER may induce would also explain the gene conversion observations of Lolle et al. because the lack of BER would lead to repair via homologous strand invasion. You can check out his paper for more details.
I think that that the toxic mutator hypothesis is a very promising explanation for the observed phenotypes of hothead mutants, especially given Steve’s elaboration. I’ve been told that the people who originally published the RNA cache hypothesis also like our hypothesis. My involvement would never had happened had I not taken the opportunity to blog about this paper and independently propose the toxic mutator hypothesis. Science blogging does matter, and science blogging does make a difference.
- Comai L and Cartwright RA (2005) A toxic mutator and selection alternative to the non-Mendelian RNA cache hypothesis for hothead reversion. Plant Cell 17:2856-2858.
- Henikoff S (2005) Rapid changes in plant genomes. Plant Cell 17:2852-2855.
- Krolikowski KA et al. (2003) Isolation and characterization of the Arabidopsis organ fusion gene HOTHEAD. Plant J. (4):501-11.
- Lolle SJ et al. (2005) Genome-wide non-mendelian inheritance of extra-genomic information in Arabidopsis. Nature. 434(7032):505-9.