Sperm RNA has been linked recently to trans-generational, non-Mendelian patterns of inheritance. Originally dismissed as “residual” to spermatogenesis, some sperm RNA may have postfertilization functions including the transmission of acquired characteristics. Sperm RNA may help explain how trans-generational effects are transmitted and it may also have implications for assisted reproductive technologies (ART) where sperm are subjected to considerable, ex vivo manual handling. The presence of sperm RNA was originally a controversial topic because nuclear gene expression is switched off in the mature mammalian spermatozoon. With the recent application of next generation sequencing (NGS), an unexpectedly rich and complex repertoire of RNAs has been revealed in the sperm of several species that makes its residual presence counterintuitive. What follows is a personal survey of the science behind our understanding of sperm RNA and its functional significance based on experimental observations from my laboratory as well as many others who have contributed to the field over the years and are continuing to contribute today. The narrative begins with a historical perspective and ends with some educated speculation on where research into sperm RNA is likely to lead us in the next 10 years or so. 1. Introduction The recent publication of two reports on transgenerationally acquired inheritance (henceforth called TAC) in the mouse has brought the subject of sperm RNA back sharply into focus. The first of these [1] examined the transmission of a conditioned aversion to a particular odor in the F0s, which carried through to conditioned (and odor)-na？ve F1 and F2 pups. The second report [2] demonstrated the inheritance of cognitive and behavioural conditioning in the F0s by F1 and F2 pups that had no prior experience of the conditioning (Figure 1). Although only the latter report went on to demonstrate a change in the (small noncoding) sperm RNA profile of conditioned mice that could be linked to the conditioning response and transmission, these reports, in association with earlier reports showing the transmission of paramutation effects by sperm RNA [3], strongly suggest that the odor conditioning was also transmitted by or associated with sperm RNA (or possibly sperm RNA-altered DNA methylation). In hindsight, the connection between sperm RNA and TAC now seems more obvious given that the transmission must go through the germ line [4]. Whether the RNA somehow marks the sperm genome before its entry into the ooplasm at fertilisation or is required to make its mark at
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