Genomic structure and expression of the humanserotonin 2A receptor gene (HTR2A) locus:identification of novel HTR2A and antisense(HTR2A-AS1) exons

BMC Genetics

Research Article

Joo Heon Shin¹  Yuan Gao¹  Richard E. Straub¹  Thomas M. Hyde²  Daniel R. Weinberger³  Leanne Munsie⁴  Laura K. Nisenbaum⁴  Ryan M. Smith⁴  John Calley⁴  Cara L. Ruble⁴  David C. Airey⁴ 

[1] Lieber Institute for Brain Development, Baltimore, MD, USA;Lieber Institute for Brain Development, Baltimore, MD, USA;Departments of Neurology, Psychiatry and Behavioral Sciences, John Hopkins University School of Medicine, Baltimore, MD, USA;Lieber Institute for Brain Development, Baltimore, MD, USA;Departments of Psychiatry, Neurology, Neuroscience, and the Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA;Tailored Therapeutics, Lilly Corporate Center, Eli Lilly and Company, Indianapolis, IN, USA;

关键词: Serotonin;    HTR2A;    Alternative splicing;    Antisense RNA;    mRNA expression;    Regulatory polymorphism;    Allelic expression;    Comparative genomics;    Long non-coding RNA;    5-HT2A;   

DOI  :  10.1186/s12863-015-0325-6

 received in 2015-09-09, accepted in 2015-12-22,  发布年份 2016

来源: Springer

【 摘 要 】

BackgroundThe serotonin 2A receptor is widely implicated in geneticassociation studies and remains an important drug target for psychiatric,neurological, and cardiovascular conditions. RNA sequencing redefined thearchitecture of the serotonin 2A receptor gene (HTR2A), revealing novel mRNA transcript isoforms utilizingunannotated untranslated regions of the gene. Expression of these untranslatedregions is modulated by common single nucleotide polymorphisms (SNPs), namelyrs6311. Previous studies did not fully capture the complexity of the sense- andantisense-encoded transcripts with respect to novel exons in the HTR2A gene locus. Here, we comprehensivelycatalogued exons and RNA isoforms for both HTR2A and HTR2A-AS1 usingRNA-Seq from human prefrontal cortex and multiple mouse tissues. We subsequentlytested associations between expression of newfound gene features and common SNPsin humans.ResultsWe find that the human HTR2A genespans ~66 kilobases and consists of 7, rather than 4 exons. Furthermore, therevised human HTR2A-AS1 gene spans ~474kilobases and consists of 18, rather than 3 exons. Three HTR2A exons directly overlap with HTR2A-AS1 exons, suggesting potential for complementarynucleotide interactions. The repertoire of possible mouse Htr2a splice isoforms is remarkably similar tohumans and we also find evidence for overlapping sense-antisense transcripts inthe same relative positions as the human transcripts. rs6311 and SNPs in highlinkage disequilibrium are associated with HTR2A-AS1 expression, in addition to previously describedassociations with expression of the extended 5’ untranslated region of HTR2A.ConclusionsOur proposed HTR2A and HTR2A-AS1 gene structures dramatically differ fromcurrent annotations, now including overlapping exons on the sense and anti-sensestrands. We also find orthologous transcript isoforms expressed in mice,providing opportunities to elucidate the biological roles of the human isoformsusing a model system. Associations between rs6311 and expression of HTR2A and HTR2A-AS1 suggest this polymorphism is capable of modulating theexpression of the sense or antisense transcripts. Still unclear is whether theseSNPs act directly on the expression of the sense or antisense transcripts andwhether overlapping exons are capable of interacting through complimentarybase-pairing. Additional studies are necessary to determine the extent andnature of interactions between the SNPs and the transcripts prior tointerpreting these findings in the context of phenotypes associated withHTR2A.

【 授权许可】

CC BY   
© Ruble et al. 2016