Wednesday, May 20, 2009

Interfering Clones

Since I’m new around here, I thought I’d try and start reflecting on the big picture surrounding the Redfield lab’s research, starting with that last post on Sciara. This will end up taking me several posts, because I’d like to articulate my own understanding of the evolution of sex, which is somewhat muddled and rather uneducated. So this post is meant to be introductory to make sure I have the most basic elements down.

A primary mission of the Redfield Lab is to understand why some bacteria are naturally competent. That is, why do some bacteria have the ability to take up DNA from their environment? Since natural competence requires upwards of a couple dozen gene functions, the pathway must have some direct selective benefit to naturally competent bacteria. Several non-mutually exclusive hypotheses have been posed to account for the maintenance of the natural competence mechanism, namely:
  1. The Repair Hypothesis”: As a source for DNA templates for the repair of DNA double-stranded breaks;
  2. The Food Hypothesis”: as a source of nucleotides for food; and
  3. The Sex Hypothesis”: as a way of shuffling genetic material by transformation with uptake DNA.
Of course, these hypotheses each have their pros and cons, and to my naïve eyes, each seem somewhat context-dependent and are surely not mutually exclusive. But I’d like to turn my attention mainly to the third hypothesis, which is an attractive one, but perhaps requires the highest burden of proof, since the benefits conferred in this case act not on the level of the individual but on the level of the population.

My own understanding of the evolution (or rather, the maintenance) of sex has been hampered mostly by one big problem: In introductory material, it is almost always implicitly in the context of animal sex: or more specifically obligate sexual reproduction between dioecious anisogamous diploids. When I go to a textbook or the internet to look for introductions to the subject of the evolution of sex, the issues are almost always partially confounded by this context. Never mind that for many sexual eukaryotes, sex is facultative or even rare. Never mind that for many sexual eukaryotes, haploidy is the norm. Never mind that there are plenty of critters whose gametes are of equal sizes (isogamous) and make equal contributions to the zygote (this is really extreme in some protists, where the parents are the zygotes!). Never mind that the sexes are not always kept in separate individuals. Etc. I tend to think that this is extremely misleading and I'll likely return to my favorite hypothesis for animal sex (“we’re stuck with it”) at a later date.

When I start thinking about bacteria, what is even meant by “sex” is confusing. In many cases (with the exception of natural competence) sex-like mechanisms are mediated by parasites, like transduction and conjugation systems. To quote the eminent John Roth, “In bacteria, sex is a venereal disease.” But since transformation via natural competence is often touted as an analogy to sex, I’d better get some idea of what kind of help it could provide outside the typical higher eukaryote context.

There is one common pedagogy that helps me considerably in understanding a possible advantage of sex, but this is really about the putative advantage of recombination. Even in the case of recombination, there seems to be a fine balance, as many organisms have modulated how much recombination is allowed through subtle alterations in their lifestyles. So while recombination can offer advantages, it is clearly not an absolute advantage.

Okay, so why can be recombination useful? First and foremost, recombination is used for repairing broken DNA, not for sex. This is why recombination exists. All cellular lifeforms (along with many cellular parasites) need the ability over the long-term to repair DNA double-stranded breaks and some other types of DNA damage by recombination. DNA replication itself becomes a problem in the absence of recombination mechanisms. In this context, rather than increasing diversity, recombination is anti-mutagenic. So first, the advantage of recombination between individuals has to be disentangled from the advantage of recombination within individuals. At least for me, this isn’t as easy as it sounds, but for now, I’ll just distinguish sexual recombination as the kind that shuffles the genetic material between two related individuals.

One common explanation given for the advantage of sex is to escape Muller’s ratchet, which posits that in the absence of sexual recombination, genetic drift can cause weakly deleterious mutations to fix and accumulate in populations merely by chance. This requires the effective population size to be small enough for a population to feel the effects of genetic drift. In infinite populations, all deleterious mutations, no matter how weak, will be eliminated by natural selection. But in finite populations the ratchet causes more and more weakly deleterious mutations to slowly arise in a genetic background, slowly leading to the extinction of the population as its mean fitness inexorably goes to zero... i.e. mutational meltdown.

An affiliated idea (or perhaps simply a more generalized form?), the Hill-Robertson effect, suggests that selection is less efficient for two linked loci under selection than for two unlinked loci under selection. (In a perfectly asexual organism, all loci are perfectly linked.) The following figure (from Wikipedia) illustrates a version of this, called clonal interference.
The x-axis is time and the y-axis is the abundance of a given genotype, where everyone starts out ab. The top graph illustrates a sexual population, while the bottom graph illustrates an asexual population. In the asexual population, beneficial mutations (capital letters) that arise at different loci in different individuals cannot recombine to make the most fit genotype (AB), so one ends up lost (that’s the interference). In order for the two beneficial mutations to end up on the same genetic background, they must independently arise on the same background. With sexual recombination, the two mutations can arise on different individuals and still end up on the same genetic background. I think that this type of clonal interference would still occur in infinite populations, but am not really sure. (This is relevant, since in bacteria, population sizes may often be so large as to reduce the problem of drift.)

I can imagine that clonal interference could be a problem for bacteria, even with large population sizes, and how natural competence could allow a group of bacteria to escape from this interference. So the “Sex Hypothesis” is certainly plausible. The difficulty, then, is how to demonstrate that this is really why natural competence is maintained. Maybe “why?” is simply always a difficult question to approach experimentally...

Okay, so there we go: Presumably, one major advantage of sex is that it allows for recombination between different individuals, which lets fit alleles get together and bad alleles to get culled by selection more rapidly.

For now, I’ll leave it there and just mention that it isn’t necessarily a good thing for the individual to have recombination with some arbitrary related DNA from its environment (or by sex), even assuming that it isn’t somehow damaged. If you have perfectly good co-adapted genes in your genome, replacing one of your alleles with some other one may end up making you less fit...

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