White matter microstructure in relatives of people with schizophrenia or bipolar disorder: an ENIGMA meta-analysis.

Traditional genetics posits DNA as the sole carrier of genetic information, transmitted to offspring via genes in sperm and oocytes [–]. Recent advances in the study of small RNA molecules in sperm have revealed that spermatozoa carry not only DNA but also a novel class of epigenetic regulators—tRNA-derived fragments (tRFs) [–]. tRFs are small non-coding RNAs generated through the enzymatic cleavage of mature tRNAs [, ] that are abundant in sperm and delivered to the embryo upon fertilization []. These fragments play crucial roles in influencing embryonic development and mediating the transmission of paternal epigenetic information. Sharma et al. demonstrated that approximately 80% of small RNAs in mammalian sperm are 28–34 nt in length and are highly enriched in mature spermatozoa []. These tRFs respond to paternal environmental changes (e.g., diet, stress, toxin exposure) and enter the oocyte during fertilization to regulate embryonic developmental programs and alter offspring phenotypes []. In contrast to traditional genetic perspectives, tRFs serve as vectors of paternal epigenetic information. They mediate the transgenerational transmission of environmental cues by regulating embryonic epigenetic reprogramming, genome activation, and transposon silencing, thereby influencing embryonic development and offspring health []. This discovery provides a new perspective on how paternal factors transmitted via sperm can impact developmental and health outcomes in descendants. This review aims to elucidate the critical functions of sperm tRFs in embryonic development, further our understanding of how paternal environment influences offspring development, and provide a theoretical basis for future clinical intervention strategies. While the discovery of sperm tRFs as epigenetic carriers since 2016 has been pivotal, recent advances have further delineated their specificity and therapeutic potential []. This review synthesizes these developments, highlighting the unique role of mitochondrial tRFs (mt-tRFs) in metabolic inheritance and the emerging framework of tRFs as integrators of paternal environmental cues. We incorporate recent insights from models elucidating tRF biogenesis and function [] to provide an updated perspective on their mechanistic diversity and clinical translation.