Next Generation Sequencing Detects Premeiotic Errors in Human Oocytes

Abstract

Autosomal aneuploidy is the leading cause of embryonic and foetal death in humans. This arises mainly from errors in meiosis I or II of oogenesis. A largely ignored source of error stems from germinal mosaicism, which leads to premeiotic aneuploidy. Molecular cytogenetic studies employing metaphase fluorescence in situ hybridization and comparative genomic hybridisation suggest that premeiotic aneuploidy may affect 10–20% of oocytes overall. Such studies have been criticised on technical grounds. We report here an independent study carried out on unmanipulated oocytes that have been analysed using next generation sequencing (NGS). This study confirms that the incidence of premeiotic aneuploidy in an unselected series of oocytes exceeds 10%. A total of 140 oocytes donated by 42 women gave conclusive results; of these, 124 (88.5%) were euploid. Sixteen out of 140 (11.4%) provided evidence of premeiotic aneuploidy. Of the 140, 112 oocytes were immature (germinal vesicle or metaphase I), of which 10 were aneuploid (8.93%); the remaining 28 were intact metaphase II - first polar body complexes, and six of these were aneuploid (21.4%). Of the 16 aneuploid cells, half contained simple errors (one or two abnormal chromosomes) and half contained complex errors. We conclude that germinal mosaicism leading to premeiotic aneuploidy is a consistent finding affecting at least 10% of unselected oocytes from women undergoing egg collection for a variety of reasons. The importance of premeiotic aneuploidy lies in the fact that, for individual oocytes, it greatly increases the risk of an aneuploid mature oocyte irrespective of maternal age. As such, this may account for some cases of aneuploid conceptions in very young women.

Chromosome Changes in Soma and Germ Line: Heritability and Evolutionary Outcome

“…Changes in chromosome structure lead to altered genome functioning and the emergence of species-specific features. The most significant contribution in changing the species gene pool comes from those rearrangements that arise in the cells participating in gamete generation, including PGCs [160,161]. Rearrangements arising during zygotic cleavage and early embryonic development provide significant input to genetic variation, as well as germ line de novo mutations at pre-meiotic stages and all stages of meiosis [162], including the culminating moment-fertilization, which not only gives rise to new life, but also due to meiotic drive determines the structure of the chromosome set of a zygote.…”

Understanding recurrent pregnancy loss: recent advances on its etiology, clinical diagnosis, and management

“…Recently, Ghevaria et al. [ 72 ] has focused on the maternal aneuploidy mosaicism (germinal mosaicism) that arises either in the primordial germ cells (gonadal mosaicism) or during the premeiotic mitotic divisions of the oogonia. Their study estimated that the incidence of premeiotic aneuploidy in non-selected oocytes was greater than 10%.…”

Molecular Clues to Understanding Causes of Human-Assisted Reproduction Treatment Failures and Possible Treatment Options

“…Analysis of genome-wide maps of recombination and chromosome segregation in human oocytes uncovered a new reverse chromosome segregation pattern concerning sister chromatid separation at meiosis I, influencing the elimination of aneuploid embryos and is responsible for the chromosomal drive against non-recombinant chromatids at meiosis II [ 28 ]. Moreover, in addition to the errors in meiosis I or II of oogenesis [ 29 ], oocyte autosomal aneuploidy can also arise from germinal mosaicism, leading to premeiotic aneuploidy ( Figure 2 ) that affects at least 10% of unselected oocytes irrespective of maternal age and may, thus, account for some cases of aneuploid conceptions in very young women [ 30 ].…”