A high incidence of meiotic silencing of unsynapsed chromatin is not associated to substantial pachytene loss in heterozygous male mice carrying multiple simple Robertsonian translocations

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., cH2AX, 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.