# Adrian Bird on genome ecology

I recently read this essay by Adrian Bird on ”The Selfishness of Law-Abiding Genes”. That is a colourful title in itself, but it doesn’t stop there; this is an extremely metaphor-rich piece. In terms of the theoretical content, there is not much new under the sun. Properties of the organism like complexity, redundancy, and all those exquisite networks of developmental gene regulation may be the result of non-adaptive processes, like constructive neutral evolution and intragenomic conflict. As the title suggests, Bird argues that this kind of thinking is generally accepted about things like transposable elements (”selfish DNA”), but that the same logic applies to regular ”law-abiding” genes. They may also be driven by other evolutionary forces than a net fitness gain at the organismal level.

He gives a couple of possible examples: toxin–antitoxin gene pairs, RNA editing and MeCP2 (that’s probably Bird’s favourite protein that he has done a lot of work on). He gives this possible description of MeCP2 evolution:

Loss of MeCP2 via mutation in humans leads to serious defects in the brain, which might suggest that MeCP2 is a fundamental regulator of nervous system development. Evolutionary considerations question this view, however, as most animals have nervous systems, but only vertebrates, which account for a small proportion of the animal kingdom, have MeCP2. This protein therefore appears to be a late arrival in evolutionary terms, rather than being a core ancestral component of brain assembly. A conventional view of MeCP2 function is that by exerting global transcriptional restraint it tunes gene expression in neurons to optimize their identity, but it is also possible to devise a scenario based on self-interest. Initially, the argument goes, MeCP2 was present at low levels, as it is in non-neuronal tissues, and therefore played little or no role in creating an optimal nervous system. Because DNA methylation is sparse in the great majority of the genome, sporadic mutations that led to mildly increased MeCP2 expression would have had a minimal dampening effect on transcription that may initially have been selectively neutral. If not eliminated by drift, further chance increases might have followed, with neuronal development incrementally adjusting to each minor hike in MeCP2-mediated repression through compensatory mutations in other genes. Mechanisms that lead to ‘constructive neutral evolution’ of this kind have been proposed. Gradually, brain development would accommodate the encroachment of MeCP2 until it became an essential feature. So, in response to the question ‘why do brains need MeCP2?’, the answer under this speculative scenario would be: ‘they do not; MeCP2 has made itself indispensable by stealth’.

I think this is a great passage, and it can be read both as a metaphorical reinterpretation, and as substantive hypothesis. The empirical question ”Did MeCP2 offer an important innovation to vertebrate brains as it arose?”, is a bit hard to answer with data, though. On the other hand, if we just consider the metaphor, can’t you say the same about every functional protein? Sure, it’s nice to think of p53 as the Guardian of the Genome, but can’t it also be viewed as a gangster extracting protection money from the organism? ”Replicate me, or you might get cancer later …”

The piece argues for a gene-centric view, that thinks of molecules and the evolutionary pressures they face. This doesn’t seem so be the fashionable view (sorry, extended synthesists!) but Bird argues that it would be healthy for molecular cell biologists to think more about the alternative, non-adaptive, bottom-up perspective. I don’t think the point is to advocate that way of thinking to the exclusion of the all other. To me, the piece reads more like an invitation to use a broader set of metaphors and verbal models to aid hypothesis generation.

There are too may good quotes in this essay, so I’ll just quote one more from the end, where we’ve jumped from the idea of selfish law-abiding genes, over ”genome ecology” — not in the sense of using genomics in ecology, but in the sense of thinking of the genome as some kind of population of agents with different niches and interactions, I guess — to ”Genetics Meets Sociology?”

Biologists often invoke parallels between molecular processes of life and computer logic, but a gene-centered approach suggests that economics or social science may be a more appropriate model …

I feel like there is a circle of reinforcing metaphors here. Sometimes when we have to explain how something came to be, for example a document, a piece of computer code or a the we do things in an organisation, we say ”it grew organically” or ”it evolved”. Sometimes we talk about the genome as a computer program, and sometimes we talk about our messy computer program code as an organism. Like viruses are just like computer viruses, only biological.

Literature

Bird, Adrian. ”The Selfishness of Law-Abiding Genes.” Trends in Genetics 36.1 (2020): 8-13.

