Telomeres and genomic instability during early development

Abstract

Genomic instability is widespread during early embryo development. Aneuploidy, mosaicism, and copy number variants (CNVs) commonly appear in human preimplantation embryos. Both age-dependent meiotic aneuploidy and age-independent mitotic aneuploidy and CNVs occur In human embryos. Telomere attrition, which contributes to genomic instability in somatic cells, also may promote genomic instability in preimplantation embryos. Telomere dynamics during gametogenesis are strikingly dimorphic between females and males. Sperm telomeres lengthen with advancing paternal age, while oocyte telomeres are among the shortest in the body. Spermatogonia express telomerase activity throughout the life of the male, while oocytes and cleavage stage embryos express low or un-measureable levels of telomerase activity. Telomere attrition in oocytes contributes to meiotic dysfunction, including spindle dysmorphologies, reduced synapsis and chiasmata, as well as delayed, arrested and fragmented embryos. Cleavage stage embryos, with such inefficient telomere reconstitution, likely undergo NHEJ, which produces anaphase lag, chromosome bridges, micronuclei, and genomic instability, including mosaicism and CNVs. Cleavage stage embryos reconstitute the short telomeres inherited from their mothers by Alternative Lengthening of Telomeres (ALT), a DNA recombination based method involving RAD 50, MRE 11, Werner and Bloom proteins, as well as telomere sister chromatid exchange. ALT robustly reconstitutes telomeres, but also predisposes to genomic instability.