Evidence for dysregulation of genome-wide recombination in oocytes with nondisjoined chromosomes 21

Abstract

In oocytes with nondisjoined chromosomes 21 due to a meiosis I (MI) error, recombination is significantly reduced along chromosome 21; several lines of evidence indicate that this contributes to the nondisjunction event. A pilot study found evidence that these oocytes also have reduced recombination genome-wide when compared with controls. This suggests that factors that act globally may be contributing to the reduced recombination on chromosome 21, and hence, the nondisjunction event. To identify the source of these factors, we examined two levels of recombination count regulation in oocytes: (i) regulation at the maternal level that leads to correlation in genome-wide recombination across her oocytes and (ii) regulation at the oocyte level that leads to correlation in recombination count among the chromosomes of an oocyte. We sought to determine whether either of these properties was altered in oocytes with an MI error. As it relates to maternal regulation, we found that both oocytes with an MI error (N = 94) and their siblings (N = 64) had reduced recombination when compared with controls (N = 2723). At the oocyte level, we found that the correlation in recombination count among the chromosomes of an oocyte is reduced in oocytes with MI errors compared with that of their siblings or controls. These results suggest that regulation at the maternal level predisposes MI error oocytes to reduced levels of recombination, but additional oocyte-specific dysregulation contributes to the nondisjunction event.

Inefficient Crossover Maturation Underlies Elevated Aneuploidy in Human Female Meiosis

“…Studies of human aneuploidy reveal that chromosomes which have undergone mis-segregation exhibit lower numbers and/or altered positions of COs as compared to regularly segregated chromosomes (Nagaoka et al, 2012; Oliver et al 2012, 2014; Middlebrooks et al, 2014). …”

“…CO patterns on mis-segregated chromosome 21q bivalents differ from those on regularly segregated bivalents in all three canonical respects. (i) The frequency of COs is ~30% lower: 1.23 versus 1.75 (Middlebrooks et al, 2014). (ii) The frequency of zero-CO bivalents is dramatically higher: ~45% versus ~6%.…”

“…Aneuploidy for chromosome 21, which is associated with lower-than-normal number of COs (above), tends to occur in nuclei with lower numbers of total COs (Middlebrooks et al, 2014). This observation raised the possibility that, as a general feature of normal meiosis, in any given nucleus, CO levels might vary coordinately on all bivalents.…”

Generation of meiomaps of genome-wide recombination and chromosome segregation in human oocytes

“…Until the introduction of genome-wide sequence analysis 8 and meiomapping, studies of the relationship between recombination and meiotic chromosome segregation in humans were confined to population-based studies [20][21][22][23] . Most of these analyses are limited to trisomies that are compatible with in utero development, and therefore such analyses cannot ascertain the meiotic origins of monosomies, the vast majority of which do not give rise to clinically recognized pregnancies.…”

Genetic Etiology of Chromosome 21 Nondisjunction and Down syndrome Birth: Aberrant Recombination and Beyond

“…They inferred that specific chromosomes may be at higher risk for NDJ when the number of genome-wide recombination events is less than some threshold. The same group of researchers continued their study recruiting larger sample size and very recently they have published the data on genome wide variation in recombination in oocyte carrying nondisjoined Ch 21 [29]. In this study Middlebrooks et al [29] examined two levels of recombination regulation in oocytes: Firstly, regulation at the maternal level that leads to correlation in genome-wide recombination across her oocytes and secondly, regulation at the oocyte level that leads to correlation in recombination count among the chromosomes of an oocyte.…”