Telomere DNA Deficiency Is Associated with Development of Human Embryonic Aneuploidy

Abstract

Aneuploidy represents the most prevalent form of genetic instability found in human embryos and is the leading genetic cause of miscarriage and developmental delay in newborns. Telomere DNA deficiency is associated with genomic instability in somatic cells and may play a role in development of aneuploidy commonly found in female germ cells and human embryos. To test this hypothesis, we developed a method capable of quantifying telomere DNA in parallel with 24-chromosome aneuploidy screening from the same oocyte or embryo biopsy. Aneuploid human polar bodies possessed significantly less telomere DNA than euploid polar bodies from sibling oocytes (−3.07 fold, P = 0.016). This indicates that oocytes with telomere DNA deficiency are prone to aneuploidy development during meiosis. Aneuploid embryonic cells also possessed significantly less telomere DNA than euploid embryonic cells at the cleavage stage (−2.60 fold, P = 0.002) but not at the blastocyst stage (−1.18 fold, P = 0.340). The lack of a significant difference at the blastocyst stage was found to be due to telomere DNA normalization between the cleavage and blastocyst stage of embryogenesis and not due to developmental arrest of embryos with short telomeres. Heterogeneity in telomere length within oocytes may provide an opportunity to improve the treatment of infertility through telomere-based selection of oocytes and embryos with reproductive competence. Human eggs (oocytes) are exceptionally prone to the erroneous acquisition of too few (monosomy) or too many (trisomy) chromosomes during development (meiosis). In fact, this type of instability, termed aneuploidy, represents the most common genetic cause of miscarriage in pregnant women (i.e. trisomy 16) and developmental delay in newborns (i.e. Down syndrome from trisomy 21). Although aneuploidy has become a growing problem for women as they delay childbearing into the late thirties, the underlying molecular etiology remains unknown. Since telomere DNA is known to protect the ends of chromosomes from degradation during cell division and is associated with aneuploidy in cancer cells in adults, we tested whether telomere DNA plays a role in aneuploidy development in human oocytes and embryos (where aneuploidy is much more common). We demonstrate that telomere DNA deficiency is indeed associated with aneuploidy in oocytes and early preimplantation (cleavage) stage embryos. This association is reversed upon development to late preimplantation (blastocyst) stage embryos as a result of telomere DNA elongation. These results indicate that telomere DNA deficiency may cause inappropriate chromosome segregation during human oocyte cell division (meiosis) and may serve as a marker for oocytes and embryos that lack the ability to produce healthy children.