Stochastic Gain and Loss of Novel Transcribed Open Reading Frames in the Human Lineage

Abstract

In addition to known genes, much of the human genome is transcribed into RNA. Chance formation of novel open reading frames (ORFs) can lead to the translation of myriad new proteins. Some of these ORFs may yield advantageous adaptive de novo proteins. However, widespread translation of non-coding DNA can also produce hazardous protein molecules, which can misfold and\or form toxic aggregates. The dynamics of how de novo proteins emerge from potentially toxic raw materials and what influences their long-term survival are unknown. Here, using transcriptomic data from human and five other primates, we generate a set of transcribed human ORFs at six conservation levels to investigate which properties influence the early emergence and long-term retention of these expressed ORFs. As these taxa diverged from each other relatively recently we present a fine scale view of the evolution of novel sequences over recent evolutionary time. We find that novel human-restricted ORFs are preferentially located on GC-rich gene-dense chromosomes, suggesting their retention is linked to pre-existing genes. Sequence properties such as intrinsic structural disorder and aggregation propensity–which have been proposed to play a role in survival of de novo genes–remain relatively unchanged over time. Even very young sequences code for proteins with low aggregation propensities, suggesting that genomic regions with many novel transcribed ORFs are concomitantly less likely to produce ORFs which code for harmful toxic proteins. Our data indicate that the survival of these novel ORFs is largely stochastic rather than shaped by selection.

De novo birth of functional, human-specific microproteins

“…GC% 0.53 vs. 0.57, Wilcoxon's test P-value=0.13), and there is no correlation of GC% to time since origination (P-value=0.76). A similar trend (young ORFs having lower GC% than older ORFs) was observed by Dowling et al 38 , albeit between slightly different phylogenetic groups.…”

“…In human, early studies relying on gene annotations [33][34][35][36] established that de novo genes can indeed form, even in as short an evolutionary timeframe as the split of human from chimpanzee. Later studies adopted broader search strategies, starting from entire transcriptomes and incorporating ribosome profiling data to identify translated ORFs 37,38 .…”

New genomic signals underlying the emergence of human proto-genes

“…A total of 27550 human proto-genes were retrieved from the dataset created by [33]. We only considered putative de novo genewith a minimum expression strength of Reads Per million Mapped reads (RPM) > 0.5.…”

“…Secondly, we aim to understand if the three mechanisms of emergence ("overprinting", "exonisation", or "from scratch"), as well as the approximate age of emergence, influence the properties of the protogenes. We investigated four properties by studying 27550 proto-genes from the human lineage published by [33] : (1) the presence of introns, (2) the enrichment and nature of motifs specific for transcription, (3) the properties of 5' untranslated region (UTR), and (4) the presence of protein domains.…”

Lineage-Specific Genes and Family Expansions in Dictyostelid Genomes Display Expression Bias and Evolutionary Diversification during Development

“…Recent gene duplications can result in lineage-specific genes and expansions relative to other lineages, as can differential gene loss across species. The same is true for de novo genes that arise independent of duplications [20][21][22], and therefore comparative genomic approaches are useful in identifying new genes that are restricted to a single lineage. Rapid diversification is typical for new genes [23], contributing to novel functions and to gene family expansions that shape the evolution of phenotypes [18,24,25].…”