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

A brief taxonomy of mutation

This post is an archive from the old blog, originally written in 2007.

I’ve been discussing in the “Sunday syndrome” column various disorders caused by genetic aberrations, but I haven’t really explained how such aberrations occur.  There are several different types of aberration that occur, and several different mechanisms that cause them.  In the Thursday paper, I’ll look at one of the mechanisms, and another will be discussed in a few weeks; for now I will just name and categorise the aberrations that occur.

In eukaryotes, genes are laid out on DNA molecules, which are organised into specific structures, chromosomes, by associating with proteins. In humans, the normal compliment of these is 22 pairs of “autosomes” and two sex-determining chromosomes (the X and Y).  The fact that the chromosomes are in pairs is important, as it means that there are two copies of most genes (except on the sex chromosomes, and in a few special cases which will be discussed in a later Sunday syndrome post).  Genetic aberrations can be classified in a system which indicates the type of change, and roughly indicates the amount of material involved.  “Chromosomal aberrations” are those aberrations that involve so much genetic material that the difference can be seen with a microscope (an arbitrary benchmark in terms of the science).   Numerical chromosomal aberrations, or “aneuplodies”, involve the loss of one or more whole chromosomes, to create an “monoploid” condition; or one or more extra copy of one or more chromosome, to create a “triploid” condition.  Structural chromosomal aberrations include the loss, or gain, of part of a chromosome: a partial deletion, ranging in size from a few genes, to an entire arm of a chromosome; a partial duplication, with the extra section being tagged onto the same, or another chromosome; or part of the chromosome breaking off and being attached to the wrong chromosome.  Alongside chromosomal aberrations, beyond the reach of the microscope, are the micro-mutations — the staple of evolution and individual variation, and the source of our more subtle syndromes.

Why loss of material should be detrimental is obvious: the cell is missing genes and therefore looses some functionality.  It is less obvious why we should have any problem tolerating addition of material, such that we have three copies of genes that we would otherwise have two copies off; or why we should have any problem loosing just one of the two copies of a gene.  The main reason, which I’ll discuss in more depth in a future Sunday syndrome post, is that quantity and concentration is important in determining a gene’s activity.  Some genes have a continuum of slightly modified activity along their concentration gradient; others have a threshold, beyond which their activity suddenly and radically shifts.  Another reason why loosing one of a pair of chromosomes is harmful is that it allows the expression of harmful mutants: part of the advantage of having two copies of every gene, is that these harmful genes are masked by their normal (“wild-type”) alleles (that is, they are “recessive” to the “dominant” wild-types).

There are many syndromes caused by partial deletions and partial duplications of chromosomes.  The deletions we see are those that affect fewer genes, and genes which do not have critical roles in development.  Large scale deletions simply don’t survive to term: only one true monosomy is ever seen in live births, and that is because it is a special case.  In Turner’s syndrome, only one X chromosome, and no Y chromosome is present.  The reason Turner’s is a viable genotype is that the X chromosome is only ever present in a single dose: males have an X and Y, while females switch off one of their two X chromosomes in every cell (“Lyonisation”) as “dosage compensation”, bringing them in line with the males.  All except a handful of genes, that is: because there are a handful of active genes on the Y chromosome, a corresponding handful of genes on the inactive X are exempt from Lyonisation .  Turner’s, therefore, is not exempt from symptoms, which include short stature, webbing of the neck, abnormal hands and feet, lack of maturation of the genitalia, and predisposition to heart disease and renal malfunction.  Miscarriage also remains common.

Duplication of material is generally more tolerated: the difference in gene proportions is one third, not a half, and harmful recessive alleles are not unleashed.  An extra Y chromosome has little effect, except to boost height, and individuals have been reported with more than two Y chromosomes.  Around one in every thousand females is thought to have three X chromosomes (“triple X syndrome”), a condition that has no serious symptoms (because Lyonisation switched off all but one X), but which may be correlated with increased height, early onset of puberty, and very mild learning difficulties.  The presence of more than three X chromosomes has been observed in live births.  Males with two X chromosomes, alongside their Y, have Klinefelter’s syndrome, and usually have under-developed testicles, and correspondingly lower production of testosterone, shifting their pattern of hormone expression towards that of the female.  The consequences of this vary, but infertility, effeminate facial features and body shape, and breast development are common; frequency of breast cancer and osteoporosis, which are hormone-dependent diseases, are also higher in Klinefelter’s than in other males.  Many with Klinefelter’s still manage to go through life undiagnosed, however, and many others are only discovered during fertility treatment.  As in the case of chromosome deletions, the effect of duplications on the autosomes are more severe.  Only three of the 22 potential autosomal trisomies survive to term in a significant proportion of cases, and even in these, the majority still miscarry.  The most common of these istrisomy 21 — the chromosome with the smallest number of genes — which causes Down’s syndrome, with obvious mental and physical effects. Trisomy 18 causes Edwards’ syndrome, while trisomy 14 causes Patau’s syndrome.  Both chromosomes contain relatively few genes, and both syndromes are characterised by severe mental and physical abnormalities, and predisposition to diseases.

The smaller the amount of material deleted or duplicated, and the less important that material in development, the better tolerated the aberration, in terms of disability, disease development, fertility, and so on.  Partial aneuplodies may result in similar syndromes to full aneuplodies, depending on the parts of the chromosome affected.  Partial trisomy of chromosome 21, if it occurs in the “Down’s syndrome critical region” of around 20-40 genes (a tenth of the whole chromosome), will cause Down’s syndrome.  Below the level of structural aberrations we get to the micro-mutations.  These include small scale deletions or duplications of one or two genes, as well as deletion, insertion and substitutions within genes.  These mutations may knock out a gene altogether, upset the balance of gene concentrations, or merely alter a gene’s function subtly.  These are far more common, but far less drastic in their effects.  The effects depend, of course, on the gene’s normal role in development: is it a pivotal player in a handful of developmental programs, or a mostly redundant component of a system that is not even active in early years?  At the level of micro-mutations it becomes difficult to determine the difference between “syndrome” and “normal variation”: mutations of this kind are a normal part of evolution, and every one of us carries many “abnormal” (or at least, “rare”) gene variants, but would not classify ourselves as suffering from a disorder because of them; this will be the subject of another future Sunday syndrome.

That there is such a diverse range of genetic abnormalities that can lead to developmental abnormalities (and I’ve only scratched the surface of this detail), alongside a diverse range of environmental variables involved, reflects the complexity of developmental processes.  The fact that we see such extensive deletions as Down’s, Edwards’ and Patau’s syndromes in live births is an amazing illustration of the ability of these developmental processes to tolerate harmful genetic aberrations.