A bit of Hox gene nostalgia

I had the most random epiphany over my morning tea today. I don’t even know what got me thinking about the Cambrian explosion (as if I needed a reason…). Might have been remembering something from the Euro Evo Devo conference I recently went to. (I kind of wanted to post about that, because I saw some awesome things, but too much effort. My brain isn’t very cooperative these days.)

Anyway.

I was thinking about explanations of the Cambrian explosion and remembering how the relevant chapter in The Book of Life (otherwise known as the book that made me an evolutionary biologist)  tried to make it all about Hox genes. It’s an incredibly simplistic idea, and almost certainly wrong given what we now know about the history of Hox genes (and animals)*. At the time, and for a long time afterwards, I really wanted it to be true because it appeals to my particular biases. But I digress.

Then it dawned on me just how new and shiny Hox genes were when this book was written. I thought, holy shit, TBoL is old. And how far evo-devo as a field has come since!

The Book of Life was first published in 1993. That is less than a decade after the discovery of the homeobox in fruit fly genes that controlled the identity of segments (McGinnis et al., 1984; Scott and Weiner, 1984), and the finding that homeoboxes were shared by very distantly related animals (Carrasco et al., 1984). It was only four years after the recognition that fly and vertebrate Hox genes are activated in the same order along the body axis (Graham et al., 1989; Duboule and Dollé, 1989).

This was a HUGE discovery. Nowadays, we’re used to the idea that many if not most of the genes and gene networks animals use to direct embryonic development are very ancient, but before the discovery of Hox genes and their clusters and their neatly ordered expression patterns, this was not at all obvious. What were the implications of these amazing, deep connections for the evolution of animal form? It’s not surprising that Hox genes would be co-opted to explain animal evolution’s greatest mysteries.

It also occurred to me that 1993 is the year of the zootype paper (Slack et al., 1993). Slack et al. reads like a first peek into a brave new world with limitless possibilities. They first note the similarity of Hox gene expression throughout much of the animal kingdom, then propose that this expression pattern (their “zootype”) should be the definition of an animal. After that, they speculate that just as the pattern of Hox genes could define animals, the patterns of genes controlled by Hoxes could define subgroups within animals. Imagine, they say, if we could solve all those tough questions in animal phylogeny by looking at gene expression.

As always, things turned out More Complicated, what with broken and lost Hox clusters and all the other weird shit developmental “master” genes get up to… but it was nice to look back at the bright and simple childhood of my field.

(And my bright and simple childhood. I read The Book of Life in 1998 or 1999, not entirely sure, and in between Backstreet Boys fandom, exchanging several bookfuls of letters with my BFF and making heart-shaped eyes at long-haired guitar-playing teenage boys, I somehow found true, eternal, nerdy love. *nostalgic sigh*)

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*Caveat: it’s been years since I last re-read the book, and my copy is currently about 2500 km from me, so the discussion of the Cambrian explosion might be more nuanced than I remember. Also, my copy is the second edition, so I’m only assuming that the Hox gene thing is there in the original.

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References:

Carrasco AE et al. (1984) Cloning of an X. laevis gene expressed during early embryogenesis coding for a peptide region homologous to Drosophila homeotic genes. Cell 37:409-414

Duboule D & Dollé P (1989) The structural and functional organization of the murine HOX gene family resembles that of Drosophila homeotic genes. The EMBO Journal 8:1497-1505

Graham A et al. (1989) The murine and Drosophila homeobox gene complexes have common features of organization and expression. Cell 57:367-378

McGinnis W et al. (1984) A conserved DNA sequence in homoeotic genes of the Drosophila Antennapedia and bithorax complexes. Nature 308:428-433

Scott MP & Weiner AJ (1984) Structural relationships among genes that control development: sequence homology between the Antennapedia, Ultrabithorax, and fushi tarazu loci of Drosophila. PNAS 81:4115-4119

Slack JMW et al. (1993) The zootype and the phylotypic stage. Nature 361:490-492

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Celebrating the molecular revolution

I forgot to say happy Darwin Day yesterday, but to make up for that, I present to you Max Telford’s extremely cool way of celebrating.

