The History of Hothead

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The Scientist has a new article on the history of the scientific literature and controversy of the HOTHEAD mutation in Arabidopsis: “Mendel Upended? How the behavior of an Arabidopsis gene could overturn the classical laws of genetics.” Long time readers of this blog will remember that when the original paper came out I blogged my thoughts on the study and eventually turned my blog thoughts into a scientific coauthorship. (See Blog About Hothead and Get an Easy Paper for more background.)

Comai and I are mentioned in The Scientist’s article, although not by name:

In November, 2005, researchers at the University of Washington and the University of Georgia proposed that, rather than a novel genetic mechanism causing the reversion, the HTH gene product might be a metabolic enzyme, which when mutated produces toxic and mutagenic compounds that act on the DNA. In particular, they suggested that the HTH protein may be in a class of proteins that, given a deleterious mutation, revert precisely to the wild-type from mutagenic effects.

Other authors with more fantastical explanations get named and cited, but our reasonable example is tossed aside. (Of course, the most reasonable example, pollen contamination, gets a lot of discussion.) I guess one consolation prise is that if you search for “Susan Lolle” my blog comes up first.

What strikes me in all the discussions about HOTHEAD is that most of the geneticists quoted appear to have not studied population genetics beyond classical, Mendelian work. The way they frame the discussion makes me think that they’ve never studied well known phenomena like meiotic drive. (I’m currently participating in a seminar class, which is reading Burt and Trivers’s Genes in Conflict and meiotic drive gets first billing. It is very refreshing to be participating in popgen discussions again.)

Most organisms that people care about are diploid; they contain two copies of each gene. During reproduction, each copy of their genes has a 50% chance of being passed to their offspring. However, some genes show meiotic drive, which occurs when one copy gets passed to offspring a majority of the time. Consider two, unlinked genes—Aa and Bb—where A drives at 90% and B is normal. Therefore, an AaBb individual will produce four different gametes, which have the following frequencies: AB = 45%, Ab = 45%, aB = 5%, and ab = 5%. Now an AABb will have two different gametes: AB = 50% and Ab = 50%. An aaBb individual is similar.

Unaffected by other forces, a driving allele will go to fixation because it has the advantage over other alleles. However, meiotic drive often works by physically killing gametes that contain the other allele. The simple model of how this works is that the A allele is actually a pair of genes: one produces a time-delayed “poison” before gamete formation, and the other provides an “antidote” after gamete formation. Because the “poison” is in all gametes, but the antidote is only in gametes that contain the A allele, the a-gametes are weakened and thus the A-gametes get more than 50% of the fertilizations. Because nearly half of their gametes are removed, individuals with driving alleles can suffer reduced fertility, which can make it difficult for driving genes to go to fixation. Instead a polymorphic equilibrium is reached and the driving alleles persist in the population as a “chronic infection.”

If you think that meiotic drive is too exotic to be common, most organisms that have been studied extensively have shown its signs, the classic examples being the t-haplotypes in mice and sd inversions in Drosophila.

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Count me as one of those biologists that was unaware of meiotic drive (although I’m mol biol, not genetics). I assume you’re already aware, but that 2 gene system of poison and antidote is also a common mechanism used by bacterial plasmids to insure they don’t get lost from a growing population.

In retrospect, I suppose it’s not surprising to see the same fundamental mechanism in eukaryotes. After all, plasmids did RNAi first as well.

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