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 encode higher levels of intrinsic structural disorder (ISD) than nonoverlapping genes (39% 25% in our viral dataset). This might be because of the intrinsic properties of the genetic code, because one member per pair was recently born in a process that favors high ISD, or because high ISD relieves increased evolutionary constraint imposed by dual-coding. Here, we quantify the relative contributions of these three alternative hypotheses. We estimate that the recency of gene birth explains [Formula: see text] or more of the elevation in ISD in overlapping regions of viral genes. While the two reading frames within a same-strand overlapping gene pair have markedly different ISD tendencies that must be controlled for, their effects cancel out to make no net contribution to ISD. The remaining elevation of ISD in the older members of overlapping gene pairs, presumed due to the need to alleviate evolutionary constraint, was already present prior to the origin of the overlap. 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 gene birth events contained completely within the body of an ancestral gene favor high ISD in the ancestral gene (23 phylogenetically independent events 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 ( Willis and Masel, 2018 ; Wilson et al, 2017 ; Foy et al, 2019 ; Mukherjee et al, 2015 ) and domains ( Bornberg-Bauer and Albà, 2013 ; Buljan and Bateman, 2009 ; Ekman and Elofsson, 2010 ; Moore and Bornberg-Bauer, 2012 ) have been reported to have high ISD, although some have claimed this depends on taxon ( Vakirlis et al, 2018 ). We use IUPred to estimate ISD from amino acid sequence alone, allowing estimation across large-scale genomic data sets that contain many sequences of undetermined structure ( Mészáros et al, 2018 ).…”

De novo gene birth

“…In support of this, an analysis of ISD in mice found that young genes have higher ISD than old genes, while random non-genic sequences tend to show the lowest levels of ISD [98]. Although the observed trend may have partly resulted from a subset of young genes derived by overprinting [74], higher ISD in young genes was also seen among overlapping gene pairs [127]. Whether this trend holds over shorter timescales is debated [77, 128].…”

Asymmetric evolution in viral overlapping genes is a source of selective protein adaptation

“…Another approach to infer the genealogy of overlapping genes is the codon-usage method. It is based on the assumption that the ancestral gene, which has co-evolved over a long period of time with the other viral genes, has a distribution of synonymous codons significantly closer to that of the viral genome than the de novo gene (Keese and Gibbs, 1992;Sabath et al, 2012;Pavesi et al, 2013;Willis and Masel, 2018). Due to the shortness of most overlapping genes, the method has been improved, with the aim to evaluate the correlation between the codon-usage patterns of overlapping and non-overlapping genes with a Fig.…”