Developmental buffering, or how to live with your bad genes

Mutate. Select. Repeat. Mutate. Select. Repeat. You can't understand evolutionary biology if you don't get the significance of that process. And yet, if you think that's all there is to it, you're way off track. [PZ explained this very nicely](http://pandasthumb.org/archives/2010/07/its-more-than-g.html) here last week. Let's focus on one simple point that he made, and look at some recent and significant work on that subject that shows just how misleading some of the common simplifications of evolutionary biology can become.

[Here's PZ](http://pandasthumb.org/archives/2010/07/its-more-than-g.html) on simple views of mutation and selection:

Stop thinking of mutations as unitary events that either get swiftly culled, because they're deleterious, or get swiftly hauled into prominence by the uplifting crane of natural selection. Mutations are usually negligible changes that get tossed into the stewpot of the gene pool, where they simmer mostly unnoticed and invisible to selection.

I think this is an extremely important point, both for those seeking to answer creationist propaganda and for anyone else trying to understand the process of evolutionary change. The common picture, painted all too often by commentators of various stripes, depicts a world in which mutations run a harrowing gauntlet of selection that is likely to foolishly discard both the gems and the proto-gems of biological function. Oh sure, the cream eventually rises to the top, but only through the magic of seemingly endless eons and limitless opportunities. I hope that most readers of the Panda's Thumb are annoyed by this crude caricature, but it's the standard tale, and when the narrator only has a paragraph, it's the one we're most likely to hear.

To improve the situation, we might first add the concept of random drift. And that helps a lot. Then we would emphasize the selective neutrality of the vast majority of all mutations, as PZ did. And that helps a lot, too. Let's look at another helpful concept, one from the evo-devo playbook, almost crazy at first glance but remarkably interesting and important.

Suppose that one reason many mutations are selectively near-neutral is because genetic systems are able to tolerate mutations that have the capacity to be strongly deleterious. Suppose, in other words, that organisms are robust enough to live with seriously nasty genetic problems. This would mean that such mutations could escape selection, and that populations could harbor even more genetic diversity than our simplistic account would seem to suggest.

Some very nice work in the fruit fly ("[Phenotypic robustness conferred by apparently redundant transcriptional enhancers](http://dx.doi.org/10.1038/nature09158)"), performed by Frankel and colleagues and published in _Nature_ in July, shows us one way this sort of thing can work. The authors were studying genetic control elements (called [enhancers](http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=cooper&part=A991&rendertype=figure&id=A996)) that turn genes on and off. Specifically, they were looking at how the expression of a gene called _shavenbaby_ was affected by a set of enhancers. (The _shavenbaby_ gene [controls the development of hair-like structures](http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0040290) on the surface of the fly larva - i.e., maggot - and so alterations in the embryo's patterning that result from changes in _shavenbaby_ function are easily detectable by simple microscopy.) Now, like many genes that control development, _shavenbaby_ is regulated by a few different enhancers, some that are close to the gene and others that are apparently redundant and are further away. These latter elements are [called "shadow" enhancers](http://dx.doi.org/10.1126/science.1160631), as they are remote and distinct from the primary enhancers but highly similar in activity.

Why all this redundancy? Others had proposed that shadow enhancers might confer "phenotypic robustness" - i.e., developmental or functional robustness - by maintaining function in the face of significant challenges (environmental changes, for example), and Frankel et al. set out to test that hypothesis. First they deleted the shadow enhancer region, and this had a very mild effect, consistent with the idea that the shadow enhancers are redundant with respect to the function of the primary enhancers. But then they examined development in the absence of the shadow enhancers, now introducing environmental stress (extremes of temperature), and found dramatic developmental defects. They concluded that the _shavenbaby_ shadow enhancers normally contribute to phenotypic robustness through what they term "developmental buffering." In other words, the animal's critical developmental pathways are buffered against many disastrous alterations, in part through the action of redundant control systems.

That's interesting all by itself, but the authors went one crucial step further. What if the redundant enhancers can also buffer against genetic disasters? The experiment was straightforward: they deleted one copy of a major developmental control gene (called _[wingless](http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=cooper&part=A2271#A2276)_). Those animals are just fine, until they lose the buffering of the _shavenbaby_ shadow enhancers. Without the redundant system, the loss of one _wingless_ gene leads to a significant change in developmental patterning. The conclusion, I think, is quite interesting: the impact of the shadow enhancers only becomes apparent when the system is stressed, by environmental challenges and even by genetic problems elsewhere in the genome.

Such developmental buffering systems are thought to be common in animal genomes, and this means that animal development is capable of tolerating significant genetic dysfunction. It means, I think, that simplistic stories about deleterious mutants being readily discarded from populations are even less useful than we already should have realized, and that's without the [deliberate misuse](http://sfmatheson.blogspot.com/2008/08/why-im-not-behe-fan-part-iib-abusing.html) of such outlines by anti-evolution spinmeisters.

And one last thing. Why my little comment about the evo-devo playbook? Well, one concept championed by evo-devo thinkers is the notion of "evolvability." The idea (roughly) is that the ability to generate diversity is something that we should expect to see in evolution. Like most other evo-devo proposals, it's been [savaged by some smart critics](http://dx.doi.org/10.1073/pnas.0702207104). But phenotypic buffering by redundant developmental control elements is just the kind of thing that "evolvability" was meant to encompass when it was [discussed by Kirschner and Gerhart more than a decade ago](http://www.pnas.org/content/95/15/8420.long). So I say we give credit where it's due. Anyone else?