Function’ in Biology and the Problematic Case of De Novo Gene Emergence

FEATURE ARTICLE PHILOSOPHY OF BIOLOGY The meanings of ’function’ in biology and the problematic case of de novo gene emergence Abstract 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. DOI: https://doi.org/10.7554/eLife.47014.001 DIANE MARIE KEELING, PATRICIA GARZA, CHARISSE MICHELLE NARTEY* AND ANNE-RUXANDRA CARVUNIS* Introduction amplified when the word is part of everyday The scientific enterprise is inherently rhetorical language. (Condit, 1999; Fahnestock, 2002; Ceccar- A striking example of different interpretations elli, 2001). When we describe observations, of words leading to controversy was the debate, articulate hypotheses or develop theories, we prompted by the first papers from the ENCODE consciously or unconsciously select words to Project, about what fraction of the human convey the meaning of our work. These words, genome is ’functional’. Is it approximately 80%, rather than our own understanding, are what is as suggested by biochemical evidence, or is it published, read, interpreted and possibly built closer to 10%, as it appears from evolutionary *For correspondence: charisse. upon for the years to follow. Language influen- evidence (The ENCODE Project Consortium, [email protected] (CMN); ces how we communicate, how we think, and 2012; Doolittle, 2013; Graur et al., 2013; [email protected] (A-RC) how we practice science. A specific and contex- Kellis et al., 2014)? tual use of language is therefore paramount to a Of course, the answer to this question Competing interests: The entirely depends on what exactly is meant by authors declare that no productive global scientific endeavor. In prac- competing interests exist. tice, however, confusion and even conflict can the word ’function’. For most evolutionary biolo- arise when the same word is understood differ- gists, function relates to selection (that is, the Funding: See page 10 ently by authors and readers. effect for which the gene was selected in the Reviewing editor: Peter A reader’s interpretation of a word in a text past at the organismal level). For most molecular Rodgers, eLife, United Kingdom depends on who the reader is. What is their field geneticists and biochemists, it is generally asso- Copyright Keeling et al. This of training? In what country did they grow up? In ciated with a molecule’s activity (such as catalysis article is distributed under the what decade were they born? What are their or binding), independent of the historical factors terms of the Creative Commons metaphysical presuppositions? All these and that led to its existence. These meanings are Attribution License, which countless other factors act as a filter between epistemological constructions influenced by sci- permits unrestricted use and redistribution provided that the the words themselves and the meanings that entific training. In everyday language, the word original author and source are readers assign to them. These factors are out of ’function’ is associated with many additional credited. the author’s control, and their effect can be concepts ranging from someone’s professional Keeling et al. eLife 2019;8:e47014. DOI: https://doi.org/10.7554/eLife.47014 1 of 12 Feature Article Philosophy of Biology The meanings of ’function’ in biology and the problematic case of de novo gene emergence occupation to the purpose for which a machine or incorporated into grant proposals for mecha- has been engineered. Yet some argue that the nistic studies. Today, scientists cannot agree on evolutionary meaning of function is the only one the number of functional genes in the human that is relevant for DNA sequences (Graur et al., genome (Pertea et al., 2018; Jungreis et al., 2013) and that when referring to other mean- 2018), or on what evidence should be required ings scientists should use other words such as to elevate noncoding RNAs from mere transcrip- ’effect’ or ’activity’ (Doolittle et al., 2014). tional noise to functional regulatory elements This position, and the arguments against it, (Doolittle, 2018). The general confusion about echo an ongoing conversation in the philosophy what exactly is meant by ‘function’ across the lit- of science (Cummins, 1975; Millikan, 1989; erature is such that some have pleaded for the Neander, 1991; Amundson and Lauder, 1994; community to deal with the ‘F-word’ urgently Garson, 2011; Griffiths, 2009). In brief, the (Doolittle et al., 2014; Doolittle, 2018). conversation divides those who argue function As an interdisciplinary group of scholars, we should mean why an entity does what it does sought to understand to what extent the exis- (the selected effect definition of function) and tence of differing meanings of ‘function’ actually those who argue it can also mean what an entity impairs the scientific enterprise. We focused our does (the causal role definition of function) attention on a relatively recent subfield of evolu- (Laubichler et al., 2015). Function strictly tionary genomics studying the specific