Mechanisms of aneuploidy induction in human oogenesis and early embryogenesis

Abstract

The mechanisms of aneuploidy induction in human oogenesis mainly involve nondisjunction arising during the first and second meiotic divisions. Nondisjunction equally affects both whole chromosomes and chromatids, in the latter case it is facilitated by “predivision” or precocious centromere division. Karyotyping and CGH studies show an excess of hypohaploidy, which is confirmed in studies of preimplantation embryos, providing evidence in favour of anaphase lag as a mechanism. Preferential involvement of the smaller autosomes has been clearly shown but the largest chromosomes are also abnormal in many cases. Overall, the rate of chromosomal imbalance in oocytes from women aged between 30 and 35 has been estimated at 11% from recent karyotyping data but accruing CGH results suggest that the true figure should be considerably higher. Clear evidence has been obtained in favour of germinal or gonadal mosaicism as a predisposing factor. Constitutional aneuploidy in embryos is most frequent for chromosomes 22, 16, 21 and 15; least frequently involved are chromosomes 14, X and Y, and 6. However, embryos of women under 37 are far more likely to be affected by mosaic aneuploidy, which is present in over 50% of 3-day-old embryos. There are two main types, diploid/aneuploid and chaotic mosaics. Chaotic mosaics arise independently of maternal age and may be related to centrosome anomalies and hence of male origin. Aneuploid mosaics most commonly arise by chromosome loss, followed by chromosome gain and least frequently by mitotic nondisjunction. All may be related to maternal age as well as to lack of specific gene products in the embryo. Partial aneuploidy as a result of chromosome breakage affects a minimum of 10% of embryos.

Enigmatic In Vivo iduronate-2-sulfatase (IDS) mutant transcript correction to wild-type in Hunter syndrome

“…We also considered the alternative possibility that a small proportion of cells from the three patients might contain an extra maternal X chromosome (47,XXY) bearing a wild-type IDS allele, as a consequence of either mitotic non-disjunction or 'anaphase lag' [Delhanty, 2005]. Malsegregation of the X chromosome is known to occur at a relatively high frequency [Carere et al, 1999].…”

Quantitative decision-making in preimplantation genetic (aneuploidy) screening (PGS)

“…Several studies analyzing human metaphase II oocytes with either CGH-FISH or CGH showed aneuploidy rates as high as 40-60% [44]. Aneuploidy rates in human embryos have been reported to vary between 15-85% [28].…”

“…It has been argued that the first few cell division cycles during early embryonic development may be particularly sensitive to mitotic errors when all the necessary cell cycle check points are not activated and maternal cytoplasmic factors are needed during the early phase of embryonic development [44,49,50]. The relationship between the mix of cells that are diploid/ aneuploidy and diploid/mosaic and of their ability to develop to morphologically normal appearing blastocysts is not well established, although chaotic mosaics display high rates of developmental arrest [28,51].…”

Errors in Chromosome Segregation During Oogenesis and Early Embryogenesis

“…Most recently it has been suggested that the maternal age effect is a multifactorial trait, and may be influenced by environmental factors ( 8,9 ). Another intriguing possibility it that normal women may be trisomy 21 ovarian mosaics ( [11][12][13] with the potential for oocytes containing three chromosomes 21 accumulating during maturation and when reaching MI undergoing obligatory secondary non-disjunction at AI.…”