Nuclear transfer: preservation of a nuclear genome at the expense of its associated mtDNA genome(s)

Abstract

Nuclear transfer technology has uses across theoretical and applied applications, but advances are restricted by continued poor success rates and health problems associated with live offspring. Development of reconstructed embryos is dependent upon numerous interlinking factors relating both to the donor cell and the recipient oocyte. For example, abnormalities in gene expression following somatic cell nuclear transfer (SCNT) have been linked with an inability of the oocyte cytoplasm to sufficiently epigenetically reprogram the nucleus. Furthermore, influences on the propagation of mitochondria and mitochondrial DNA (mtDNA) could be of great importance in determining the early developmental potential of NT embryos and contributing to their genetic identity. mtDNA encodes some of the subunits of the electron transfer chain, responsible for cellular ATP production. The remaining subunits and those factors required for mtDNA replication, transcription and translation are encoded by the nucleus, necessitating precise intergenomic communication. Additionally, regulation of mtDNA copy number, via the processes of mtDNA transcription and replication, is essential for normal preimplantation embryo development and differentiation. Unimaternal transmission following natural fertilization usually results in the presence of a single identical population of mtDNA, homoplasmy. Heteroplasmy can result if mixed populations of mtDNA genomes co-exist. Many abnormalities observed in NT embryos, fetuses, and offspring may be caused by deficiencies in OXPHOS, perhaps resulting in part from heteroplasmic mtDNA populations. Additionally, incompatibilities between the somatic nucleus and the cytoplast may be exacerbated by increased genetic divergence between the two genomes. It is important to ensure that the nucleus is capable of sufficiently regulating mtDNA, requiring a level of compatibility between the two genomes, which may be a function of evolutionary distance. We suggest that abnormal expression of factors such as TFAM and POLG in NT embryos will prematurely drive mtDNA replication, hence impacting on early development.