Introduction

Separation of chromosomes in meiosis is a well-guarded process such that errors in chromosome segregation are rare events. For instance, only 1 in every 100000 divisions in yeast is associated with non-disjunction. Aneuploidy in germ cells of mammals like the mouse is generally much higher, in the range 0.5–1% [1]. Furthermore, there is a gender-specific difference in susceptibility to meiotic errors during germ cell formation in mammals, particularly in humans. On average, only 1–4% of sperm in healthy men have numerical chromosomal aberrations, while on average about 20% of all human meiosis II oocytes are aneuploid [1–4]. The correlation between the incidence of the birth of a trisomic child with Down's syndrome and maternal age was first recognized in 1933 by Penrose [5], confirmed by chromosomal analysis of spontaneous abortions and live births and, since the introduction of assisted reproduction, by evidence from polar bodies, oocytes, and embryos (e.g., [3, 6–8]). However, the cause(s) of the extraordinary susceptibility of aging oocytes to meiotic errors was obscure until recently.

Meiotic stages at which errors may occur

In typical mitosis there is division of sister chromatids derived from replication of each chromosome, and each pair therefore carries the same alleles along their arms (Figure 28.1A). In contrast, in meiosis I the two originally paternally and maternally derived homologs, each containing two sister chromatids, separate during first meiotic division (termed reductional division, Figure 28.1B, Ciii). They are normally physically attached to each other by at least one chiasma from recombination between sister chromatids of parental homologs (indicated by X in Figure 28.1B, Ci, Ciii). Chiasmata are held in place by cohesion between sister chromatid arms and centromeres (Figure 28.1Ci–Ciii) placed on chromatids before S-phase (Figure 28.1Ci), which is maintained until anaphase I (Figure 28.1Ciii, B) (reviewed in [9]). The paternal and maternal alleles along chromatid arms of recombined chromosomes switch left and right of a chiasma or exchange (indicated by different coloring in Figure 28.1B, Ci, E–J). Hence, the distribution of polymorphisms can be used to trace the origin and recombinational history of a chromosome in a zygote or child.