Gene birth contributes to structural disorder encoded by overlapping genes

Abstract

The same nucleotide sequence can encode two protein products in different reading frames. Overlapping gene regions are known to encode higher levels of intrinsic structural disorder (ISD) than non-overlapping genes (39% vs. 25% in our viral dataset). Two explanations for elevated ISD have been proposed: that high ISD relieves the increased evolutionary constraint imposed by dual-coding, and that one member per pair was recently born de novo in a process that favors high ISD. Here we quantify the relative contributions of these two alternative hypotheses, as well as a third hypothesis that has not previously been explored: that high ISD might be an artifact of the genetic code. We find that the recency of de novo gene birth explains ∼ 32% of the elevation in ISD in overlapping regions of viral genes, with the rest attributed, by a process of elimination, to relieving constraint. While the two reading frames within a same-strand overlapping gene pair have markedly different ISD tendencies, their effects cancel out such that the properties of the genetic code do not contribute overall to elevated ISD. Same-strand overlapping gene birth events can occur in two different frames, favoring high ISD either in the ancestral gene or in the novel gene; surprisingly, most de novo gene birth events contained completely within the body of an ancestral gene favor high ISD in the ancestral gene (23 phylogenetically independent events vs. 1). This can be explained by mutation bias favoring the frame with more start codons and fewer stop codons.

Universal and taxon-specific trends in protein sequences as a function of age

“…Young genes Mukherjee et al 2015;Willis & Masel 2018;Wilson et al 2017) (Vakirlis et al 2018). We confirm that across our entire dataset, ISD is higher in young pfams (figure 1, linear model: R 2 = 0.13, p = 3×10 -245 ) and genes (Supplementary figure 1A, linear model for all genes: R 2 = 0.057, p =1×10 -229 ).…”

Mutation bias can shape adaptation in large asexual populations experiencing clonal interference

“…N is likely reasonably small for the natural bird popu-455 lations studied by Storz et al [16]. While N is much larger for the natural viral populations studied by Willis and Masel [40], the rate U of the beneficial de novo birth of new overlapping genes is likely so low that U N 1. There were 5 times more birth events in the +1 read-460 ing frame, which has more and longer ORFs, than there were in the +2 reading frame, on which the genetic code bestows a tendency toward the favored protein property of high intrinsic structural disorder.…”

“…This selectionist view persisted through the Modern Synthesis 35 [2], following the metaphor of populations as vast "gene pools" with ample amounts of genetic variation already available for natural selection to act on. With abundant mutations each of tiny effect already present and available to recombine to produce any possible phenotype, 40 bias in variation was thought irrelevant.…”

Are Antisense Proteins in Prokaryotes Functional?

“…However, their occurrence in bacteriophage in particular should raise the suspicion that they may be common in bacteria as well, given for instance the large amounts of genetic material transferred from temperate phage genomes to bacterial genomes Brockhurst, 2017, Owen et al, 2019). The properties of same-strand overlaps between viral genes have been studied, (Pavesi et al, 2018, Willis andMasel, 2018), but even in viruses, relatively little attention has been given to antisense overlaps. There is however increasing evidence for functional translated antisense open reading frames too, notably the antisense protein Asp in HIV-1 (Cassan et al, 2016, Affram et al, 2019, Nelson et al, 2019.…”