Meiotic Nondisjunction: Insights into the Origin and Significance of Aneuploidy in Human Spermatozoa

Abstract

Chromosome aneuploidy refers to changes in the chromosome complement of a genome and can include gain or loss of genetic material. The human genome is delicately balanced, and for the most part perturbations in the chromosome complement are often incompatible with embryonic development. The importance and clinical relevance of paternally derived aneuploidy is often overshadowed by the large maternal contribution; as a result, the paternal contribution to pregnancy loss due to chromosome aneuploidy is rarely considered within the clinic. However, there is increasing evidence to suggest that certain men have significantly higher levels of sperm aneuploidy, which is mirrored by an increase in aneuploidy within their embryos and offspring. Therefore, the paternal contribution to aneuploidy at least for some individuals may have greater clinical significance than is currently perceived. Thus, the main focus of this chapter is to provide insights into the origin and clinical relevance of paternally derived aneuploidy. Furthermore, this section will review the general mechanisms through which aneuploidy arises during spermatogenesis and how numerical (whole chromosome) and structural chromosome aberrations (cytogenetically visible or submicroscopic) may lead to clinically relevant aneuploidy potentially resulting in pregnancy loss, congenital malformations, and cognitive impairment.

Meiotic nondisjunction and sperm aneuploidy in humans

“…3). Yet, interindividual differences exist, with tenfold or higher frequencies reported in some infertile men , Harton & Tempest 2012, Templado et al 2013, Ioannou & Tempest 2015. The existence of interindividual variation has been reported in fertile and infertile men and should be taken into account when considering reported global levels of sperm aneuploidy levels (Fig.…”

“…The sperm cell is an essential prerequisite to fertilization and embryogenesis. Nevertheless, our understanding of the role of sperm in embryogenesis is poorly understood and largely overshadowed by the maternal oocyte (Ioannou & Tempest 2015). The gametes differ in terms of their known functions in these processes, which likely explains why there is a focus on the maternal rather than the paternal contribution.…”

“…Sperm aneuploidy levels range from 1 to 25% and 3 to 81% in individuals with numerical and structural chromosome aberrations, respectively (Fig. 3) (Harton & Tempest 2012, Ioannou & Tempest 2015. Since these studies often only test a handful of chromosomes (those involved in the aberration), sperm aneuploidy levels are likely to be even higher.…”

Ablation of Ggnbp2 impairs meiotic DNA double‐strand break repair during spermatogenesis in mice

“…These proteins are co‐ordinately recruited to DSB sites to facilitate DNA DSB repair via homologous recombination. Defects in DNA DSB repair can cause chromosome mis‐segregation underling aneuploidy‐related pathologies or meiotic arrest of spermatocytes leading to male infertility 17, 20, 23, 24…”

“…Defects in DNA DSB repair can cause chromosome mis-segregation underling aneuploidy-related pathologies or meiotic arrest of spermatocytes leading to male infertility. 17,20,23,24 Gametogenetin (GGN) is a testis-enriched germ cell-specific protein and has three splice variants. 25 The largest variant GGN1 is demonstrated to be the predominant form in the testis and localizes in spermatocytes, spermatids and spermatozoa but not in spermatogonia in mouse and human testes.…”