dna repair


Evelyn Fox Keller on genes, evolution, and epigenetics

This is another archival repost from the old blog, first published way back in March 2008.

I’ve been following CBC’s How To Think About Science series, and caught the Evelyn Fox Keller episode the other day. It was interesting, but there were a couple of issues that I just can’t let pass. Keller talks about the hype of genomics ten years ago — during the human (and other) genome projects, when huge amounts of a new kind of raw data were piling up, and everyone was speculating about the interesting things we could do with it. Leaving aside the fact that many of the claims about genomics have and are coming true (albeit, over a longer time-frame than mainstream media imagined it would), I have a problem with Keller’s own bit of hype.

It’s epigenetics, of course — reversible and heritable changes (both between generations of cells and generations of individuals) in gene expression patterns which do not alter the DNA sequence itself. Epigenetics is where all the hype is in biology at the moment. Don’t get me wrong: I think the field is interesting and exciting. But as the hottest newest branch of biology, everybody knows the name, and few know the details. It’s cited as the mechanism of faith healing, mind reading, and homeopathy. In Keller’s case, epigenetics is cited as a problem for theneo-Darwinian view of evolution. By “neo-Darwinism”, Keller particularly means the gene-centered view of evolution. The name “Dawkins” may have arisen once or twice. The problem that Keller thinks that epigenetics has for mainstream modern evolutionary biology is that organisms may be able to control their mutation rates in response to changes in environmental conditions, and thus alter the rate of evolution.

Keller is referring, I suppose, to the checkpoints and DNA repair mechanisms that spot and fix errors in DNA replication during gametogenesis (the production of sperm and eggs). It’s difficult to make a copy of three billion base pairs without making a few mistakes, and too many mistakes in too many important genes add up to a miscarriage. So there are some molecular machines which follow the copiers around, checking that they got it right. The machines do their best to fix the typos, and in extreme circumstances, will kill the cell if the mistakes are too big. Where epigenetics comes in is in the regulation of those molecular machines. Epigenetics hires and fires the copyeditors. Specifically, there are epigenetic mechanisms which pack away genes — wrap them around proteins called histones, to form structures called chromatin. Locked away in these packages, the genes can not be switched on, and no new copyediting machines can be produced.

The hypothesis that mutation rates may be under control by some mechanism which recognises changes in the environmental conditions and responds by altering the expression levels of the copyeditors is, I’m sure you’ll agree, a fascinating one. But a problem for the neo-Darwinian picture of evolution? I’m not sure I see the connection, there. Here is how I imagine such a mechanism working: in the cells producing sperm and eggs, a set of receptors monitor environmental conditions; when environmental conditions change, those receptors pass the message on to the nucleus, where a set of machines make the appropriate changes to gene expression. Why do I propose such a mechanism? Because just such mechanisms coordinate development, transmit the messages of hormones, detect pain smell light taste, determine the activity of drugs, and do a-hundred-and-one other things in the cell. They are the default way of getting a cellular response to an external stimulus. And it has already been empirically determined that such a mechanism exists in the case of DNAcopyeditors. The DNA copyeditors are not switched on 24/7 — after all, they are needed primarily during cell division. The mechanism which switches them on was discovered by researchers interested in cancers, who found that this mechanism is often damaged in tumours, leaving thecopyeditors in a permanent ‘off’ state.

Perhaps it doesn’t work this way. Whatever. My point is that it is very easy to imagine a mechanism by which environmental changes lead to heritable changes in mutation rates — a mechanism which can be created by the simple modification of another very similar mechanism. That modification? Orthodox neo-Darwinian evolution. The receptors and signals, the gene expression machinery and the chromatin re-modellers are all the product of orthodox neo-Darwinian evolution. And the system no doubt remains at the whim of natural selection. The idea that evolution itself evolves is fascinating, but it does not appear problematic or revolutionary to me.

I said I had a second issue with the programme, didn’t I? Ah, yes, still on the topic of Dawkins and the idea of the selfish gene. Keller suggests that the ideas expressed by Dawkins have been surpassed and overturned by the modern developments of molecular biologists. Developments such as the fact that genes have complicated networks of interactions with each other. Gosh. It’s almost as though Keller hasn’t read The Selfish Gene. In TSG (Or was it The Extended Phenotype?), Dawkins is very careful to point out the fact that the “genes” of population geneticists — Mendelian particles of inheritance, and the “genes” for which the word “gene” was coined a century ago — are not quite the same thing as the “genes” of molecular and developmental biologists. Dawkins’ selfish genes need not be defined by start and stop codons, upstream promoters, or discreet messenger RNA products. Which makes Keller’s criticism largely irrelevant.

Whatever. Who cares? Somebody slightly mischaracterised an obscure academic problem, buried in an obscure podcast. Well, the main reason I care is that Keller is herself telling us that we should be more precise when talking about genes. When first used, the term “gene” was just a placeholder for a phenomenon we understood little about, she reminds us. Over time, we’ve filled in the details. The problem is, the population geneticists and evolutionary biologists have filled in different details to the molecular geneticists and developmental biologists. They’ve all continued to use the term “gene”, but they’re now using it to mean different things to each other. Oh, wait, haven’t I heard this somewhere before?

I guess it’s just that Richard Dawkins is so shrill and screechy that it’s impossible to read him carefully.

Filipe V. Jacinto and Manel Esteller, 2007. Mutator pathways unleashed by epigenetic silencing in human cancer. Mutagenesis 22(4):247-253; Free full text