# Journal club of one: ‘Splendor and misery of adaptation, or the importance of neutral null for understanding evolution’

In this paper from a couple of years ago, Eugene Koonin takes on naïve adaptationism, in the style of The Spandrels of Saint Marcos and the Panglossian paradigm (Gould & Lewontin 1979). The spandrels paper is one of those classics that divide people. One of its problems was that it is easy to point out what one shouldn’t do (tell adaptive stories without justification), but harder to say what one should do. But anti-adaptationism has moved forward since the Spandrels, and the current paper has a prescription.

Spandrels contained a list of possible alternatives to adaptation, which I think breaks down into two categories: population genetic alternatives (including neutral or deleterious fixations due to drift and runaway selection driving destructive features rather than fit to the environment), and physiological or physical alternatives (features that arise due to selection on something else, which are the metaphorical spandrels of the title, and fit to the environment that happens due to natural laws unrelated to biological evolution).

Eugene Koonin elaborates on the population genetic part, concentrating more on chance and less on constraint. He brings up examples of molecular structures that may have arisen through neutral evolution. The main idea is that when a feature has fixed, it doesn’t go away so easily, and there can be a ratchet-like process of increasing complexity. Evolution doesn’t Haussmannise, but patches, pieces, and cobbles together what is already there.

As a theoretical example, Michael Lynch (2007) used population genetic models to derive conditions for when molecular networks can extend and become complex by neutral means. (Spoiler: it’s when transcription factor binding motifs arise often in the weakly constrained DNA around genes.) Eugene Koonin thinks that the thing to do with this insight is to use it as a null model:

A simplified and arguably the most realistic approach is to assume a neutral null model and then seek evidence of selection that could falsify it. Null models are standard in physics but apparently not in biology. However, if biology is to evolve into a ”hard” science, with a solid theoretical core, it must be based on null models, no other path is known.

I disagree with this for two reasons. I’m not at all convinced that biology must be based on setting up null models and rejecting them … or that physics is. In some statistical approaches, inference proceeds by setting up a null hypothesis (and model), and trying to shoot it down. But those hypotheses are different from substantial scientific hypotheses. I would suspect that biology spends too much time rejecting nulls, not too little.

Bausman & Halina (2018) summarise the argument against null hypotheses like this in their recent paper Biology & Philosophy:

The pseudo-null strategy is an attempt to move hypotheses away from parity by shifting the burden of disproving the null to the alternative hypotheses on the authority of statistics. As we have argued, there is no clear justification for this strategy, however, so the hypotheses should be treated on a par.

That is, they reject the analogy between statistical testing and scientific reasoning. They take their examples from ecology and psychology, but there is the same tendency in molecular evolution.

Also, constructive neutral evolution is as a pretty elaborate process. Just like adaptation should not be assumed as a default model without positive supporting evidence, neither should it. The default alternative for some elaborate feature of an organism need not be ‘constructive neutral evolution’, but ‘we don’t know how it came about’.

On the other hand, maybe the paper shouldn’t be read as an attempt to set constructive neutral evolution up as the default, but, like Spandrels, to repeat that adaptation isn’t everything:

It is important to realize that this changed paradigm by no means denies the importance of adaptation, only requires that it is not taken for granted. As discussed above, adaptation is common even in the weak selection regime where non-adaptive processes dominate. But the adaptive processes change their character as manifested in the switch from local to global evolutionary solutions, CNE, and pervasive (broadly understood) exaptation.

Naïve adaptationism is certainly not dead, but just whisper $\frac {1}{N_e s}$ and the ghost goes away. I would have been more interested in an attack on sophisticated adaptationism. How about the organismal level? Do ratchet-like neutral processes bias or direct the evolution of form and behaviour of say animals and plants?

Literature

Bausman W & Halina M (2018) Not null enough: pseudo-null hypotheses in community ecology and comparative psychology Philosophy & Biology

Gould SJ & Lewontin R (1979) The spandrels of San Marco and the Panglossian paradigm: a critique of the adaptationist programme Proceedings of the Royal Society B.

Koonin EV (2016) Splendor and misery of adaptation, or the importance of neutral null for understanding evolution BMC Biology.

Lynch M (2007) The evolution of genetic networks by non-adaptive processes Nature Reviews Genetics.