Overlapping Genes Coding Constraints Schematic
Figure 1: Overlapping genes must satisfy functional as well as coding constraints. (a) Schematic of a pair of overlapping genes, in which multiple reading frames of a single coding sequence are translated into different proteins. (b) Definition and nomenclature of reading frames studied in this work. (c) Compatible pairs of amino acids a and b (as defined in (b)) that can be encoded across from each other in each of the three reading frames. (d) Diagrammatic representation of the fitness landscape of overlapping genes, which must satisfy the constraints of folding and function of each gene fam
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Paper title: The fitness landscape of overlapping genes Abstract: Natural genomes sometimes encode two different proteins in staggered reading frames of the same DNA sequence. Despite the prevalence of these 'overlapping genes' across the tree of life, it remains unknown whether arbitrary protein pairs can overlap, to what extent such overlaps are feasible, or what design principles govern them. Here, we study compatibility, frustration, and connectivity in the fitness landscape of overlapping genes. We computationally design sequences de novo that satisfy the dual functional constraints of two distinct protein families. The joint fitness landscape, inferred via Potts models from multiple sequence alignments, reveals a fundamental trade-off between the two proteins and provides a simple criterion for when overlap is feasible. We find widespread compatibility between protein families, with one class of reading frames markedly more permissible than others. By exploring alternative genetic codes, we find that the natural genetic code is uniquely well-suited to support overlapping genes. Constructing mutational paths between sequences, we find that sequence-diverse overlapped genes can be connected via a network of near-neutral mutations. Overall, our results suggest that protein fitness landscapes are sufficiently flexible so as to accommodate the stringent, orthogonal requirements of overlapping genes. Passages referencing this figure: [ 44 ] . Particularly in the confined space of a viral capsid, they are thought to serve as a form of data compression [ 6 ] . In other contexts, they have been suggested to serve as sites for the de novo origin of genes [ 36 , 19 ] . More recent work has engineered overlaps in the lab between naturally non-overlapping genes, mutationally entangling otherwise unrelated functions [ 3 , 5 , 26 ] . Figure 1: Overlapping genes must satisfy functional as well as coding constraints. (a) Schematic of a pair of overlapping genes, in which multiple reading frames of a single coding sequence are translated into different proteins. (b) Definition and nomenclature of reading frames studied in this work. (c) Compatible pairs of amino acids a and b (as defined in (b)) that can be encoded across from ea verlap is an intrinsic, latent feature of the standard genetic code and real protein fitness landscapes. II Results II.1 Overlapping imposes stringent coding constraints We begin by characterising the raw coding constraints imposed by overlapping. In this work, we restrict ourselves to studying overlapping genes encoded on opposite strands of DNA. The three alternative reading frames are shown in Fig. 1 b, which we denote frames 0, -1, and -2. Due to the degeneracy of the genetic code, an amino acid sequence may be encoded on one strand by several possible choices of nucleotide sequence. As there are 61 / 20 ∼ 3 61/20\sim 3 codons per amino acid on average, a particular amino acid sequence of length L L could be encoded by 3 L 3^{L} different nucleotide sequences – with each one potentiall final energies of each protein product, normalised as z-scores to the distribution of natural energies, for the different replicates in (b). (d) Comparison of crystal structures of representative mem
