Stops making sense: translational trade-offs and stop codon reassignment

Background Efficient gene expression involves a trade-off between (i) premature termination of protein synthesis; and (ii) readthrough, where the ribosome fails to dissociate at the terminal stop. Sense codons that are similar in sequence to stop codons are more susceptible to nonsense mutation, and are also likely to be more susceptible to transcriptional or translational errors causing premature termination. We therefore expect this trade-off to be influenced by the number of stop codons in the genetic code. Although genetic codes are highly constrained, stop codon number appears to be their most volatile feature. Results In the human genome, codons readily mutable to stops are underrepresented in coding sequences. We construct a simple mathematical model based on the relative likelihoods of premature termination and readthrough. When readthrough occurs, the resultant protein has a tail of amino acid residues incorrectly added to the C-terminus. Our results depend strongly on the number of stop codons in the genetic code. When the code has more stop codons, premature termination is relatively more likely, particularly for longer genes. When the code has fewer stop codons, the length of the tail added by readthrough will, on average, be longer, and thus more deleterious. Comparative analysis of taxa with a range of stop codon numbers suggests that genomes whose code includes more stop codons have shorter coding sequences. Conclusions We suggest that the differing trade-offs presented by alternative genetic codes may result in differences in genome structure. More speculatively, multiple stop codons may mitigate readthrough, counteracting the disadvantage of a higher rate of nonsense mutation. This could help explain the puzzling overrepresentation of stop codons in the canonical genetic code and most variants.

Conjecture, proof, and sense in Wittgenstein's philosophy of mathematics

One of the key tenets in Wittgenstein’s philosophy of mathematics is that a mathematical proposition gets its meaning from its proof. This seems to have the paradoxical consequence that a mathematical conjecture has no meaning, or at least not the same meaning that it will have once a proof has been found. Hence, it would appear that a conjecture can never be proven true: for what is proven true must ipso facto be a different proposition from what was only conjectured. Moreover, it would appear impossible that the same mathematical proposition be proven in different ways. — I will consider some of Wittgenstein’s remarks on these issues, and attempt to reconstruct his position in a way that makes it appear less paradoxical.

Keep making sense

In a number works Jerry Fodor has defended a reductive, causal and referential theory of cognitive content. I argue against this, defending a quasi-Fregean notion of cognitive content, and arguing also that the cognitive content of non-singular concepts is narrow, rather than wide.

Making sense of survival: refining the treatment of state preferences in neorealist theory

The assumption that ‘states' primary goal is survival’ lies at the heart of the neorealist paradigm. A careful examination of the assumption, however, reveals that neorealists draw upon a number of distinct interpretations of the ‘survival assumption’ that are then treated as if they are the same, pointing towards conceptual problems that surround the treatment of state preferences. This article offers a specification that focuses on two questions that highlight the role and function of the survival assumption in the neorealist logic: (i) what do states have to lose if they fail to adopt self-help strategies?; and (ii) how does concern for relevant losses motivate state behaviour and affect international outcomes? Answering these questions through the exploration of governing elites' sensitivity towards regime stability and territorial integrity of the state, in turn, addresses the aforementioned conceptual problems. This specification has further implications for the debates among defensive and offensive realists, potential extensions of the neorealist logic beyond the Westphalian states, and the relationship between neorealist theory and policy analysis.