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Health

Jim Manzi on epistasis

Gene ExpressionBy Razib KhanOctober 31, 2008 1:58 AM

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Jim Manzi has a long post up on epistasis, that is, gene-gene interactions:

We could call this process of competing algorithms struggling to find the best solution as fast as possible "meta-evolution". That is, each potential search method must compete for survival. The fact that the algorithm that has won this (idealized) competition in the real world has the form of a GA seems to indicate that there is some structure to the relationship between gene vectors and physical outcomes, but that it is much more complex that simple linear combinations without interaction terms, otherwise nature never would have evolved the evolutionary algorithm with all of its computational overhead. If epistatic interactions were not central, meta-evoltuion should have killed off evolution as we know it a long, long time ago.

That's a mouthful. Read the whole thing for context. Remember that there are different ways to conceive of epistasis. Molecular biologists naturally think of epistasis as biochemical interactions between genes; e.g., locus A produces a gene product which modulates the activity of gene B. Obviously if you conceptualize the mechanistic processes of genes they are interlaced with a nearly infinite number of epistatic cross-linkages. But from an evolutionary perspective you are thinking about something different, specifically you're interested in interaction effects within traits which exhibit heritable variation. For example, you can conceive of a trait's genetic architecture as being additive and independent; each gene's effect has no relation to any other gene, and the effects are cumulative. This is obviously not true for all traits; changing the state on one locus might modulate a set of other loci. R. A. Fisher and Sewall Wright are generally understood to have disagreed somewhat on the role of epistasis in evolution, with Fisher being more skeptical of its ubiquity than Wright. In particular Wright relied on epistatic effects in his Shifting Balance Theory which imagined populations exploring adaptive landscapes. Here is what James F. Crow, who knew both Fisher and Wright, told me several years ago:

1) In 2002 in "Perspective: Here's to Fisher, additive genetic variance, and the fundamental theorem of natural selection," you conclude, "is there any other quantity that captures so much evolutionary meaning in such a simple way?" in reference to additive genetic variance. And yet, what about other factors like statistical epistasis? Do gene-gene interactions pack enough of an evolutionary punch to be anything more than a footnote in God's Book? Have you seen Loren Rieseberg's work at Indiana which points to the importance of loci of large effect? [my question] The remarkable thing about additive genetic variance is that it predicts the effect of selection, even in the presence of dominance and epistasis. Nature seems to follow least-squares principles. The result is that the additive component of variance pulls out of dominance and epistatic variance those components associated with allele frequency change under selection. Of course the theory is not exact, but it is a very good first approximation. Fisher did not ignore epistasis, as some have said; rather he showed how selection can utilize epistatic (and dominance) components of variance. On a more technical level, Kimura showed that under selection with loose linkage the population rather soon attains a state in which the linkage-disequilibrium variance approximately cancels the epistatic variance. Thus, under this circumstance the effects of selection are better predicted by ignoring additive by additive epistatic variance than by including it. See my book with Kimura (1970, p. 217 ff). I am aware of Rieseberg's work on sunflowers. QTL mapping and various other molecular methods are indeed finding alleles with large effect in many species. It is inevitable that the first genes discovered will be those with largest effect, so I expect alleles with smaller effects to follow. How large a part genes with large effect have played in evolution is still up in the air, as far as I know. But they are getting more emphasis now than in the recent past.

I am wary of saying much more, this is a complex topic. After all, consider that epistatic components of variation may be converted to additive genetic variance. If I had to guess, I would offer that perhaps epistatic dynamics play an essential role in what we would term speciation, while most microevolutionary action is along the dimension of additive genetic variance. But whatever the truth of it, I do not think that the importance of interaction effects negates the fact that as a first approximation a linear model can be highly fruitful. For a full understanding of the shape of reality we must map epistasis, but without it we may still have sight of the major landmarks necessary for our journey. Though I suppose that is conditional upon where we wish to go.... Related:Through the rugged roads of gene land.

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