A High Incidence of Meiotic Silencing of Unsynapsed Chromatin Is Not Associated with Substantial Pachytene Loss in Heterozygous Male Mice Carrying Multiple Simple Robertsonian Translocations

Abstract

Meiosis is a complex type of cell division that involves homologous chromosome pairing, synapsis, recombination, and segregation. When any of these processes is altered, cellular checkpoints arrest meiosis progression and induce cell elimination. Meiotic impairment is particularly frequent in organisms bearing chromosomal translocations. When chromosomal translocations appear in heterozygosis, the chromosomes involved may not correctly complete synapsis, recombination, and/or segregation, thus promoting the activation of checkpoints that lead to the death of the meiocytes. In mammals and other organisms, the unsynapsed chromosomal regions are subject to a process called meiotic silencing of unsynapsed chromatin (MSUC). Different degrees of asynapsis could contribute to disturb the normal loading of MSUC proteins, interfering with autosome and sex chromosome gene expression and triggering a massive pachytene cell death. We report that in mice that are heterozygous for eight multiple simple Robertsonian translocations, most pachytene spermatocytes bear trivalents with unsynapsed regions that incorporate, in a stage-dependent manner, proteins involved in MSUC (e.g., γH2AX, ATR, ubiquitinated-H2A, SUMO-1, and XMR). These spermatocytes have a correct MSUC response and are not eliminated during pachytene and most of them proceed into diplotene. However, we found a high incidence of apoptotic spermatocytes at the metaphase stage. These results suggest that in Robertsonian heterozygous mice synapsis defects on most pachytene cells do not trigger a prophase-I checkpoint. Instead, meiotic impairment seems to mainly rely on the action of a checkpoint acting at the metaphase stage. We propose that a low stringency of the pachytene checkpoint could help to increase the chances that spermatocytes with synaptic defects will complete meiotic divisions and differentiate into viable gametes. This scenario, despite a reduction of fertility, allows the spreading of Robertsonian translocations, explaining the multitude of natural Robertsonian populations described in the mouse.

Reduced recombination patterns in Robertsonian hybrids between chromosomal races of the house mouse: chiasma analyses

“…As the reduction in Rb heterozygotes is related to meiotic pairing defects in the centromeric region of trivalents (Davisson and Akeson, 1993), the same mechanism cannot apply to Rb bivalents that show conventional pairing patterns (Manterola et al, 2009). Such discrepancies require further assessment to determine the nature of the mechanisms involved in the modifications of recombination patterns (Dumas and Britton-Davidian, 2002;Colombo, 2013;Capilla et al, 2014).…”

“…Hybrid breakdown and the proximal decrease in recombination are, to a large extent, both related to pairing disturbances during meiosis leading to germ cell death and aneuploidy due to malsegregation (King, 1993). Meiotic pairing of trivalents involves either no (asynapsis) or heterologous synapsis in the proximal regions, that is, respectively open and closed configurations (Davisson and Akeson, 1993;Manterola et al, 2009). These pairing alterations will lead to recombination suppression in this region, as crossing over requires homologously and timely synapsed segments.…”

“…These pairing alterations will lead to recombination suppression in this region, as crossing over requires homologously and timely synapsed segments. Although asynaptic cells are generally eliminated through apoptosis, a recent study demonstrated that 37% of such cells were able to bypass the apoptotic meiotic checkpoints enabling the meiocyte to develop into viable sperm (Manterola et al, 2009). Thus, all surviving meiocytes of Rb heterozygotes are expected to show reduced proximal recombination.…”

Spermatogenesis in house mouse in a Robertsonian polymorphism zone

“…Meiotic non-disjunction (e.g. Gropp et al 1982), meiotic failure (Miklos 1974, Burgoyne & Baker 1984, Manterola et al 2009, and association of impaired autosomal segments with sex chromosomes (Johannisson & Winking 1994) have been postulated as mechanisms responsible for the reduction in fertility in carriers of heterozygous Rb fusions. They may, therefore, act as postmating isolating mechanisms.…”

Fertility assessment in hybrids between monobrachially homologous Rb races of the house mouse from the island of Madeira: implications for modes of chromosomal evolution

“…The reasons for the differences between sexes are not clear, but may be related to more efficient meiotic checkpoints in males than in females, that trigger an apoptotic pathway more readily during spermatogenesis than oogenesis (Kouznetsova et al, 2007). In chaincarrying male heterozygotes, reproductive impairment is thought to result from altered gene expression due to inappropriate interaction with the XY pair, or possibly to epigenetic causes (Manterola et al, 2009). Only one C4/XY association was observed in this study, although more cells may initially have been present and Fertility of hybrid Rb house mice from Madeira AC Nunes et al eliminated during earlier stages of meiosis (that is, prophase).…”