In 1988, on Darwin Day, no less, a 5-page little paper was published in Science that would absolutely revolutionalise the study of animal evolution. Field et al. (1988) was one of the earliest studies to apply this newfangled thing called molecular biology to the phylogeny of animals. Methods for molecular phylogenetics (or indeed any kind of phylogenetics) were extremely limited by the performance of the computers of the time, but that didn’t stop scientists from trying them. And once someone kicked this snowball, the avalanche couldn’t be stopped.

This early attempt yielded some huge surprises. Arthropods, which were thought to have arisen from segmented worms, were not closely related to any kind of worm. Brachiopods, long thought to belong to their own major group, showed up deep among worms, molluscs and other uncontroversial protostomes instead. Cnidarians such as hydras and sea anemones, and bilaterians such as ourselves, arose independently from single-celled ancestors.

Some of their conclusions – among them the last one about several origins for animals – were contradicted by more sophisticated analyses. Nevertheless, what they stirred up was the beginning of our current understanding of animal phylogeny. For the 25th anniversary of this pivotal publication, Max Telford, animal phylogeneticist extraordinaire of University College London, went back to the roots of his field and reanalysed Field et al.’s data (Telford, 2013).

Could the data and methods of the time have yielded a more accurate tree? How does a “modernised” dataset fare under the latest methods? What advances in methodology and understanding led the molecular phylogenetics of animals from the first tentative steps in the 1980s to where we are today?

Analysing the original data with methods similar to the original, of course, repeats most of the original mistakes.  It’s when Telford starts tweaking things that the interesting stuff starts to happen. For example, just switching from the original method to a more complex one that was available but would have taken years to run at the time pulls all animals back together. “Updating” the analysis by using more complete sequences of the same gene, slower-evolving relatives of some original species, and modern methods impossible to run on 80s computers comes very close to today’s consensus. In other words, Field et al. basically did the best they could. Since then, data availability, careful sampling and far more computer muscle have changed some of their conclusion – but confirmed others.

Telford highlights one way in which the classics got lucky, too. Back in the eighties, sequencing nucleic acids was a difficult affair. Field et al. (1988) picked 18S ribosomal RNA mostly because it was less difficult than most others. But, as Telford points out, they also hit on a really good gene for phylogenetics. The 18S is quite long, providing an abundance of data. It has both very conserved and variable regions, so it has something to say on all levels of divergence. And, as Telford’s updated analysis shows, it can actually give reasonably accurate results on its own, which cannot always be said of single genes. For long years after Field et al. (1988), 18S rRNA continued to be used to probe into animal relationships, and had a few more revolutions up its sleeve (Aguinaldo et al., 1997; Ruiz-Trillo et al., 1999) before yielding to huge multi-gene datasets.

Contemplating Telford’s little historical excursion, I’m reminded of Isaac Asimov’s fantastic essay The Relativity of Wrong. We’ve come a long way from our first bumbling attempts at molecular phylogenetics. We were wrong many times, and I can guarantee you we’re still wrong about a lot of things. But I like to think that, as with the shape of the earth, we are not quite as wrong as our predecessors. Over the years, some great branches of the animal tree have crystallised from a sea of studies. With dogged determination, science approaches the truth.

I think that’s a good note to end on when we commemorate the birthday of a scientist who spent decades perfecting his theory of evolution before publishing perhaps the most important book in the history of biology. Happy belated Darwin Day! 🙂

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References:

Aguinaldo AMA et al. (1997) Evidence for a clade of arthropods and other molting animals. Nature 387:489-493

Asimov I (1989) The Relativity of Wrong. The Skeptical Inquirer 14(1):35-44.

Field KG et al. (1988) Molecular phylogeny of the animal kingdom. Science 239:748-753

Ruiz-Trillo I et al. (1999) Acoel flatworms: earliest extant bilaterian metazoans, not members of platyhelminthes. Science 283:1919-1923

Telford MJ (2013) Field et al. redux. EvoDevo 4:5