Blog About Hothead and Get an Easy Paper

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:

Reed,

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.

References

TrackBack URL for this entry: http://scit.us/cgi-bin/mt/mt-tb.fcgi/623.
Sent by The Panda's Thumb on November 3, 2005 12:53 AM

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... [Read More]

Sent by The Loom on November 3, 2005 10:43 AM

Back in March I described a provocative paper that suggested that plants might be able to get around Mendel's laws of heredity. Reed Cartwright, the grad student behind De Rerum Natura, left a comment expressing some deep skepticism. Now he... [Read More]

Sent by blogs for industry on November 5, 2005 1:25 AM

Not by me...I have plenty of things I need to submit that are not related to blogging...but Reed Cartwright's blogged his thoughts about the Hothead paper by Lolle et al. that appeared earlier this year in Nature. So in early September, Steve [Henik... [Read More]

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Posted by John Wilkins on November 3, 2005 12:48 AM

Congratulations, Reed. It’s good to see that the blogging medium can generate more than just the latest “meme” and political opinion.

I hope your hypothesis gets a good long run - hope for it to be controversial so it gets a high citation index…

Posted by Reed A. Cartwright on November 3, 2005 12:53 AM

Thanks, John.

Posted by Ivan on November 3, 2005 1:47 AM

Its an interesting hypothesis. Your response focuses on pollen selection, but if I remember the original paper correctly, they found some homozygous revertant embryos suggesting that there were revertents in the ovules as well, where you don’t have the larger numbers to get the selection. I assume you think the frequency is low enough that it is reflecting the actual reversion frequency?

If my notes from Lolles talk at ASPB this summer are correct, they have PCR evidence of indels reverting where the reversion has the same length as the original indel. I think this would answer your concern about the restriction site markers?

Ivan

Posted by Reed A. Cartwright on November 3, 2005 2:45 AM

Yeah, there is some additional data about the HOTHEAD reversions, but it isn’t published yet so we couldn’t really refer/respond to it.

However, I would not be surprised that they find reversions of insertions given the large scale genomic instability in these plants and the possibility that selection could really favor restoration of a functioning hothead.

Posted by Nick on November 3, 2005 9:26 AM

Congratulations. So, was Comai Wallace to your Darwin, or vice versa?

Anyone planning to test the toxic mutator hypothesis?

Posted by Reed A. Cartwright on November 3, 2005 9:41 AM

Luca and Steve have the seeds to do it. I don’t know if I will be further involved in the project.

I wouldn’t be suprised if Lolle and Pruitt look into it as well.

Posted by Patrick on November 3, 2005 11:17 AM

I wandered over here from the Panda’s Thumb. I’m not too familiar with hotheads and such, so I can’t comment on that, but congratulations! :)

Posted by sennoma on November 3, 2005 1:06 PM

Ah, this story does me good. In a time of “oh we can’t present that at the conference, someone will scoop us” and “meet with Prof X but don’t tell him about blah”, it’s wonderful to see a scientist behaving, well, honorably. Kudos to Prof Comai and congratulations to an enterprising blogger!

Posted by Don on November 3, 2005 2:29 PM

I don’t know. Seems real sciencey. What’s with all the peer review and the cycling, the corrections and the co-authorship?

I mean really, where’s the design inference, the hand-waving!?

You didn’t even bother polling the public on any of this either. How do you expect this to get any traction?

Posted by Bruce Thompson GQ on November 3, 2005 9:28 PM

Excellent, eexxcellent. Nothing like scooping the bigwigs and getting recognition to boot. Scientists blogging away tossing out new ideas in an un-refereed environment allows for a new level of interaction between individuals and disciplines, generating all kinds of new synergy. It’s nice to see the bigwigs also check to see if anybody is tossing out ideas into cyberspace.

Delta Pi Gamma (Scientia et Fermentum)

Posted by Jim Hu on November 4, 2005 3:54 AM

Reed,

Congrats on the paper it’s great to see blogs stimulating the discussion. Two quibbles:

1) It would have been very cool to acknowledge the blogosphere for useful discussions (if the editors would have allowed it)
2) I’m still not convinced that the mutator hypothesis addresses the SNP data!

Did Plant Cell ask Lolle et al to provide a response?

Posted by Reed A. Cartwright on November 4, 2005 3:41 PM

I think Plant Cell did try to get something from Lolle et al. to support the RNA cache hypothesis, but from what I’ve been told Lolle et al. like our hypothesis, which may have made them reluctant to write a response without more data.

Posted by Mandi on November 17, 2005 1:25 PM

The only word in this entry I understood was “Steve” and I thought you were talking about the stuffed Panda.

Posted by sunil on November 30, 2005 10:46 PM

Very nice!

So now i can say that blogging can lead to something really “useful” :-)

Posted by Anne Jameson on December 2, 2005 5:02 PM

Reed, only you would get coauthor based on your blog. LOL. You go boy!

Posted by JiggaDigga on April 7, 2006 12:50 AM

Great reading, keep up the great posts.
Peace, JiggaDigga