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Tuesday, September 22, 2020

The Function Wars Part VIII: Selected effect function and de novo genes

Discussions about the meaning of the word "function" have been going on for many decades, especially among philosphers who love that sort of thing. The debate intensified following the ENCODE publicity hype disaster in 2012 where ENCODE researchers used the word function an entirely inappropriate manner in order to prove that there was no junk in our genome. Since then, a cottege indiustry based on discussing the meaning of function has grown up in the scientific literature and dozens of papers have been published. This may have enhanced a lot of CV's but none of these papers has proposed a rigorous definition of function that we can rely on to distinguish functional DNA from junk DNA.

The world is not inhabited exclusively by fools and when a subject arouses intense interest and debate, as this one has, something other than semantics is usually at stake.

Stephen Jay Gould (1982)

That doesn't mean that all of the papers have been completely useless. The net result has been to focus attention on the one reliable definition of function that most biologists can accept; the selected effect function. The selected effect function is defined as ...

From an evolutionary viewpoint, a function can be assigned to a DNA sequence if and only if it is possible to destroy it. All functional entities in the universe can be rendered nonfunctional by the ravages of time, entropy, mutation, and what have you. Unless a genomic functionality is actively protected by selection, it will accumulate deleterious mutations and will cease to be functional. Dan Graur (2016) p. 493

It's importatnt to note that this version of selected effect function only refers to sequences that are currently under purifying selection. This point is often ignored in other definitions of selected effect functions because they focus on the historical origins of function where they restrict the definition to sequences that have arisen by natural selection. Purifying selection is an essential and sufficient property of selected effect function.1 We are about to see why.

I often quote Gould in these posts in order to emphasize that debates over the meaning of function are not just quibbling over semantics. Unfortunately, Gould isn't always right—sometimes the debate really is about semantics and in that sense it is not helpfull, Today I have an example of a paper that falls into that category.

Keeling, D.M., Garza, P., Nartey, C.M. and Carvunis, A.-R. (2019) "Philosophy of Biology: The meanings of 'function' in biology and the problematic case of de novo gene emergence." Elife 8: e47014. doi: 10.7554/eLife.47014.001

The word function has many different meanings in molecular biology. Here we explore the use of this word (and derivatives like functional) in research papers about de novo gene birth. Based on an analysis of 20 abstracts we propose a simple lexicon that, we believe, will help scientists and philosophers discuss the meaning of function more clearly.

De novo genes are genes that have arisen relatively recently. They are often confined to just one species in which case they are a subset of orphan genes. The authors focus attention on these genes because they illustrate some of the problems with recognizing function.

Keeling et al. looked at 20 published papers to see what criteria were being used to identify real examples of de novo genes. As you might expect, the papers often looked at features such as whether a putative gene was transcribied or translated as evidence that it was functional. This is perfectly acceptable give that the putative gene is not conserved in other species. It does not mean that that the sequence in question is a real gene just because a transcript or a protein is present. Some of the authors of those 20 papers recognize this and some don't. All this tells us that is that some scientists are confused about the meaning of "function" but that's not news.

The purpose of this post is to highlight another issue that really annoyed me. Here's what Keeling et al. say about the selected effect definition of function.

[De novo genes] cannot have upon birth a function by the selected effect definition (Millikan, 1989), since their existence cannot have been caused historically by a past selection.

The correct definition of selected effect function is not restricted to DNA sequences that have been subject to natural selection in the past.2 It is sufficient that a sequence be subject to purifying selection in the present and that's a criterion that can be tested in the case of de novo genes by looking at variation within a population. Several putative genes fail that criterion so they can be eliminated by applying the correct selected effect definition of function.

The myth that function can only be defined by the history of a trait was propagated by a philospher named Ruth Garrett Millikan in the 1980s and it seems to have widely adopted in spite of the fact that modern biologists have refuted it. This is a case where Keeling et al. are trying to make a case against seleted effect function by semantics and not by critical thinking. This is not helpful.

Function Wars
(My personal view of the meaning of function is described at the end of Part V.)

1. We can all agree that specific nucleotide sequences that are under purifying selection are functional but it's much more difficult to identify non-sequence-dependant blocks of DNA, such as spacer DNA. Nevertheless, those blocks are retained by purifying selction so they fit the definition.

2. There's another example in addition to de novo genes. A functional gene could have evolved by constructive neutral evolution in which case it is not the product of historical natural selection but is till under purifying selection (see Doolittle and Brunet (2017); Brzović and Šustar (2020); Linquist et al. (2020))

Brzović, Z., and Šustar, P. (2020) Postgenomics function monism. Studies in History and Philosophy of Science Part C: Studies in History and Philosophy of Biological and Biomedical Sciences, 101243.[doi: 10.1016/j.shpsc.2019.101243

Linquist, S., Doolittle, W.F. and Palazzo, A.F. (2020) Getting clear about the F-word in genomics. PLOS Genetics 16(4): e1008702. [doi: 10.1371/journal.pgen.1008702]

Millikan, R.G. (1989) In defense of proper functions. Philosophy of science 56:288-302. doi: 10.1086/289488

Graur, D. (2016) Molecular and Genome Evolution, Sinauer Associates, Inc.

1 comment :

Dave said...

It's probably true that Ruth Garrett Millikan overstepped a little bit into the realm of biology when she said what she did about proper functions. However, it's important to understand that - originally - the purpose of her whole theory of 'proper functions' was to account for what philosophers of mind call the 'intentionality' of thought. Most of what she wrote is wrong, but it's still extremely interesting. The book where her ideas originated from is called: Language, Thought, and Other Biological Categories. She writes stuff that would irritate a lot of biologists, but if you can get through it I think reading it would be a positive experience.