Integration of maternal genome into the neonate genome through breast milk mRNA transcripts and reverse transcriptase

Abstract

Human milk samples contain microvesicles similar to the retroviruses. These microvesicles contain mRNA transcripts and possess reverse transcriptase activity. They contain about 14,000 transcripts representing the milk transcriptome. Microvesicles are also enriched with proteins related to "caveolar-mediated endocytosis signaling" pathway. It has recently been reported that microvesicles could be transferred to other cells by endocytosis and their RNA content can be translated and be functional in their new location. A significant percentage of the mammalian genome appears to be the product of reverse transcription, containing sequences whose characteristics point to RNA as a template precursor. These are mobile elements that move by way of transposition and are called retrotransposons. We thought that retrotransposons may stem from about 14,000 transcriptome of breast milk microvesicles, and reviewed the literature.The enhanced acceptance of maternal allografts in children who were breast-fed and tolerance to the maternal MHC antigens after breastfeeding may stem from RNAs of the breast milk microvesicles that can be taken up by the breastfed infant and receiving maternal genomic information. We conclude that milk microvesicles may transfer genetic signals from mother to neonate during breastfeeding. Moreover, transfer of wild type RNA from a healthy wet-nurse to the suckling neonate through the milk microvesicles and its subsequent reverse transcription and integration into the neonate genome could result in permanent correction of the clinical manifestations in genetic diseases.

Figure 1

Formation of breast milk microvesicles. Breast milk microvesicles form directly from the apical parts of the mammary epithelial cells by an apocrine mechanism or indirectly from the cytoplasmic crescents of milk fat globules (MFG) by shedding, budding or blebbing, similar to the mechanism by which enveloped viruses are secreted from the cells.

Figure 2

Fate of breast milk microvesicles after endocytosis by target cells. After caveolar endocytosis, microvesicles translocate Arf1, Rab1 and SNARE proteins to the outer surface of the vacuolar membrane by a syringe-like mechanism. These proteins help the microvesicles to pass from caveola to the endoplasmic reticulum and fusion of the vacuoles with ER. In ER, decoating of the microvesicular membrane occurs with the help of Hsp 70 and cyclophilin A and the released RNA is translocated into the nucleus directly together with reverse transcriptase (RT). In the nucleus, the linear copy of the microvesicular RNA is inserted into chromosomal DNA with the aid of cellular endonuclease and transcribed into a double-stranded DNA by the microvesicular RT. New DNA achieves the status of a cellular gene and replicated by cellular enzymes in concert with chromosomal DNA as in nonretroviral retrotransposons.