case of defined as selected effect is the historical expla- de novo gene birth. This field attempts to under- nation for the existence of an entity (Milli- stand how new ‘functional’ genes can emerge kan, 1989). Function as causal role is ahistorical without having derived from another gene as and describes the contribution of an entity to a their ancestor. The process of de novo gene complex system (Cummins, 1975). Other theo- birth was long thought to be implausible on the ries of biological function have been proposed basis that, as Francois Jacob wrote: "the proba- (Wouters, 2003; Mossio et al., 2009; bility that a functional protein would appear de Roux, 2014), but the selected effect/causal role novo by random association of amino acids is perspectives have dominated the conversation practically zero" (Jacob, 1977). However, the in the context of genomics. explosion of new genome sequences has Far from a fruitless dispute over semantics, revealed that many genes have species- or line- the rhetorico-scientific debate has sparked a age-specific sequences (Khalturin et al., 2009), number of thoughtful studies that have suggesting that they lack gene ancestors. Stud- advanced thinking at the interface of evolution- ies of a growing number of individual gene can- ary biology and genomics. For instance, one didates have confirmed their de novo study interrogates the relationship between emergence, fueling many genomic and evolu- organismal complexity and the number of func- tionary studies to evaluate the scale and mecha- tional elements in a genome (Doolittle, 2013), nisms of the de novo gene birth phenomenon another highlights the discrepancies between (Tautz and Domazet-Losˇo, 2011; different lines of evidence used to infer function- McLysaght and Hurst, 2016; Van Oss and Car- ality of DNA loci (Kellis et al., 2014), and vunis, 2019). another refines the evolutionary classifications of The meanings of function are at the heart of genomic functions (Graur et al., 2015). How- what constitutes a de novo gene birth event. For ever, only a small fraction of biologists – mostly a genomic sequence to be labelled as a gene, it evolutionary biologists – are aware of the rhetor- must by definition have a function; it must ical context. Most scientific publications do not express a product that participates in cellular explicitly include a definition of ’function’ to clar- processes and affects phenotypes in a way that ify the meaning of the reported findings. is being maintained by selection. If such a gene It can be argued that this imprecision has tan- has evolved de novo, the locus it came from by gible implications for the scientific practice. For definition was not a gene, thus did not have a better or worse, in biological research there is a function, or at least not a function of the same conflation between what is ’functional’ and what nature as the one the new gene has. The molec- ’matters’. Only those genomic sequences ular objects of study are thus transitioning deemed ’functional’ are worthy of being curated between a state without a function and a state by reference databases, of being named, cloned with a function. They cannot have upon birth a Keeling et al. eLife 2019;8:e47014. DOI: https://doi.org/10.7554/eLife.47014 2 of 12 Feature Article Philosophy of Biology The meanings of ’function’ in biology and the problematic case of de novo gene emergence function by the strict selected effect definition (Ardern, 2018) and there is a pressing need to (Millikan, 1989), since their existence cannot find the right words to express what it does, have been caused historically by a past selection. why and how. The transformative nature of the de novo emer- In addition to these fundamental considera- gence process thus renders the debates about tions, the de novo field is interdisciplinary and when and how a locus actually becomes func- relatively young. It is therefore rich in diverse tional highly contentious. perspectives and trainings, and de novo Let us consider a hypothetical example to researchers lack a commonly accepted jargon. illustrate the difficulty of thinking about the func- All these challenges make de novo gene evolution of recently emerged coding elements. tion a well-suited test bed to evaluate what Imagine a locus that has become transcribed meanings of function are circulating in this field and translated for the first time in somebody’s and whether, and to what extent, the meanings gamete, generating a novel protein whose of function hinder scientific communication. expression propagates to future generations. The corresponding protein has no activity what- Constructing a model of function soever. Does this locus correspond to a de novo for de novo gene birth research functional gene? Not according to the selected We sought to construct an understanding of effect definition, since there is no past selection function specifically tailored to de novo gene to explain why the locus is here.

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