A hominid-specific shift in cerebellar expression, upstream retrotransposons, and a potential cis-regulatory mechanism: bioinformatics analyses of the mu-opioid receptor gene.

The mu-opioid receptors (MOR, OPRM1) mediate the effects of beta-endorphin and modulate many biological functions including reward processing and addiction. The present study aimed to use bioinformatics to determine OPRM1 brain expression profiles in higher primates and to look for regulatory mechanisms. We used the same computational pipeline to analyze publicly available expression data from postmortem brain regions across humans, chimpanzees, and rhesus macaques. The most intriguing finding was high OPRM1 cerebellar expression in humans and chimpanzees and low expression in macaques. Together with previous reports of low cerebellar OPRM1 expression in mice, this suggests an evolutionary shift in the expression profiles. Bioinformatic analysis of the OPRM1 upstream region revealed a functional CTCF-binding region that evolved from tandem insertions of retrotransposons L1P1 and L1PA1 upstream (-60 kb) of OPRM1. The insertions arose in different time points after the split of small apes from great apes, and their combined sequence is unique. Furthermore, the derived G allele of SNP rs12191876, in the inserted region, is associated with an increased OPRM1 expression in the cerebellum of postmortem human brains (p = 4.7e-5). The derived G allele became the major allele (60-90%) in the populations represented in the 1000 Genomes Project and may be beneficial. This study provides a foundation for building new knowledge about evolutionary differences in OPRM1 brain expression. Further investigations are needed to elucidate the role of the inserted region and its SNPs in OPRM1 expression, and to assess the biological function and relevance of OPRM1 expression in the cerebellum.