Sperm-Mediated Transgenerational Inheritance

Abstract

Spermatozoa of virtually all species can spontaneously take up exogenous DNA or RNA molecules and internalize them into nuclei. In this article I review evidence for a key role of a reverse transcriptase (RT) activity, encoded by LINE-1 retrotransposons, in the fate of the internalized nucleic acid molecules and their implication in transgenerational inheritance. LINE-1-derived RT, present in sperm heads, can reverse-transcribe the internalized molecules in cDNA copies: exogenous RNA is reverse-transcribed in a one-step reaction, whereas DNA is first transcribed into RNA and subsequently reverse-transcribed. Both RNA and cDNA molecules can be delivered from sperm cells to oocytes at fertilization, further propagated throughout embryogenesis and inherited in a non-Mendelian fashion in tissues of adult animals. The reverse-transcribed sequences are extrachromosomal, low-abundance, and mosaic distributed in tissues of adult individuals, where they are variably expressed. These “retrogenes” are transcriptionally competent and induce novel phenotypic traits in animals. Growing evidence indicate that cancer tissues produce DNA- and RNA-containing exosomes. We recently found that these exosomes are released in the bloodstream and eventually taken up into epididymal spermatozoa, consistent with the emerging view that a transgenerational flow of extrachromosomal RNA connects soma to germline and, further, to next generation embryos. Spermatozoa play a crucial bridging role in this process: they act as collectors of somatic information and as delivering vectors to the next generation. On the whole, this phenomenon is compatible with a Lamarckian-type view and closely resembles Darwinian pangenesis.

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“…The most obvious sources are somatic tissues in the father. Human cells xenografted into the bloodstreams of male mice were able to transfer reporter construct mRNAs to host spermatozoa, and direct EV transfer has been observed into epididymal spermatozoa in mice and even in male turtles . Significantly, soma‐to‐gamete transfer via sperm is not exclusive to male donors.…”

“…The effects of extracellular DNA and EV transmission to spermatozoa are not necessarily limited to the gametes or zygotes . The soma‐to‐germ line EV transfers influence epigenetic programming and development of next‐generation embryos . In addition, there is RT activity in both spermatozoa and zygotes, and RT is essential for early embryonic development before being silenced in differentiated cells .…”

“…The soma‐to‐germ line EV transfers influence epigenetic programming and development of next‐generation embryos . In addition, there is RT activity in both spermatozoa and zygotes, and RT is essential for early embryonic development before being silenced in differentiated cells . Consequently, EV‐transmitted or exogenous RNA can be converted to cDNA at any stage of animal reproduction prior to cellular differentiation .…”

“…Human cells xenografted into the bloodstreams of male mice were able to transfer reporter construct mRNAs to host spermatozoa, and direct EV transfer has been observed into epididymal spermatozoa in mice and even in male turtles. [144][145][146] Significantly, soma-to-gamete transfer via sperm is not exclusive to male donors. Somatic EV-mediated protein transfer to sperm from the mother also occurs prefertilization in the mouse uterus.…”

“…145 In addition, there is RT activity in both spermatozoa and zygotes, and RT is essential for early embryonic development before being silenced in differentiated cells. 145 Consequently, EV-transmitted or exogenous RNA can be converted to cDNA at any stage of animal reproduction prior to cellular differentiation. 148,149 In experiments with exogenous RNA-treated spermatozoa, extrachromosomal EV−derived cDNA copies were reported to be present in a minority of adult tissue cells from both the F0 and F1 generations.…”