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Placental development and genomic imprinting coevolved with parental conflict over resource distribution to mammalian offspring. The imprinted genes IGF2 and IGF2R code for the growth promoter insulin-like growth factor 2 (IGF2) and its inhibitor, mannose 6-phosphate (M6P)/IGF2 receptor (IGF2R), respectively. M6P/IGF2R of birds and fish do not recognize IGF2. In monotremes, which lack imprinting, IGF2 specifically bound M6P/IGF2R via a hydrophobic CD loop. We show that the DNA coding the CD loop in monotremes functions as an exon splice enhancer (ESE) and that structural evolution of binding site loops (AB, HI, FG) improved therian IGF2 affinity. We propose that ESE evolution led to the fortuitous acquisition of IGF2 binding by M6P/IGF2R that drew IGF2R into parental conflict; subsequent imprinting may then have accelerated affinity maturation.

The role of infectious disease in driving human genetic variations (polymorphisms) was first clearly espoused by J. B. S. Haldane in 1949 ( 1 ). Once the major histocompatibility complex (MHC) was established as the most polymorphic mammalian genetic system, searches began for human MHC [or human leukocyte antigen (HLA)] associations with infectious disease resistance. Such findings have been rare, though, possibly because susceptibility genes have been deselected over evolution. But the appearance of completely new infections caused by viruses, such as HIV-1, has opened opportunities to look at such selection in the MHC as it happens. On page 1551 of this issue, the International HIV Controllers Study ( 2 ), demonstrates the central role of HLA class I in controlling HIV-1 infection.