To understand how SNP rs563649 can affect the expression or function of the MOR-1K isoforms, we searched for functional regulatory elements within the 5′-UTR of MOR-1K transcripts. We found that this functional variation is located within a structurally conserved IRES in the 5′-UTR of MOR-1K transcripts (Fig. 3A). This IRES is conserved in human and chimpanzee, but absent in rodents. Stems II and III in IRESs can participate in coaxial stacking within a common Y-type structure and are likely required for ribosome binding to IRES (41). Nucleotides in loops II and III may interact with each other (‘kissing hairpins’) or with ribosomal proteins, which can result in altered binding of ribosome to IRES and, consequently, affect translation through a ‘zipper’ mechanism (41). It has been shown that precise secondary structure is important for the function of IRESs. A single nucleotide substitution producing structural changes in the c-myc IRES resulted in increased translation initiation by internal ribosome entry and was associated with oncogenesis (59). SNP rs563649 is located in the IRES loop II, where the major allele C likely allows a
