Abstract
Genetic variants can influence the expression of mRNA and protein. Genetic regulatory loci such as expression quantitative trait loci (eQTLs) and protein quantitative trait loci (pQTLs) exist in several species. However, it remains unclear how human genetic variants regulate mRNA and protein expression. Here, we characterized six mechanistic models for the genetic regulatory patterns of single-nucleotide polymorphisms (SNPs) and their actions on post-transcriptional expression. Data from Yoruba HapMap lymphoblastoid cell lines were analyzed to identify human cis-eQTLs and pQTLs, as well as protein-specific QTLs (psQTLs). Our results indicated that genetic regulatory loci primarily affected mRNA and protein abundance in patterns where the two were well-correlated. While this finding was observed in both humans and mice (57.5% and 70.3%, respectively), the genetic regulatory patterns differed between species, implying evolutionary differences. Mouse SNPs generally targeted changes in transcript expression (51%), whereas in humans, they largely regulated protein abundance, independent of transcription levels (55.9%). The latter independent function can be explained by psQTLs. Our analysis suggests that local functional genetic variants in the human genome mainly modulate protein abundance independent of mRNA levels through post-transcriptional mechanisms. These findings clarify the impact of genetic variation on phenotype, which is of particular relevance to disease risk and treatment response.
Highlights
Single-nucleotide polymorphisms (SNPs) play an important role in the regulation of transcription and translation (Montgomery et al, 2010; Schafer et al, 2015)
An additional three regulatory patterns that describe an association between mRNA and protein levels are shown in the bottom row of Figure 1: single-nucleotide polymorphisms (SNPs) that affect transcript levels and thereby downstream protein abundance, SNPs that play an independent role in regulating protein abundance, which is separately influenced by transcript levels, and SNPs that cause both transcriptional and translational changes, but in which transcriptional changes influence protein levels
Our results showed that protein quantitative trait loci (pQTL) and protein-specific QTLs (psQTLs) were enriched in pattern #5 (SNP > protein, mRNA > protein), which indicated that many local human genetic variants affected protein abundance regardless of transcription levels
Summary
Single-nucleotide polymorphisms (SNPs) play an important role in the regulation of transcription and translation (Montgomery et al, 2010; Schafer et al, 2015). Genetic variants can regulate protein abundance in a post-transcriptional way, regardless of transcription levels (Cox et al, 2007; White and Sharrocks, 2010; Foss et al, 2011; Battle et al, 2015). These mechanisms affect protein production and can be associated with complex traits or diseases. Such variants have been identified in mice (Chick et al, 2016), this global regulatory process has yet to be fully investigated in humans
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
