Abstract
BackgroundThe serotonin 2A receptor is widely implicated in genetic association studies and remains an important drug target for psychiatric, neurological, and cardiovascular conditions. RNA sequencing redefined the architecture of the serotonin 2A receptor gene (HTR2A), revealing novel mRNA transcript isoforms utilizing unannotated untranslated regions of the gene. Expression of these untranslated regions is modulated by common single nucleotide polymorphisms (SNPs), namely rs6311. Previous studies did not fully capture the complexity of the sense- and antisense-encoded transcripts with respect to novel exons in the HTR2A gene locus. Here, we comprehensively catalogued exons and RNA isoforms for both HTR2A and HTR2A-AS1 using RNA-Seq from human prefrontal cortex and multiple mouse tissues. We subsequently tested associations between expression of newfound gene features and common SNPs in humans.ResultsWe find that the human HTR2A gene spans ~66 kilobases and consists of 7, rather than 4 exons. Furthermore, the revised human HTR2A-AS1 gene spans ~474 kilobases and consists of 18, rather than 3 exons. Three HTR2A exons directly overlap with HTR2A-AS1 exons, suggesting potential for complementary nucleotide interactions. The repertoire of possible mouse Htr2a splice isoforms is remarkably similar to humans and we also find evidence for overlapping sense-antisense transcripts in the same relative positions as the human transcripts. rs6311 and SNPs in high linkage disequilibrium are associated with HTR2A-AS1 expression, in addition to previously described associations with expression of the extended 5’ untranslated region of HTR2A.ConclusionsOur proposed HTR2A and HTR2A-AS1 gene structures dramatically differ from current annotations, now including overlapping exons on the sense and anti-sense strands. We also find orthologous transcript isoforms expressed in mice, providing opportunities to elucidate the biological roles of the human isoforms using a model system. Associations between rs6311 and expression of HTR2A and HTR2A-AS1 suggest this polymorphism is capable of modulating the expression of the sense or antisense transcripts. Still unclear is whether these SNPs act directly on the expression of the sense or antisense transcripts and whether overlapping exons are capable of interacting through complimentary base-pairing. Additional studies are necessary to determine the extent and nature of interactions between the SNPs and the transcripts prior to interpreting these findings in the context of phenotypes associated with HTR2A.Electronic supplementary materialThe online version of this article (doi:10.1186/s12863-015-0325-6) contains supplementary material, which is available to authorized users.
Highlights
The serotonin 2A receptor is widely implicated in genetic association studies and remains an important drug target for psychiatric, neurological, and cardiovascular conditions
The serotonin 2A receptor (5-HT2A) is a G proteincoupled receptor (GPCR) that serves as a primary target for serotonin signaling and is expressed on many cell types in the brain and periphery. 5-HT2A remains of great scientific interest due to its many roles in normal biological functions, which include cerebral cortex excitability [1], platelet aggregation [2], smooth muscle contraction [3], vasoconstriction and dilation [4], inflammatory processes [5], and hormone signaling [6]
We examined HTR2A and HTR2A-AS1 gene structure by mapping RNA-Seq junction reads from human prefrontal cortex, utilizing conventional definitions for exon structure independent of established gene annotations
Summary
The serotonin 2A receptor is widely implicated in genetic association studies and remains an important drug target for psychiatric, neurological, and cardiovascular conditions. RNA sequencing redefined the architecture of the serotonin 2A receptor gene (HTR2A), revealing novel mRNA transcript isoforms utilizing unannotated untranslated regions of the gene. Expression of these untranslated regions is modulated by common single nucleotide polymorphisms (SNPs), namely rs6311. The current gene model consists of 4 exons, spanning more than 65kB, and includes evidence for alternative splicing of exon 2 (NM_001165947) Based on length, these two RefSeq annotations (NM_000621.4 and NM_001165947.2) likely reflect the transcripts detected by Northern blot in 1990 [19]. This includes an RNA isoform containing a novel 118-bp exon residing in intron 3 of the current annotation [20] and four additional exon boundary changes resulting in novel RNA isoforms: a truncated exon 2, a retained intron between exons 1 and 2, a 5’ extension of exon 1, and a 3’ extension of exon 4 [21]
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