Olfactory receptor pseudo-pseudogenes

Abstract

Pseudogenes are generally considered to be non-functional DNA sequences that arise from protein-coding genes through nonsense or frame-shift mutations1. Although certain pseudogene-derived RNAs have regulatory roles2, and some pseudogene fragments are translated3, no clear functions for pseudogene-derived proteins are known. Olfactory receptor families contain many pseudogenes, reflecting low selection pressures to maintain receptors that are either functionally redundant or detect odours no longer relevant for a species’ fitness4. Here we have characterised a pseudogene in the chemosensory variant ionotropic glutamate receptor (IR) repertoire5,6 of Drosophila sechellia, an insect endemic to the Seychelles that feeds only on ripe fruit of Morinda citrifolia7. This locus, DsecIr75a, bears a premature termination codon (PTC) that appears to be fixed in the population. Unexpectedly, DsecIr75a encodes a functional receptor, due to efficient translational readthrough of the PTC. Readthrough occurs only in neurons, and is independent of the type of termination codon but dependent upon the sequence downstream of the PTC. Furthermore, while the intact D. melanogaster IR75a orthologue detects acetic acid – a chemical cue important for this species to locate fermenting food8,9 but at trace levels in Morinda fruit10 – DsecIR75a has evolved distinct odour-tuning properties, through amino acid changes in its ligand-binding domain. We identify functional PTC-containing loci within different olfactory receptor repertoires and species, suggesting that such “pseudo-pseudogenes” represent a widespread phenomenon.

Modern human origins: multiregional evolution of autosomes and East Asia origin of Y and mtDNA

“…Remarkably, the stop codon set showed similar pattern as the random set, with AFR having the largest PGD. This indicates functionality rather than neutrality for the average genome wide SNPs since stop codon SNPs are definitely functional given its dramatic effect on protein structure (40). To verify the results of stop codon SNPs, we also found similar PGD pattern in the splicing SNPs that are also expected to be functional (Supplementary Information 1 and Fig.…”

“…The link between traits/diseases and the amount of SNPs shows an optimum genetic diversity level maintained by selection, thereby providing direct experimental disproof for the neutral assumption for common SNPs (21,22,37,38). Other types of experimental evidence invalidating the neutral assumption have also been found (39,40).…”

Poor human olfaction is a 19th-century myth

“…However, follow up work from a broader range of species found no support for a sudden loss of functional odor receptor genes in conjunction with trichromacy (21). Critically, new evidence shows that 60% of human olfactory receptor “pseudogenes” are actually transcribed into mRNA in the human olfactory epithelium (22) and work in model organisms suggests that some olfactory receptor pseudogenes may actually result in functional receptors (23). Should these non-coding RNAs or unexpectedly-coding RNAs turn out to be a powerful regulatory network unique to primates (say, for matching olfactory receptor gene expression to the environment; 24, 25), would we then conclude that it is the basis for superior olfactory function in primates?…”

Amlexanox Enhances Premature Termination Codon Read-Through in COL7A1 and Expression of Full Length Type VII Collagen: Potential Therapy for Recessive Dystrophic Epidermolysis Bullosa

“…Not only the specific sequence of the stop codon but also the nucleotide immediately following the stop codon has been shown to affect the amount of read-through product. In addition, endogenous (natural) read-through is a mechanism that governs protein isoform expression, most notably demonstrated in Drosophila (Jungreis et al, 2011), and is both tissue specific and dependent on the 3′ nucleotide context (Prieto-Godino et al, 2016). These findings suggest that the termination of translation is dependent on factors in addition to the precise trinucleotide sequence of the PTC.…”