An exon splice enhancer primes IGF2:IGF2R binding site structure and function evolution

Many mammals have imprinted alleles, where the paternal or maternal version is solely expressed during reproduction. In humans, one such imprinted gene set is the growth promoter insulin-like growth factor 2 (IGF2) and its binding inhibitor, IGF2R mannose 6-phosphate/IGF2 receptor. To avoid parental conflict in fetal growth, imprinting regulates expression of these genes so that expression of IGF2R in the fetus quenches IGF2 and prevents fetus overgrowth through high-affinity binding of IGF2 to IGF2R. Williams et al. (p. [1209][1]) demonstrate that high-affinity binding of IGF2 to IGF2R is present in placental and marsupial mammals; absent in birds and fish; and present, with a 10-fold lower affinity, in monotreme (egg-laying) mammals. The appearance of exonic splicing enhancers in exon 34 of the IGF2R of monotremes appears to have been a key mutational event leading to the establishment of higher affinity, which may have been driven by selection to minimize parental conflict. [1]: /lookup/doi/10.1126/science.1228633